Mental disorders account for six of the 20 leading causes of disability worldwide with a very high prevalence of psychiatric morbidity in youth aged 15–24 years. However, healthcare professionals are faced with many challenges in the identification and treatment of mental and substance use disorders in young people (e.g. young people’s unwillingness to seek help from healthcare professionals, lack of training, limited resources etc.) The challenge of youth mental health for primary care is especially evident in urban deprived areas, where rates of and risk factors for mental health problems are especially common. There is an emerging consensus that primary care is well placed to address mental and substance use disorders in young people especially in deprived urban areas. This study aims to describe healthcare professionals’ experience and attitudes towards screening and early intervention for mental and substance use disorders among young people (16–25 years) in primary care in deprived urban settings in Ireland.
The chosen method for this qualitative study was inductive thematic analysis which involved semi-structured interviews with 37 healthcare professionals from primary care, secondary care and community agencies at two deprived urban centres.
We identified three themes in respect of interventions to increase screening and treatment: (1) Identification is optimised by a range of strategies, including raising awareness, training, more systematic and formalised assessment, and youth-friendly practices (e.g. communication skills, ensuring confidentiality); (2) Treatment is enhanced by closer inter-agency collaboration and training for all healthcare professionals working in primary care; (3) Ongoing engagement is enhanced by motivational work with young people, setting achievable treatment goals, supporting transition between child and adult mental health services and recognising primary care’s longitudinal nature as a key asset in promoting treatment engagement.
Especially in deprived areas, primary care is central to early intervention for youth mental health. Identification, treatment and continuing engagement are likely to be enhanced by a range of strategies with young people, healthcare professionals and systems. Further research on youth mental health and primary care, including qualitative accounts of young people’s experience and developing complex interventions that promote early intervention are priorities. (350 words)
Young people; Urban deprivation; Mental health; Substance use; Primary care; General practice
Escape of prostate cancer (PCa) cells from ionizing radiation–induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.
While Texel lambs have increased resistance to infection with the gastrointestinal nematode Teladorsagia circumcincta compared to Suffolk lambs, the underlying resistance mechanisms are still unknown. The aim of this study was to compare parasitological, humoral and cellular responses of Texel and Suffolk lambs over time following a single experimental infection with T. circumcincta. Gastrointestinal nematode free (but not naïve) lambs received a single oral dose of 3 × 104 infective T. circumcincta larvae. The variables examined included worm burden, mucosal and serum IgA, abomasal mast cells and eosinophils, haematological parameters and plasma pepsinogen. Texel lambs had significantly lower worm burden on day 14 and lower plasma pepsinogen concentration from day 14 onwards than Suffolks and their response in mucosal IgA to infection occurred earlier. The results from the study suggest that an earlier local IgA response in the Texel contributes to the resistant characteristics of the breed, while the increased level of plasma pepsinogen in the Suffolk lambs implies greater abomasal tissue damage arising from the nematode infection.
schizophrenia; vision; perception; risk; cognition; blindness; brain
A group of stainless steel arc welding processes was compared for emission rates of fume and hexavalent chromium, and costs per meter length of weld. The objective was to identify those with minimal emissions and also compare relative labor and consumables costs. The selection included flux-cored arc welding (FCAW), shielded-metal arc welding (SMAW), and multiple gas metal arc welding (GMAW) processes. Using a conical chamber, fumes were collected, and fume generation rates and hexavalent chromium (Cr6+) were measured. GMAW processes used were short-circuit (SC) and pulsed-spray modes. Flux-cored welding used gas shielding. Costs were estimated per meter of a 6.3-mm thick horizontal butt weld. Emission rates of Cr6+ were lowest for GMAW processes and highest for SMAW; several GMAW processes had less than 2% of the SMAW generation rate. Labor and consumable costs for the processes studied were again highest for SMAW, with those of several GMAW types about half that cost. The results show that use of any of the GMAW processes (and flux-cored welding) could substantially reduce fume and Cr6+ emissions, and greatly reduce costs relative to SMAW.
welding; hexavalent chromium; welding fume
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.
