Damage sensing through TLR9 Promotes Viral Clearance and Recovery During Influenza Infection.

Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA, which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mitochondrial DNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data show that TLR9-mediated sensing of tissue damage promotes an inflammatory response during early infection, driven by the myeloid cells and associated cytokine responses. Along with the diminished inflammatory response, the absence of damage sensing through TLR9 led to impaired viral clearance manifested as a higher and prolonged influenza burden in the lung. The absence of TLR9 led to extensive infection of myeloid cells including monocytes and macrophages rendering them highly inflammatory, despite having a low initial inflammatory response. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we show elevated circulating TLR9 ligands in the plasma samples of patients with influenza, demonstrating its clinical relevance. Overall, over data show an essential role of damage sensing through TLR9 in promoting anti-influenza immunity.

Circulating Mitochondrial DNA Is Associated With High Levels of Fatigue in Two Independent Sarcoidosis Cohorts.

BACKGROUND: Patients with sarcoidosis who develop severe clinical phenotypes of pulmonary fibrosis or multiorgan disease experience debilitating symptoms, with fatigue being a common chief complaint. Studies that have investigated this patient-related outcome measure (PROM) have used the Fatigue Assessment Scale (FAS), a self-reported questionnaire that reflects mental and physical domains. Despite extensive work, its cause is unknown and treatment options remain limited. Previously, we showed that the plasma of patients with sarcoidosis with extrapulmonary disease endorsing fatigue was enriched for mitochondrial DNA (mtDNA), a ligand for the innate immune receptor toll-like receptor 9 (TLR9). Through our cross-disciplinary platform, we investigated a relationship between sarcoidosis-induced fatigue and circulating mtDNA. RESEARCH QUESTION: Is there a psychobiologic mechanism that connects sarcoidosis-induced fatigue and mtDNA-mediated TLR9 activation? STUDY DESIGN AND METHODS: Using a local cohort of patients at Yale (discovery cohort) and the National Institutes of Health-sponsored Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis study (validation cohort), we scored the FAS and quantified in the plasma, mtDNA concentrations, TLR9 activation, and cytokine levels. RESULTS: Although FAS scores were independent of corticosteroid use and Scadding stage, we observed a robust association between FAS scores, which included mental and physical domains, and multiorgan sarcoidosis. Subsequently, we identified a significant correlation between plasma mtDNA concentrations and all domains of fatigue. Additionally, we found that TLR9 activation is associated with all aspects of the FAS and partially mediates this PROM through mtDNA. Last, we found that TLR9-associated soluble mediators in the plasma are independent of all facets of fatigue. INTERPRETATION: Through our cross-disciplinary translational platform, we identified a previously unrecognized psychobiologic connection between sarcoidosis-induced fatigue and circulating mtDNA concentrations. Mechanistic work that investigates the contribution of mtDNA-mediated innate immune activation in this PROM and clinical studies with prospective cohorts has the potential to catalyze novel therapeutic strategies for this patient population and those with similar conditions.

α1 Adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is increasingly associated with nerve-driven processes and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here, we report that noradrenaline (NA) derived from the lung's adrenergic nerve supply drives α-smooth muscle actin (αSMA)-expressing fibroblast accumulation via mechanisms involving α1 adrenoreceptors and mtDNA. Using the bleomycin model, we compared ablation of the lung's adrenergic nerve supply with surgical adrenal resection and found that NA derived from local but not adrenal sources contributes to experimentally induced lung fibrosis and the emergence of an αSMA+ve fibroblast population expressing adrenoreceptor α-1D (ADRA1D). Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed these changes and suppressed extracellular mtDNA accumulation. Cultured normal human lung fibroblasts displayed α1 adrenoreceptors and in response to costimulation with TGFß1 and NA adopted ACTA2 expression and extracellular mtDNA release. These findings were opposed by terazosin. Evaluation of a previously studied IPF cohort revealed that patients prescribed α1 adrenoreceptor antagonists for nonpulmonary indications demonstrated improved survival and reduced concentrations of plasma mtDNA. Our observations link nerve-derived NA, α1 adrenoreceptors, extracellular mtDNA, and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuroinnate connection may yield new avenues for investigation in the clinical and basic science realms.

