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Objective. This longitudinal study examines the relationship of alcohol consumption to mortality and changes in mental and functional health in older adults. Method.In a national population health survey, 4,187 participants aged 50 and older at baseline provided information on alcohol consumption, potential confounders, and follow-up vital status. Logistic regression estimated the odds ratio for mortality, increase in psychological distress, and decline in functional health 10 years later. Results. Compared with lifelong abstainers, light and moderate drinkers were at nonsignificantly lower risk of mortality. Among survivors, alcohol consumption showed no consistent relationship with increases in psychological distress. Occasional and light drinkers had significantly reduced risk of a substantial functional health decline, whereas moderate drinkers had nonsignificantly reduced risk. Discussion. Findings suggest that light-to-moderate alcohol consumption reduces the risk of substantial functional health decline in older middle-aged drinkers. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Health sciences programs are being designed to attract students who are likely to stay and practice in rural and northern Canada. Consequently, student recruitment and screening are increasingly including assessment of suitability for rural practice. Although retention factors among rural physicians and nurses have been investigated, little is known about factors that contribute to the retention of other healthcare professionals who work in rural areas. The primary objective of this project was to identify the personal characteristics and experiences of allied health professionals who have worked long term in northern British Columbia (BC), Canada. METHODS: The study used a qualitative descriptive approach. Six speech language pathologists, four psychologists, four occupational therapists, eight social workers, and four physiotherapists practicing long term in northern BC were recruited, using a convenience sample and the snowball technique, to participate in semi-structured telephone interviews. The interviews were audiotaped and transcribed verbatim. A thematic content analysis identified the motivations for their decision to begin or stay working in northern communities, the reasons for choosing rural or northern education and key themes concerning personal characteristics and experiences. A process of member checking and an external audit validated the analysis and findings. RESULTS: There were two major themes for choosing rural and northern education. For some, selection of rural or northern training was based on accessibility to health education programs; all participants who chose rural and northern education had already decided that they were going to practice rurally. Generally, participants identified past positive experiences and rural background as influencing their practice location decision. Participants named the community's need for healthcare professionals, career advancement opportunities, welcoming employers, peer support, as well as promises of continuing education and interprofessional teamwork as key to their decision. Professional preferences for variety, challenges, and trying new aspects of the job such as teaching also impacted their decision. Also identified were individual factors and personal preferences such as the need for adventure, wilderness, and outdoor recreation, and community factors (eg people's friendliness and the slow pace). Such factors also influenced retention; however, retention was also affected by factors such as job satisfaction, and some community factors were only associated with retention. The analysis revealed a number of personal characteristics and experiences shared by long-term healthcare professionals, and that there is not one particular factor that determines duration of practice in rural and northern communities. CONCLUSION: The findings imply a combination of varying personal values impact the decision to come or stay in rural and northern communities. Personal characteristics and experiences help to shape these personal values. Over time and depending on stage of life, personal values change. Age and stage of life, rural background, and location of family members also have bearing on personal values, which in turn impact recruitment and retention. An explicit identification of values that have emerged out of personal characteristics and experiences may be useful in the selection of students for rural health education programs, as well as the recruitment and retention of healthcare professionals in rural and northern areas. [ABSTRACT FROM AUTHOR]

Dermatologic care within the military faces unique ethical challenges. Service members are stationed across nationally and globally diverse settings, and therefore, dermatologic care rendered ranges from within resource-rich, advanced military medical treatment facilities to austere, resource-limited, deployed field environments. Additionally, military service members are often at unique risk for dermatologic disease, given occupational, environmental, and geographic exposures not commonly faced by their civilian counterparts. This review explores topics in dermatoethics via case analyses of ethical considerations within the scope of dermatologic care for military service members.

Wound healing is crucial for survival, prevention of infection, and restoration of tissue function. The immune system drives this process with 3 main phases: inflammation, proliferation, and remodeling. Keloids and hypertrophic scars reveal disruptions in these phases, underscoring the balance needed for healing. Limb amputation, a life-changing event, demands careful consideration for healing and function. Factors such as amputation level, surgical technique, and prosthetic fitting shape outcomes, while complications such as heterotopic ossification challenge recovery. Treatment advances including statins and stem cell therapy hold promise, with dermatologists poised to contribute substantially to postamputation care.