Burkholderia mallei and Burkholderia pseudomallei are potentially lethal pathogens categorized as biothreat agents due, in part, to their ability to be disseminated via aerosol. There are no protective vaccines against these pathogens and treatment options are limited and cumbersome. Since disease severity is greatest when these agents are inhaled, efforts to develop pre- or post-exposure prophylaxis focus largely on inhalation models of infection. Here, we demonstrate a non-invasive and technically simple method for affecting the inhalational challenge of BALB/c mice with B. pseudomallei and B. mallei. In this model, two investigators utilized common laboratory tools such as forceps and a micropipette to conduct and characterize an effective and reproducible inhalational challenge of BALB/c mice with B. mallei and B. pseudomallei. Challenge by oropharyngeal aspiration resulted in acute disease. Additionally, 50% endpoints for B. pseudomallei K96243 and B. mallei ATCC 23344 were nearly identical to published aerosol challenge methods. Furthermore, the pathogens disseminated to all major organs typically targeted by these agents where they proliferated. The pro-inflammatory cytokine production in the proximal and peripheral fluids demonstrated a rapid and robust immune response comparable to previously described murine and human studies. These observations demonstrate that OA is a viable alternative to aerosol exposure.
Low spatial frequency (SF) processing has been shown to be impaired in people with schizophrenia, but it is not clear how this varies with clinical state or illness chronicity. We compared schizophrenia patients (SCZ, n = 34), first episode psychosis patients (FEP, n = 22), and healthy controls (CON, n = 35) on a gender/facial discrimination task. Images were either unaltered (broadband spatial frequency, BSF), or had high or low SF information removed (LSF and HSF conditions, respectively). The task was performed at hospital admission and discharge for patients, and at corresponding time points for controls. Groups were matched on visual acuity. At admission, compared to their BSF performance, each group was significantly worse with low SF stimuli, and most impaired with high SF stimuli. The level of impairment at each SF did not depend on group. At discharge, the SCZ group performed more poorly in the LSF condition than the other groups, and showed the greatest degree of performance decline collapsed over HSF and LSF conditions, although the latter finding was not significant when controlling for visual acuity. Performance did not change significantly over time for any group. HSF processing was strongly related to visual acuity at both time points for all groups. We conclude the following: 1) SF processing abilities in schizophrenia are relatively stable across clinical state; 2) face processing abnormalities in SCZ are not secondary to problems processing specific SFs, but are due to other known difficulties constructing visual representations from degraded information; and 3) the relationship between HSF processing and visual acuity, along with known SCZ- and medication-related acuity reductions, and the elimination of a SCZ-related impairment after controlling for visual acuity in this study, all raise the possibility that some prior findings of impaired perception in SCZ may be secondary to acuity reductions.
We examined mother-child cooperative behavior, children’s emotion regulation and executive function, as well as combinations of these factors, as predictors of moral reasoning in 89 10-year-old children. Dyadic cooperation was coded from videotaped observations of laboratory puzzle and speech tasks. Emotion regulation was derived from maternal report, and executive functioning was assessed with the Tower of London task. Moral reasoning was coded during mother-child conversations about morally ambiguous, peer-conflict situations. Two significant interactions indicated that children from more cooperative dyads who also had higher executive function skills had higher moral reasoning scores than other children, and children lower in both emotion regulation and executive function had lower moral reasoning scores than other children. The results contribute to the literature on the multiple and interactive levels of influence on moral reasoning in childhood.
parent-child; cooperative behavior; executive functioning; emotion regulation; moral reasoning
In this prospective study of localized prostate cancer patients and their partners, we analyzed how partner issues evolve over time, focusing on satisfaction with care, influence of cancer treatment and its impact on relationship with patient, cancer worry, and personal activities.
Our study aims were twofold: 1) to determine whether the impact of treatment on patients and partners moderate over time and (2) if receiving surgery (i.e., radical prostatectomy) influences partner issues more than other treatments.
Patients newly diagnosed with localized prostate cancer and their female partners were recruited from 3 states to complete surveys by mail at 3 time points over 12 months.
Main Outcome Measures
The four primary outcomes assessed in the partner analysis included satisfaction with treatment, cancer worry, and the influence of cancer and its treatment on their relationship (both general relationship and sexual relationship).
This analysis included 88 patient-partner pairs. At 6 months, partners reported that cancer had a negative impact on their sexual relationship (39% - somewhat negative and 12% - very negative). At 12 months, this proportion increased substantially (42% – somewhat negative and 29% - very negative). Partners were significantly more likely to report that their sexual relationship was worse when the patient reported having surgery (p=0.0045, OR=9.8025, 95% CI 2.076–46.296). A minority of partners reported significant negative impacts in other areas involving their personal activities (16% at 6 months and 25% at 12 months) or work life (6% at 6 months, which increased to 12% at 12 months).
