Engineering novel complement activity into a pulmonary surfactant protein

Complement neutralizes invading pathogens, stimulates inflammatory and adaptive immune responses, and targets non- or altered-self structures for clearance. In the classical and lectin activation pathways, it is initiated when complexes composed of separate recognition and activation subcomponents bind to a pathogen surface. Despite its apparent complexity, recognition-mediated activation has evolved independently in three separate protein families, C1q, mannose-binding lectins (MBLs), and serum ficolins. Although unrelated, all have bouquet-like architectures and associate with complement-specific serine proteases: MBLs and ficolins with MBL-associated serine protease-2 (MASP-2) and C1q with C1r and C1s. To examine the structural requirements for complement activation, we have created a number of novel recombinant rat MBLs in which the position and orientation of the MASP-binding sites have been changed. We have also engineered MASP binding into a pulmonary surfactant protein (SP-A), which has the same domain structure and architecture as MBL but lacks any intrinsic complement activity. The data reveal that complement activity is remarkably tolerant to changes in the size and orientation of the collagenous stalks of MBL, implying considerable rotational and conformational flexibility in unbound MBL. Furthermore, novel complement activity is introduced concurrently with MASP binding in SP-A but is uncontrolled and occurs even in the absence of a carbohydrate target. Thus, the active rather than the zymogen state is default in lectin·MASP complexes and must be inhibited through additional regions in circulating MBLs until triggered by pathogen recognition

A cross-sectional study on tobacco use and dependence among women: Does menthol matter?

Background: The question of whether mentholation of cigarettes enhances tobacco dependence has generated conflicting findings. Potential mediating factors in a putative relationship between menthol use and tobacco dependence may include race and gender. While an association between menthol use and dependence is mixed, research on the role of race solely among women smokers is scarce. This study examined whether women menthol smokers have higher tobacco use and dependence than non-menthol smokers. Further, the study investigated differences between White and African American smokers. Methods: A cross-sectional study was conducted among 928 women seeking tobacco dependence treatment in Boston, Massachusetts. Measures obtained included preferred brand and menthol content, dependence markers (cigarettes per day (CPD); time to first cigarette in the morning; number of and longest previous quit attempts) and smoking history (age of initiation; years smoking; menthol or non-menthol cigarette preference). Analysis of variance (ANOVA) was used to detect interactions between menthol preference by race for continuous variables, and Pearson’s chi-squared test was used for analyses with dichotomous variables. Results: A greater proportion of menthol smokers smoked their first cigarette within five minutes of waking (p < 0.01) and were less likely to have a previous quit attempt longer than 90 days (p < 0.01). ANOVAs revealed no main effects for menthol preferences. However, African American smokers smoked fewer CPD (p<.001), started smoking later in life (p= .04), and had been smoking the same brand for longer (p= .04). Conclusions: Women menthol smokers showed signs of greater tobacco dependence than non-menthol smokers. African Americans smoked fewer CPD but nevertheless had evidence of greater dependence

Pathways to care for critically ill or injured children: A cohort study from first presentation to healthcare services through to admission to intensive care or death

Purpose Critically ill or injured children require prompt identification, rapid referral and quality emergency management. We undertook a study to evaluate the care pathway of critically ill or injured children to identify preventable failures in the care provided. METHODS: A year-long cohort study of critically ill and injured children was performed in Cape Town, South Africa, from first presentation to healthcare services until paediatric intensive care unit (PICU) admission or emergency department death, using expert panel review of medical records and caregiver interview. Main outcomes were expert assessment of overall quality of care; avoidability of severity of illness and PICU admission or death and the identification of modifiable factors. RESULTS: The study enrolled 282 children, 252 emergency PICU admissions, and 30 deaths. Global quality of care was graded good in 10% of cases, with half having at least one major impact modifiable factor. Key modifiable factors related to access to care and identification of the critically ill, assessment of severity, inadequate resuscitation, and delays in decision making and referral. Children were transferred with median time from first presentation to PICU admission of 12.3 hours. There was potentially avoidable severity of illness in 185 (74%) of children, and death prior to PICU admission was avoidable in 17/30 (56.7%) of children. CONCLUSIONS: The study presents a novel methodology, examining quality of care across an entire system, and highlighting the complexity of the pathway and the modifiable events amenable to interventions, that could reduce mortality and morbidity, and optimize utilization of scarce critical care resources; as well as demonstrating the importance of continuity and quality of care