Introduction: This prospective intervention study was designed to determine the efficacy of a standardized Preflight/Postflight Stretches (PPS) protocol to reduce subjective neck and back pain scores in helicopter aircrew. Aircrew transient back and neck pain is well documented, and there is currently no standardized preflight and postflight stretching protocol for Naval Aviation., Methods: Subjects were recruited from two carrier air wing MH-60R squadrons at Naval Air Station Jacksonville. These carrier air wing squadrons were selected to control for size (number of aircrew), age, and operational tempo (number of flight hours). Subjects consisted of both pilots and enlisted aircrew. One squadron was designated as the control group, although the second squadron served as the intervention group. Subjects from both groups filled out the questionnaire. Only the intervention group completed the PPS protocol immediately after completing the questionnaire and before departing the squadron spaces for the aircraft outside. Upon landing, the aircrew completed a postflight debrief. Only the intervention group completed the PPS protocol after debrief. Both the intervention and control groups once again completed the questionnaire. Questionnaires were matched by using a generated anonymous subject ID. The amounts of change and pain levels were then compared using the Mann-Whitney test and the Fisher's exact test, respectively., Results: The Kolmogorov-Smirnov test found the data to be nonparametric. The preflight and postflight overall (P ≤ .001), cervical (P ≤ .001), thoracic (P = .006), and lumbar (P = .004) differences between the control and intervention groups were found to be statistically significant when using the Mann-Whitney test. Preflight and postflight pain differences in the sacral region and "other" section were not found to be statistically significant (sacral, P = .618; others, P = .182). When evaluating the worsening of the pain level, 50 (92%) of the control flights in which PPS was not performed reported worse pain, compared to 21 (61.8%) in the intervention group where PPS was performed. The Fisher's exact test found the association between performing PPS and the worsening in pain to be statistically significant (P = .001) in the overall, cervical, thoracic, and lumbar regions. Therefore, the hypothesis was accepted in regard to overall pain, as well as in the cervical, thoracic, and lumbar regions., Conclusion: Aircrew back and neck pain because of flying is well documented. However, there is no standardized stretching protocol for aircrew to perform immediately preflight or postflight in U.S. Naval Aviation. This study demonstrated that PPS, a simple 5- to 7-min stretching routine, gives aircrew structure and can reduce postflight cervical, thoracic, lumbar, and overall pain. This phase proved to be safe as no adverse events were reported. The prehabilitation aspect could reduce conventional medical intervention, costly pharmacological management of neck and back pain, and be applied to other aviation populations in military and civilian communities., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Fibroepithelioma of Pinkus (FeP) is a rare skin tumor with a clinical presentation similar to benign neoplasms such as acrochordons and seborrheic keratoses. Our study analyzed if there is an association between FeP and internal tumors, specifically gastrointestinal tract tumors. We retrospectively reviewed the medical records of patients with FeP for other tumors throughout their lives until 2020. Although the quality of documentation for each patient may have differed, this study suggests that the presence of FeP does not indicate the presence of gastrointestinal tract tumors, and there is no need for altered cancer screening recommendations for those with FeP.

Background: Preoperative patient screening has been evaluated in many surgical specialties as a way to improve the overall patient experience. Current data are limited regarding patient screening for dermatologic procedures. The goal of preoperative screening is to identify patients at risk for poor outcomes and tailor the treatment plan to ensure a greater overall patient experience., Objective: To investigate the association between psychological comorbidities and acute postoperative pain in patients treated with Mohs micrographic surgery (MMS)., Materials and Methods: Subjects were recruited from a single center, single provider, uniformed service MMS practice, and asked to complete preoperative and postoperative questionnaires for scheduled MMS. Outcome variables included anticipated pain, actual pain after MMS, duration of pain, and medications used for pain., Results: Mohs micrographic surgery was well tolerated. There were no significant differences in anticipated or reported pain, or in medication use between cohorts. Significant differences in pain were noted with closure technique with complex surgical repairs generating the greatest pain across groups., Conclusion: Mohs micrographic surgery is well tolerated by patients, both with and without psychological comorbidities. Our results show no statistically significant differences, suggesting a limited role for preoperative screening as a tool to guide pain management after MMS., (Copyright © 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Verruca vulgaris is a prevalent childhood condition, but treatments are often poorly tolerated. Early treatment is preferable because delays increase the probability of pain, disfigurement, and failed eradication. However, typical treatments require multiple sessions without promising cure. We describe the use of a single intralesional treatment with the measles, mumps, and rubella (MMR) vaccine to successfully eliminate both local and distant recalcitrant warts as well as the proposed mechanism of this method. There are no other known reports of complete wart regression at distant untreated sites after a single intralesional MMR treatment.

Synthetic glycine coated 50 nm polystyrene nanoparticles (NP) (PS50G), unlike ambient NP, do not promote pulmonary inflammation, but instead, render lungs resistant to the development of allergic airway inflammation. In this study, we show that PS50G modulate the frequency and phenotype of regulatory T cells (Treg) in the lung, specifically increasing the proportion of tumor necrosis factor 2 (TNFR2) expressing Treg. Mice pre-exposed to PS50G, which were sensitized and then challenged with an allergen a month later, preferentially expanded TNFR2 + Foxp3 + Treg, which further expressed enhanced levels of latency associated peptide and cytotoxic T-lymphocyte associated molecule-4. Moreover, PS50G-induced CD103 + dendritic cell activation in the lung was associated with the proliferative expansion of TNFR2 + Foxp3 + Treg. These findings provide the first evidence that engineered NP can promote the selective expansion of maximally suppressing TNFR2 + Foxp3 + Treg and further suggest a novel mechanism by which NP may promote healthy lung homeostasis.