From partners’ perspectives, prostate cancer therapy has negative impact on sexual relationships, and appears to worsen over time.
prostate cancer; partner; sexual function
Parents' negative responsibility attributions about their child's misbehavior are related to a perception that the child has more behavior problems. The current study used a dyadic framework to explore how mothers' and fathers' attributions relate to their own perceptions and to their partner's perceptions of the child's externalizing problems. Participants included 102 couples interviewed when children were 7 years old. Results confirmed that mothers reported more externalizing behavior problems in their children than did fathers, and fathers of boys reported more child behavior problems than fathers of girls. Dyadic analyses suggested that parents' negative responsibility attributions of the child's behavior were associated with greater perceptions of child externalizing problems on behalf of parents and their partners.
Parental attributions; children's problem behavior; dyadic data analysis
Contour interpolation automatically binds targets with distractors to impair multiple object tracking (Keane, Mettler, Tsoi, & Kellman, 2011). Is interpolation special in this regard, or can other features produce the same effect? To address this question, we examined the influence of eight features on tracking: color, contrast polarity, orientation, size, shape, depth, interpolation and a combination (shape, color, size). In each case, subjects tracked 4 of 8 objects that began as undifferentiated shapes, changed features as motion began (to enable grouping), and returned to their undifferentiated states before halting. The features were always irrelevant to the task instructions. We found that inter-target grouping improved performance for all feature types, except orientation and interpolation (Experiment 1 and Experiment 2). Most importantly, target-distractor grouping impaired performance for color, size, shape, combination, and interpolation. The impairments were at times large (>15% decrement in ac curacy) and occurred relative to a homogeneous condition in which all objects had the same features at each moment of a trial (Experiment 2) and relative to a “diversity” condition in which targets and distractors had different features at each moment (Experiment 3). We conclude that feature-based grouping occurs for a variety of features besides interpolation, even when irrelevant to task instructions and contrary to the task demands, suggesting that interpolation is not unique in promoting automatic grouping in tracking tasks. Our results also imply that various kinds of features are encoded automatically and in parallel during tracking.
multiple object tracking; attention; perceptual grouping; perceptual organization
Pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancers (BTC) are often diagnosed late and at an advanced stage. Population-based screening programmes do not exist and diagnosis is primarily dependent on symptom recognition. Recently symptom-based cancer decision support tools (CDSTs) have been introduced into primary care practices throughout the UK to support general practitioners (GPs) in identifying patients with suspected PDAC. However, future refinement of these tools to improve their diagnostic accuracy is likely to be necessary.
The Health Improvement Network (THIN) is a primary care database, which includes more than 11 million electronic patient records, from 562 GP practices in the UK.
All patients with a diagnosis of PDAC or BTC between 2000 and 2010 were included in the study along with six matched controls; 2773 patients with PDAC, 848 patients with BTC and 15 395 controls.
Primary and secondary outcome measures
The primary aim of this study was to determine the early symptom profiles of PDAC and BTC. Secondary aims included comparing early symptom trends between BTC and PDAC, defining symptom onset in PDAC and evaluating trends in routine blood tests nearest to the time of diagnosis.
In the year prior to diagnosis, patients with PDAC visited their GP on a median of 18 (IQR 11–27) occasions. PDAC was associated with 11 alarm symptoms and BTC with 8. Back pain (OR 1.33 (95% CI 1.18 to 1.49) p<0.001), lethargy (1.42 (95% CI 1.25 to 1.62) p<0.001) and new onset diabetes (OR 2.46 (95% CI 2.16 to 2.80)) were identified as unique features of PDAC.
PDAC and BTC are associated with numerous early alarm symptoms. CDSTs are therefore likely to be useful in identifying these tumours at an early stage. Inclusion of unique symptoms, symptoms with an early onset and routinely performed blood tests is likely to further improve the sensitivity of these tools.