‘A nation of town criers’: civic publicity and historical pageantry in inter-war Britain

Historical pageantry emerged in 1905 as the brainchild of the theatrical impresario Louis Napoleon Parker. Large casts of volunteers re-enacted successive scenes of local history, as crowds of thousands watched on, in large outdoor arenas. As the press put it, Britain had caught ‘pageant fever’. Towards the end of the 1920s, there was another outburst of historical pageantry. Yet, in contrast to the Edwardian period, when pageants took place in small towns, this revival was particularly vibrant in large industrial towns and cities. This article traces the popularity of urban pageantry to an inter-war ‘civic publicity’ movement. In doing so, it reassesses questions of local cultural decline; the role of local government; and the relationship of civic responsibility to popular theatre

Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions

Is behavioural activation effective in the treatment of depression in young people? : A systematic review and meta-analysis

PURPOSE: Depression is currently the leading cause of illness and disability in young people. Evidence suggests that behavioural activation (BA) is an effective treatment for depression in adults but less research focuses on its application with young people. This review therefore examined whether BA is effective in the treatment of depression in young people. METHODS: A systematic review (International Prospective Register of Systematic Reviews reference: CRD42015020453), following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, was conducted to examine studies that had explored behavioural interventions for young people with depression. The electronic databases searched included the Cochrane Library, EMBASE, MEDLINE, CINAHL Plus, PsychINFO, and Scopus. A meta-analysis employing a generic inverse variance, random-effects model was conducted on the included randomized controlled trials (RCTs) to examine whether there were overall effects of BA on the Children's Depression Rating Scale - Revised. RESULTS: Ten studies met inclusion criteria: three RCTs and seven within-participant designs (total n = 170). The review showed that BA may be effective in the treatment of depression in young people. The Cochrane risk of bias tool and the Moncrieff scale used to assess the quality of the included studies revealed a variety of limitations within each. CONCLUSIONS: Despite demonstrating that BA may be effective in the treatment of depression in young people, the review indicated a number of methodological problems in the included studies meaning that the results and conclusions should be treated with caution. Furthermore, the paucity of studies in this area highlights the need for further research. PRACTITIONER POINTS: Currently BA is included within National Institute for Health and Clinical Excellence (NICE, 2009) guidelines as an evidence-based treatment for depression in adults with extensive research supporting its effectiveness. It is important to investigate whether it may also be effective in treating young people. Included studies reported reductions in depression scores across a range of measures following BA. BA may be an effective treatment of depression in young people

Employing external facilitation to implement cognitive behavioral therapy in VA clinics: a pilot study