Hyaline membrane disease (HMD): an historical and Oslerian perspective.

Hyaline membrane disease (HMD) offers an illustration of a disease discovered during the lifetime of William Osler and effectively treated in the twentieth century-the perspective that suggests that there was a straightforward progressive identification of the disease process, a discovery of the underlying biochemical agent responsible for the pathophysiology, and the pharmacological refinement of that agent to be used to treat the disease is illusory. By reviewing the timeline from the earliest pathological description of what was to be later termed HMD to the discovery of surfactant and its impact on infant mortality, this narrative will demonstrate how various random historical events served to affect the progress of developing a treatment for HMD; how the marked reduction in deaths due to HMD may have set the stage for unrealistic expectations; and how the humanities have warned us of the potential for excessive optimism in our understanding of nature.

Attributions for hallucinations in bipolar affective disorder.

BACKGROUND: Attributions for hallucinations in the "schizophrenia" spectrum disorders have been subject to extensive investigation; however, in comparison very little is known about attributions for hallucinations in the bipolar disorders spectrum. AIMS: This preliminary study is an attempt to investigate attributions for hallucinations in bipolar disorder with regard to prevalence, modality and mood state. METHOD: Forty participants were recruited from a larger randomized control trial into CBT for bipolar disorder and asked to provide information related to attributions for hallucinations both in and out of episode. Data was collected using a specially designed instrument based on the Belief about Voices Questionnaire (BAVQ). RESULTS: Just under half of the participants reported experiencing true hallucinations during their illness. Participants tended to report visual hallucinations in mania and auditory hallucinations in depression. The vast majority of participants attributed hallucinations to illness when out of episode, and unlike in previously reported analyses of attributions for hallucinations in the schizophrenia spectrum, malevolent/omnipotent attributions were comparatively rare. CONCLUSIONS: Attributions for hallucinations in bipolar disorder may be clinically distinct from attributions previously observed in the schizophrenia spectrum, and CBT aimed at reducing the distress associated with these attributions may have to be tailored accordingly.

Array lead zirconate titanate/glass piezoelectric microcantilevers for real-time detection of Bacillus anthracis with 10 spores/ml sensitivity and 1/1000 selectivity in bacterial mixtures.

An array of three identical piezoelectric microcantilever sensors (PEMSs) consisting of a lead zirconate titanate layer bonded to a glass layer was fabricated and examined for simultaneous, in situ, real-time, all-electrical detection of Bacillus anthracis (BA) spores in an aqueous suspension using the first longitudinal extension mode of resonance. With anti-BA antibody immobilized on the sensor surfaces all three PEMS exhibited identical BA detection resonance frequency shifts at all tested concentrations, 10-10(7) spores/ml with a standard deviation of less than 10%. The detection concentration limit of 10 spores/ml was about two orders of magnitude lower than would be permitted by flexural peaks. In blinded-sample testing, the array PEMS detected BA in three samples containing BA: (1) 3.3x10(3) spores/ml, (2) a mixture of 3.3x10(3) spores/ml and 3.3x10(5) S. aureus (SA) and P. aeruginosa (PA) per ml, and (3) a mixture of 3.3x10(3) spores/ml with 3.3x10(6) SA+PA/ml. There was no response to a sample containing only 3.3x10(6) SA+PA/ml. These results illustrate the sensitivity, specificity, reusability, and reliability of array PEMS for in situ, real-time detection of BA spores.

Label-free flow-enhanced specific detection of Bacillus anthracis using a piezoelectric microcantilever sensor.