A substantial number of military personnel who have served in Iraq (Operation Iraqi Freedom; OIF) and Afghanistan (Operating Enduring Freedom; OEF) develop symptoms of posttraumatic stress disorder (PTSD) in response to their military experiences and many of these same individuals will drink in a risky or problematic manner following deployment. If left untreated, PTSD symptoms and alcohol problems can become chronic and have a significant, negative impact on the lives of veterans, their families and communities. Further, OIF and OEF service members are often reluctant to seek treatment for mental health symptoms or alcohol problems secondary to stigma. In order to reach this population it is essential that new strategies and venues for delivering evidence-based care are explored. Web-based interventions are uniquely suited to this cohort of veterans in that they have the potential to reach a significant number of veterans who commonly use the Web and who might not otherwise receive care. This article will review the prevalence of PTSD and alcohol problems among OIF and OEF veterans, common barriers they experience with accessing care in traditional mental health settings, and what is known about the effectiveness of Web-based approaches for PTSD and alcohol problems. It also describes the components of a new Web-based intervention, developed by the authors, that uses motivational enhancement and cognitive-behavioral strategies to intervene with returning veterans who report PTSD symptoms and problem drinking. Recommendations for future directions in working with returning veterans with PTSD and alcohol problems will be offered.
Veterans; PTSD; Alcohol; Web intervention
The use of chemotherapy in node-negative, (O)Estrogen Receptor (ER)-positive breast cancer has changed significantly since the introduction of Oncotype DX to determine systemic recurrence risk based on tumour genomic signature.
This study aims to1.Document longitudinal changes in chemotherapy use,2.Assess the impact of new evidence on local protocol.
A cohort study was undertaken, including consecutive patients with early node-negative, ER-positive breast cancer diagnosed between 2006 and May 2013, including a period of prospective clinical trial (Trial Assigning Individualised Options for Treatment (TAILORx)) recruitment. Data were collected regarding patient demographics, tumour clinico-pathological features, Oncotype DX use and recurrence score and chemotherapy use. All therapeutic decisions were made following multidisciplinary discussion, with adherence to guidelines and consideration of trial protocol and Oncotype DX recurrence scores.
479 consecutive patients were included in the study, of whom 241 (50%) underwent Oncotype DX testing, 97 as part of the TAILORx clinical trial. Oncotype DX testing began on a trial basis in 2007 and until October 2011, only patients enrolled on TAILORx availed of genomic profiling. From October 2011, Oncotype DX was used in all eligible patients as per National Cancer Control Programme (NCCP) guidelines. A total of 216 (45%) patients received chemotherapy. The use of chemotherapy changed in inverse proportion to the availability of the genomic assay. Of those patients in whom Oncotype DX was utilised, 138 (57%) were spared chemotherapy.
This study validates the use of molecular testing in the rationalisation of systemic therapy.
Breast cancer; Oncotype DX; Oncotype; Genomic profiling; Genomic assay; Recurrence score; Adjuvant chemotherapy; Chemotherapy; Individualised therapy
The RNA chaperone Hfq fulfills important roles in small regulatory RNA (sRNA) function in many bacteria. Loss of Hfq in the dissimilatory metal reducing bacterium Shewanella oneidensis strain MR-1 results in slow exponential phase growth and a reduced terminal cell density at stationary phase. We have found that the exponential phase growth defect of the hfq mutant in LB is the result of reduced heme levels. Both heme levels and exponential phase growth of the hfq mutant can be completely restored by supplementing LB medium with 5-aminolevulinic acid (5-ALA), the first committed intermediate synthesized during heme synthesis. Increasing expression of gtrA, which encodes the enzyme that catalyzes the first step in heme biosynthesis, also restores heme levels and exponential phase growth of the hfq mutant. Taken together, our data indicate that reduced heme levels are responsible for the exponential growth defect of the S. oneidensis hfq mutant in LB medium and suggest that the S. oneidensis hfq mutant is deficient in heme production at the 5-ALA synthesis step.
Multiple infections have been linked with the development of bronchiolitis obliterans syndrome (BOS) post-lung transplantation. Lung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We hypothesized that Aspergillus colonization may promote the development of BOS and may decrease survival post-lung transplantation. We reviewed all lung transplant recipients transplanted in our center between 1/2000 and 6/2006. Bronchoscopy was performed according to a surveillance protocol and when clinically indicated. Aspergillus colonization was defined as a positive culture from bronchoalveolar lavage or two sputum cultures positive for the same Aspergillus species, in the absence of invasive pulmonary Aspergillosis. We found that Aspergillus colonization was strongly associated with BOS and BOS related mortality in Cox regression analyses. Aspergillus colonization typically preceded the development of BOS by a median of 261 days (95% CI 87 to 520). Furthermore, in a multivariate Cox regression model, Aspergillus colonization was a distinct risk factor for BOS, independent of acute rejection. These data suggest a potential causative role for Aspergillus colonization in the development of BOS post-lung transplantation and raise the possibility that strategies aimed to prevent Aspergillus colonization may help delay or reduce the incidence of BOS.