<p>Abstract</p> <p>Background</p> <p>Although for more than a decade healthcare systems have attempted to provide evidence-based mental health treatments, the availability and use of psychotherapies remains low. A significant need exists to identify simple but effective implementation strategies to adopt complex practices within complex systems of care. Emerging evidence suggests that facilitation may be an effective integrative implementation strategy for adoption of complex practices. The current pilot examined the use of external facilitation for adoption of cognitive behavioral therapy (CBT) in 20 Department of Veteran Affairs (VA) clinics.</p> <p>Methods</p> <p>The 20 clinics were paired on facility characteristics, and 23 clinicians from these were trained in CBT. A clinic in each pair was randomly selected to receive external facilitation. Quantitative methods were used to examine the extent of CBT implementation in 10 clinics that received external facilitation compared with 10 clinics that did not, and to better understand the relationship between individual providers' characteristics and attitudes and their CBT use. Costs of external facilitation were assessed by tracking the time spent by the facilitator and therapists in activities related to implementing CBT. Qualitative methods were used to explore contextual and other factors thought to influence implementation.</p> <p>Results</p> <p>Examination of change scores showed that facilitated therapists averaged an increase of 19% [95% CI: (2, 36)] in self-reported CBT use from baseline, while control therapists averaged a 4% [95% CI: (-14, 21)] increase. Therapists in the facilitated condition who were not providing CBT at baseline showed the greatest increase (35%) compared to a control therapist who was not providing CBT at baseline (10%) or to therapists in either condition who were providing CBT at baseline (average 3%). Increased CBT use was unrelated to prior CBT training. Barriers to CBT implementation were therapists' lack of control over their clinic schedule and poor communication with clinical leaders.</p> <p>Conclusions</p> <p>These findings suggest that facilitation may help clinicians make complex practice changes such as implementing an evidence-based psychotherapy. Furthermore, the substantial increase in CBT usage among the facilitation group was achieved at a modest cost.</p

Simultaneous Activation of Complement and Coagulation by MBL-Associated Serine Protease 2

The complement system is an important immune mechanism mediating both recognition and elimination of foreign bodies. The lectin pathway is one pathway of three by which the complement system is activated. The characteristic protease of this pathway is Mannan-binding lectin (MBL)-associated serine protease 2 (MASP2), which cleaves complement proteins C2 and C4. We present a novel and alternative role of MASP2 in the innate immune system. We have shown that MASP2 is capable of promoting fibrinogen turnover by cleavage of prothrombin, generating thrombin. By using a truncated active form of MASP2 as well as full-length MASP2 in complex with MBL, we have shown that the thrombin generated is active and can cleave both factor XIII and fibrinogen, forming cross-linked fibrin. To explore the biological significance of these findings we showed that fibrin was covalently bound on a bacterial surface to which MBL/MASP2 complexes were bound. These findings suggest that, as has been proposed for invertebrates, limited clotting may contribute to the innate immune response

Reducing depression in older home care clients: design of a prospective study of a nurse-led interprofessional mental health promotion intervention

Abstract Background Very little research has been conducted in the area of depression among older home care clients using personal support services. These older adults are particularly vulnerable to depression because of decreased cognition, comorbid chronic conditions, functional limitations, lack of social support, and reduced access to health services. To date, research has focused on collaborative, nurse-led depression care programs among older adults in primary care settings. Optimal management of depression among older home care clients is not currently known. The objective of this study is to evaluate the feasibility, acceptability and effectiveness of a 6-month nurse-led, interprofessional mental health promotion intervention aimed at older home care clients with depressive symptoms using personal support services. Methods/Design This one-group pre-test post-test study aims to recruit a total of 250 long-stay (> 60 days) home care clients, 70 years or older, with depressive symptoms who are receiving personal support services through a home care program in Ontario, Canada. The nurse-led intervention is a multi-faceted 6-month program led by a Registered Nurse that involves regular home visits, monthly case conferences, and evidence-based assessment and management of depression using an interprofessional approach. The primary outcome is the change in severity of depressive symptoms from baseline to 6 months using the Centre for Epidemiological Studies in Depression Scale. Secondary outcomes include changes in the prevalence of depressive symptoms and anxiety, health-related quality of life, cognitive function, and the rate and appropriateness of depression treatment from baseline to 12 months. Changes in the costs of use of health services will be assessed from a societal perspective. Descriptive and qualitative data will be collected to examine the feasibility and acceptability of the intervention and identify barriers and facilitators to implementation. Discussion Data collection began in May 2010 and is expected to be completed by July 2012. A collaborative nurse-led strategy may provide a feasible, acceptable and effective means for improving the health of older home care clients by improving the prevention, recognition, and management of depression in this vulnerable population. The challenges involved in designing a practical, transferable and sustainable nurse-led intervention in home care are also discussed. Trial Registration ClinicalTrials.gov: NCT0140792