Differentiation between species of similar biological structure is of critical importance in biosensing applications. Here, we report specific detection of Bacillus anthracis (BA) spores from that of close relatives, such as B. thuringiensis (BT), B. cereus (BC), and B. subtilis (BS) by varying the flow speed of the sampling liquid over the surface of a piezoelectric microcantilever sensor (PEMS). Spore binding to the anti-BA spore IgG coated PEMS surface is determined by monitoring the resonance frequency change in the sensor's impedance vs. frequency spectrum. Flow increases the resonance frequency shift at lower flow rates until the impingement force from the flow overcomes the binding strength of the antigen and decreases the resonance frequency shift at higher flow rates. We showed that the change from increasing to decreasing resonance frequency shift occurred at a lower fluid flow speed for BT, BC, and BS spores than for BA spores. This trend reduces the cross reactivity ratio of BC, BS, and BT to the anti-BA spore IgG immobilized PEMS from around 0.4 at low flow velocities to less than 0.05 at 3.8 mm s(-1). This cross reactivity ratio of 0.05 was essentially negligible considering the experimental uncertainty. The use of the same flow that is used for detection to further distinguish the specific binding (BA to anti-BA spore antibody) from nonspecific binding (BT, BC, and BS to anti-BA spore antibody) is unique and has great potential in the detection of general biological species.

In situ detection of Bacillus anthracis spores using fully submersible, self-exciting, self-sensing PMN-PT/Sn piezoelectric microcantilevers.

In this study, we have demonstrated in situ, all-electrical detection of Bacillus anthracis (BA) spores using lead magnesium niobate-lead titanate/tin (PMN-PT/Sn) piezoelectric microcantilever sensors (PEMS) fabricated from PMN-PT freestanding films and electrically insulated with methyltrimethoxysilane (MTMS) coatings on the tin surface. Antibody specific to BA spore surface antigen was immobilized on the platinum electrode of the PMN-PT layer. In phosphate-buffered saline (PBS) solution, the PMN-PT/Sn PEMS exhibited quality (Q) values ranging from 50 to 75. The detection was carried out in a closed-loop flow cell with a liquid volume of 0.8 ml and a flow rate of 1 ml min(-1). It was shown that one sensor, "PEMS-A" (500 microm long, 800 microm wide, with a 22 microm thick PMN-PT layer, a 20 microm thick tin layer and a 1 +/- 0.5 x 10(-12) g Hz(-1) mass detection sensitivity) exhibited resonance frequency shifts of 2100 +/- 200, 1100 +/- 100 and 700 +/- 100 Hz at concentrations of 20,000, 2000, and 200 spores ml(-1) or 16,000, 1600, and 160 total spores, respectively. Additionally, "PEMS-B" (350 microm long, 800 microm wide, with an 8 microm thick PMN-PT layer, a 6 microm thick tin layer and a 2 +/- 1 x 10(-13) g Hz(-1) mass detection sensitivity) exhibited resonance frequency shifts of 2400 +/- 200, 1500 +/- 200, 500 +/- 150 and 200 +/- 100 Hz at concentrations of 20,000, 2000, 100, and 45 spores ml(-1) or 16,000, 1600, 80, and 36 total spores, respectively.

Assessment of need for psychosocial interventions in an Asian population of carers of patients with schizophrenia.

AIM: This paper reports on a study to establish the profile of need for psychosocial family interventions and to examine the concurrent validity of the Relatives' Cardinal Needs Schedule with an Asian population of carers in England, UK. BACKGROUND: Although psychosocial interventions for schizophrenia have a strong evidence base, little is known of the needs of Asian families. A cardinal need is indicative of the existence of a problem causing the carer a strain for which the carer is willing to co-operate if help is offered and for which systematic help has not been provided in the last 12 months. METHODS: The Relatives' Cardinal Needs Schedule was used to assess needs in a small randomly selected sample of Asian carers in one English locality and to compare the results with independent measures of patient symptoms and carer distress. RESULTS: Feedback from carers indicated that the Relatives' Cardinal Needs Schedule was culturally acceptable and appropriate to their needs. There was evidence for the validity of the assessment in that there were large and statistically significant associations between the number of needs detected by the Relatives' Cardinal Needs Schedule and independent measures of both carer distress (as measured by the 28 item General Health Questionnaire) and patient symptom severity (as reliably assessed from case notes). CONCLUSION: The Relatives' Cardinal Needs Schedule may prove useful for nurses and service managers in establishing the need for psychosocial family interventions amongst Asian families in the United Kingdom.

Psychological therapies for bipolar disorder: the role of model-driven approaches to therapy integration.