Pathologic obliterative bronchiolitis (OB)/Bronchiolitis obliterans syndrome (pathologic OB/BOS) is the major obstacle to long-term survival post-lung transplantation (LT). Our group has demonstrated that pulmonary hypertension (PH) complicates the course of chronic inflammatory lung diseases that have similarities to pathologic OB/BOS and that vascular remodeling of the bronchial circulation occurs during BOS. Consequently, we hypothesized that PH is associated with pathologic OB/BOS and may result from a vasculopathy of the allograft pulmonary circulation.
We conducted a single-center, retrospective study and examined the presence of PH and vasculopathy in patients with pathologic OB/BOS. Fifty-two pathologic specimens post-LT were recovered from January 10, 1997 to January 5, 2007 and divided into two groups, those with and without pathologic OB/BOS. PH was defined as a mean pulmonary artery pressure (mPAP) > 25 mmHg by right heart catheterization (RHC) or right ventricular systolic pressure (RVSP) ≥45 mmHg by transthoracic echocardiogram (TTE).
PH was more prevalent in those LT recipients with pathologic OB/BOS (72% vs. 0%, p = 0.003). Furthermore, pulmonary arteriopathy and venopathy were more prevalent in patients with pathologic OB/BOS (84% vs. 4%, p < 0.0001, and 77% vs. 35%, p = 0.004, respectively).
PH is common in LT recipients with pathologic OB/BOS and is associated with a vasculopathy of the allograft pulmonary circulation.
Arteriopathy; bronchiolitis obliterans; chronic rejection; lung transplantation; pulmonary hypertension; vasculopathy; venopathy
Epidemiology has indicated a possible increase in lung cancer among stainless steel welders. Chromium (Cr) is a primary component of stainless steel welding fume. There is an initiative to develop alternative welding consumables [nickel (Ni)- and copper (Cu)-based alloys] that do not contain Cr. No study has been performed to evaluate the toxicity of fumes generated from Ni- and Cu-based consumables. Dose–response and time-course effects on lung toxicity of a Ni- and Cu-based welding fume (Ni–Cu WF) were examined using an in vivo and in vitro bioassay, and compared with two other well-characterized welding fumes. Even though only trace amounts of Cr were present, a persistent increase in lung injury and inflammation was observed for the Ni–Cu WF compared to the other fumes. The difference in response appears to be due to a direct cytotoxic effect by the Ni–Cu WF sample on lung macrophages as opposed to an elevated production of reactive oxygen species (ROS).
welding fume; pulmonary toxicity; chromium; nickel; copper; particulate matter
The prevalence of childhood overweight and obesity in developed countries appears to be levelling off. As trends in childhood obesity prevalence have not been examined over the past decade in the Republic of Ireland, this systematic review aims to compile and synthesise all available information on the prevalence of overweight and obesity in primary school aged children between 2002 and 2012.
Systematic review of published and grey literature containing data on objectively measured height and weight. Inclusion criteria included studies where data was collected between 2002 and 2012 from at least 200 primary school aged children in the Republic of Ireland. Database searching, Google searching, reference searching and contact with obesity experts was undertaken. Overweight, obesity and morbid obesity were defined using standard International Obesity Taskforce definitions. Study quality was assessed.
Fourteen studies (16 prevalence estimates) met the inclusion criteria. The combined prevalence of overweight and obesity within the studies ranged from 20-34%. No significant trend in overweight prevalence over time was observed (p=0.6). However, there was evidence of a slight decrease in obesity prevalence over the period (p=0.01), with a similar though non-significant decline in the prevalence of morbid obesity (p=0.2).
The findings of this systematic review require cautious interpretation though the prevalence of childhood overweight and obesity in the Republic of Ireland has reached a plateau and may be falling. These findings provide some ground for optimism though the current plateau is at an unacceptably high level. Thus current population based preventive strategies need to be sustained and intensified.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-974) contains supplementary material, which is available to authorized users.
Ireland; Prevalence; Trends; Obesity; Children
Aspergillus fumigatus produces a number of secondary metabolites, one of which, gliotoxin, has been shown to exhibit anti-fungal activity. Thus, A. fumigatus must be able to protect itself against gliotoxin. Indeed one of the genes in the gliotoxin biosynthetic gene cluster in A. fumigatus, gliT, is required for self-protection against the toxin- however the global self-protection mechanism deployed is unclear. RNA-seq was employed to identify genes differentially regulated upon exposure to gliotoxin in A. fumigatus wild-type and A. fumigatus ∆gliT, a strain that is hypersensitive to gliotoxin.
Deletion of A. fumigatus gliT resulted in altered expression of 208 genes (log2 fold change of 1.5) when compared to A. fumigatus wild-type, of which 175 genes were up-regulated and 33 genes were down-regulated. Expression of 164 genes was differentially regulated (log2 fold change of 1.5) in A. fumigatus wild-type when exposed to gliotoxin, consisting of 101 genes with up-regulated expression and 63 genes with down-regulated expression. Interestingly, a much larger number of genes, 1700, were found to be differentially regulated (log2 fold change of 1.5) in A. fumigatus ∆gliT when challenged with gliotoxin. These consisted of 508 genes with up-regulated expression, and 1192 genes with down-regulated expression. Functional Catalogue (FunCat) classification of differentially regulated genes revealed an enrichment of genes involved in both primary metabolic functions and secondary metabolism. Specifically, genes involved in gliotoxin biosynthesis, helvolic acid biosynthesis, siderophore-iron transport genes and also nitrogen metabolism genes and ribosome biogenesis genes underwent altered expression. It was confirmed that gliotoxin biosynthesis is induced upon exposure to exogenous gliotoxin, production of unrelated secondary metabolites is attenuated in A. fumigatus ∆gliT, while quantitative proteomic analysis confirmed disrupted translation in A. fumigatus ∆gliT challenged with exogenous gliotoxin.
This study presents the first global investigation of the transcriptional response to exogenous gliotoxin in A. fumigatus wild-type and the hyper-sensitive strain, ∆gliT. Our data highlight the global and extensive affects of exogenous gliotoxin on a sensitive strain devoid of a self-protection mechanism and infer that GliT functionality is required for the optimal biosynthesis of selected secondary metabolites in A. fumigatus.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-894) contains supplementary material, which is available to authorized users.
Gliotoxin; RNA-seq; Transcriptome; Secondary metabolism; Fungal proteomics
Our intestinal microbiota harbors a diverse microbial community, often containing opportunistic bacteria with virulence potential. However, mutualistic host-microbial interactions prevent disease by opportunistic pathogens through poorly understood mechanisms. We show that the epithelial interleukin-22 receptor IL-22RA1 protects against lethal Citrobacter rodentium infection and chemical-induced colitis by promoting colonization resistance against an intestinal opportunistic bacterium, Enterococcus faecalis. Susceptibility of Il22ra1−/− mice to C. rodentium was associated with preferential expansion and epithelial translocation of pathogenic E. faecalis during severe microbial dysbiosis and was ameloriated with antibiotics active against E. faecalis. RNA sequencing analyses of primary colonic organoids showed that IL-22RA1 signaling promotes intestinal fucosylation via induction of the fucosyltransferase Fut2. Additionally, administration of fucosylated oligosaccharides to C. rodentium-challenged Il22ra1−/− mice attenuated infection and promoted E. faecalis colonization resistance by restoring the diversity of anaerobic commensal symbionts. These results support a model whereby IL-22RA1 enhances host-microbiota mutualism to limit detrimental overcolonization by opportunistic pathogens.
•Il22ra1−/− mice succumb to enterococcal dissemination during C. rodentium infection•E. faecalis expands during C. rodentium-induced dysbiosis and invades epithelial cells•Organoid IL-22RA1 RNA-seq reveals diverse antimicrobial and glycosylation factors•Intestinal fucosylation enhances colonization resistance to E. faecalis
Host-commensal interactions prevent disease by opportunistic pathogens through poorly understood mechanisms. Pham et al. show that IL-22RA1 signaling can control the mucosal proliferation and subsequent epithelial translocation of an opportunistic pathogen by promoting intestinal fucosylation and thus enhancing beneficial nutrient interactions between the epithelium and commensal microbes.