OBJECTIVES: The psychological and social aspects of bipolar disorder are receiving increasing recognition. Recently, there have been promising developments in psychological interventions, but there is scope for further improvement of therapeutic outcomes. This paper argues for the use of more detailed psychological models of bipolar disorder to inform the further development of therapeutic approaches. METHOD: Evidence for psychological, family and social factors in bipolar disorder is reviewed. The efficacy of current individual and family interventions are discussed. A model, which has potential to synthesize group and individual approaches, is outlined. RESULTS: Psychological, social and family factors have important influences on the onset, course and outcome of bipolar disorder. Interventions based on vulnerability stress models have proved effective. However, to enhance efficacy future developments need to be based on models that integrate current understandings of the multiple levels at which mood fluctuations occur. A particular recent model is discussed which leads to specific proposals for future intervention research. CONCLUSIONS: Psychological and family approaches to BD have much potential. They clearly have a role in conjunction with appropriate pharmacological treatment. If this potential is to be fully realized future developments need to be based on psychological models that can accommodate the complexity of this illness.

Cognitive-behavioural therapy and motivational intervention for schizophrenia and substance misuse. 18-month outcomes of a randomised controlled trial.

BACKGROUND: Comorbid substance misuse in people with schizophrenia is associated with poor clinical and social outcomes. There are few studies of psychological treatments for this population and little long-term follow-up of their benefits. AIMS: To investigate symptom, substance use, functioning and health economy outcomes for patients with schizophrenia and their carers 18 months after a cognitive-behavioural treatment (CBT) programme. METHOD: Patients with dual diagnosis from a randomised controlled trial of motivational intervention, individual CBT and family intervention were assessed on multiple outcomes at 18-month follow-up. Carers were assessed on symptom, functioning and needs over 12 months. Health economy data were collected over 18 months. RESULTS: There were significant improvements in patient functioning compared with routine care over 18 months. No significant differences between treatment groups were found in carer or cost outcomes. CONCLUSIONS: The treatment programme was superior to routine care on outcomes relating to illness and service use, and the cost was comparable to the control treatment.

Improved health and self-esteem among patients with AIDS in a therapeutic community nursing program.

This study followed up 41 clients (26 males and 15 females) admitted into a modified therapeutic community (TC) nursing home for substance abusing clients with AIDS at 3 points in time (admission, 8 months into treatment, and after completing residential treatment, 16-18 months post baseline) using the Tennessee Self-Concept Scale and other biological and social indicators, such as CD-4 cell count, body weight, and number of close friends. Analyses of repeated measures found significant linear increases on total self-esteem, CD-4 cell count, and body weight biological indicators, and number of close friends social indicator. Discussion focused on the pertinence of the TC nursing home treatment on clients' internalized behavior self-concept change, as well as positive physical and social change indicators.

Does training in psychosocial interventions reduce burnout rates in forensic nurses?

BACKGROUND: Mental Health Nurses working in secure environments with patients suffering from serious mental illness have been shown to be at risk of clinical burnout syndrome, this can have adverse effects both on the nurses' health and the standards of care that they deliver. AIM: To evaluate the effect of Psychosocial Intervention Training (PSI) on the knowledge, attitudes and levels of clinical burnout in a group of forensic mental health nurses. DESIGN: Baseline assessments of knowledge, attitude and burnout were completed by asking a group of 33 nurses working in a medium secure psychiatric unit to complete questionnaires. Twenty of the nurses volunteered to be included in a PSI training course and were randomly allocated either to receive the training or to a waiting list control group. The duration of the training was 6 months and on completion subjects in the experimental and control group completed the questionnaires again. RESULTS: Staff in the experimental group showed significant improvements in their knowledge and attitudes about serious mental illness and a significant decrease in burnout rates, whilst staff in the control group showed a small but nonsignificant improvement in knowledge and attitudes, and increase in burnout. CONCLUSION: The findings suggest that providing forensic mental health nurses with a better understanding of serious mental illness and training them in a broader range of interventions, helps them to be more positive in their attitudes towards the clients that they work with and experience less negative effects of stress resulting from their caring role. The implications of this study for clinical practice and future research will be discussed.