Long-term conditions such as chronic obstructive pulmonary disease (COPD) are growing challenges for health services. Psychosocial co-morbidity is associated with poorer quality of life and greater use of health care in these patients but is often un-diagnosed or inadequately treated in primary care, where most care for these patients is provided. We developed a brief intervention, delivered by ‘liaison health workers’ (LHWs), to address psychosocial needs in the context of an integrated approach to physical and mental health. We report a qualitative study in which we characterize the intervention through the experience of the patients receiving it and examine how it was incorporated into primary care.
Qualitative study using patient and practice staff informants. We audio-recorded interviews with 29 patients offered the intervention (three had declined it or withdrawn) and 13 practice staff (GPs, nurses and administrators). Analysis used a constant comparative approach.
Most patients were enthusiastic about the LHWs, describing the intervention as mobilizing their motivation for self-management. By contrast with other practitioners, patients experienced the LHWs as addressing their needs holistically, being guided by patient needs rather than professional agendas, forming individual relationships with patients and investing in patients and their capacity to change. Practices accommodated and accepted the LHWs, but positioned them as peripheral to and separate from the priority of physical care.
Despite being a short-term intervention, patients described it as having enduring motivational benefits. The elements of the intervention that patients described map onto the key features of motivating interventions described by Self-Determination Theory. We suggest that the LHWs motivated patients to self-management by: (i) respecting patients’ competence to decide on needs and priorities; (ii) forming relationships with patients as individuals; and (iii) fostering patients’ sense of autonomy. While truly integrated primary care for patients with long-term conditions such as COPD remains elusive, existing practice staff might adopt elements of the LHWs’ approach to enhance motivational change in patients with long-term conditions such as COPD.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2296-15-164) contains supplementary material, which is available to authorized users.
Primary care; Long-term conditions; Qualitative research; Motivational change; Psychosocial intervention
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the GI tract that is currently treated with injected monoclonal antibodies specific for tumor necrosis factor (TNF). We developed and characterized AVX-470, a novel polyclonal antibody specific for human TNF. We evaluated the oral activity of AVX-470m, a surrogate antibody specific murine TNF, in several well-accepted mouse models of IBD.
AVX-470 and AVX-470m were isolated from the colostrum of dairy cows that had been immunized with TNF. The potency, specificity and affinity of both AVX-470 and AVX-470m were evaluated in vitro and compared with infliximab. AVX-470m was orally administered to mice either before or after induction of colitis and activity was measured by endoscopy, histopathology, immunohistochemistry and quantitative measurement of mRNA levels. Colitis was induced using either 2,4,6-trinitrobenzene sulfonate (TNBS) or dextran sodium sulfate (DSS).
AVX-470 and AVX-470m were shown to be functionally comparable in vitro. Moreover, the specificity, neutralizing potency and affinity of AVX-470 were comparable to infliximab. Orally administered AVX-470m effectively reduced disease severity in several mouse models of IBD. Activity was comparable to that of oral prednisolone or parenteral etanercept. The antibody penetrated the colonic mucosa and inhibited TNF-driven mucosal inflammation with minimal systemic exposure.
AVX-470 is a novel polyclonal anti-TNF antibody with an in vitro activity profile comparable to that of infliximab. Oral administration of a surrogate antibody specific for mouse TNF is effective in treating mouse models of IBD, delivering the anti-TNF to the site of inflammation with minimal systemic exposure.
tumor necrosis factor; ulcerative colitis; polyclonal; gut-targeted
Adverse psychosocial outcomes can be anticipated among youth exposed to Hurricane Katrina. Adolescents are particularly vulnerable to the consequences of this natural disaster and may suffer lasting consequences in the form of psychological morbidity and the development of negative health behaviors due to their exposure. We review existing literature on the effects of exposure to natural disasters and similar traumas on youth and, where data on youth are unavailable, on adults. The effect of natural disasters is discussed in terms of risk for three negative health outcomes that are of particular concern due to their potential to cause long-term morbidity: post-traumatic stress disorder, substance use disorder, and HIV-risk behavior. Where available, data from studies of the effects of Hurricane Katrina are included.
adolescents; natural disaster; post-traumatic stress disorders; HIV; substance use