The incidence of obesity has risen to epidemic proportions in recent decades, most commonly attributed to an increasingly sedentary lifestyle, and a 'western' diet high in fat and low in fibre. Although non-allergic asthma is a well-established co-morbidity of obesity, the influence of obesity on allergic asthma is still under debate. Allergic asthma is thought to result from impaired tolerance to airborne antigens, so-called respiratory tolerance. We sought to investigate whether a diet high in fats affects the development of respiratory tolerance. Mice fed a high fat diet (HFD) for 8 weeks showed weight gain, metabolic disease, and alteration in gut microbiota, metabolites and glucose metabolism compared to age-matched mice fed normal chow diet (ND). Respiratory tolerance was induced by repeated intranasal (i.n.) administration of ovalbumin (OVA), prior to induction of allergic airway inflammation (AAI) by sensitization with OVA in alum i.p. and subsequent i.n. OVA challenge. Surprisingly, respiratory tolerance was induced equally well in HFD and ND mice, as evidenced by decreased lung eosinophilia and serum OVA-specific IgE production. However, in a pilot study, HFD mice showed a tendency for impaired activation of airway dendritic cells and regulatory T cells compared with ND mice after induction of respiratory tolerance. Moreover, the capacity of lymph node cells to produce IL-5 and IL-13 after AAI was drastically diminished in HFD mice compared to ND mice. These results indicate that HFD does not affect the inflammatory or B cell response to an allergen, but inhibits priming of Th2 cells and possibly dendritic cell and regulatory T cell activation.

Aim: To examine the impact of organisational factors on bullying among peers (i.e. horizontal) and its effect on turnover intentions among Canadian registered nurses (RNs)., Background: Bullying among nurses is an international problem. Few studies have examined factors specific to nursing work environments that may increase exposure to bullying., Methods: An Australian model of nurse bullying was tested among Canadian registered nurse coworkers using a web-based survey (n = 103). Three factors - misuse of organisational processes/procedures, organisational tolerance and reward of bullying, and informal organisational alliances - were examined as predictors of horizontal bullying, which in turn was examined as a predictor of turnover intentions. The construct validity of model measures was explored., Results: Informal organisational alliances and misuse of organisational processes/procedures predicted increased horizontal bullying that, in turn, predicted increased turnover intentions. Construct validity of model measures was supported., Conclusion: Negative informal alliances and misuse of organisational processes are antecedents to bullying, which adversely affects employment relationship stability., Implications for Nursing Management: The results suggest that reforming flawed organisational processes that contribute to registered nurses' bullying experiences may help to reduce chronically high turnover. Nurse leaders and managers need to create workplace processes that foster positive networks, fairness and respect through more transparent and accountable practices., (© 2014 John Wiley & Sons Ltd.)

Dermatologists perform many procedures that require acute pain control with local anesthesia and, in some cases, management of postoperative pain. Identifying early risk factors before a procedure can better prepare both the patient and provider anticipate acute postsurgical pain needs. Taking a multimodal, algorithmic approach to managing acute postsurgical pain in dermatology practice can effectively attenuate acute postsurgical paint and reduce patient opioid requirements., (Copyright © 2015 American Academy of Dermatology, Inc. All rights reserved.)

Activin A, a member of the TGF-β superfamily of cytokines, was originally identified as an inducer of follicle stimulating hormone release, but has since been ascribed roles in normal physiological processes, as an immunoregulatory cytokine and as a driver of fibrosis. In the last 10-15 years, it has also become abundantly clear that activin A plays an important role in the regulation of asthmatic inflammation and airway remodelling. This review provides a brief introduction to the activin A/TGF-β superfamily, focussing on the regulation of receptors and signalling pathways. We examine the contradictory evidence for generalized pro- vs. anti-inflammatory effects of activin A in inflammation, before appraising its role in asthmatic inflammation and airway remodelling specifically by evaluating data from both murine models and clinical studies. We identify key issues to be addressed, paving the way for safe exploitation of modulation of activin A function for treatment of allergic asthma and other inflammatory lung diseases., (© 2015 The Authors. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.)

Cystic fibrosis (CF) is the most common life-limiting genetically acquired respiratory disorder. Patients with CF have thick mucus obstructing the airways leading to recurrent infections, bronchiectasis and neutrophilic airway inflammation culminating in deteriorating lung function. Current management targets airway infection and mucus clearance, but despite recent advances in care, life expectancy is still only 40 years. We investigated whether activin A is elevated in CF lung disease and whether inhibiting activin A with its natural antagonist follistatin retards lung disease progression. We measured serum activin A levels, lung function and nutritional status in CF patients. We studied the effect of activin A on CF lung pathogenesis by treating newborn CF transgenic mice (β-ENaC) intranasally with the natural activin A antagonist follistatin. Activin A levels were elevated in the serum of adult CF patients, and correlated inversely with lung function and body mass index. Follistatin treatment of newborn β-ENaC mice, noted for respiratory pathology mimicking human CF, decreased the airway activin A levels and key features of CF lung disease including mucus hypersecretion, airway neutrophilia and levels of mediators that regulate inflammation and chemotaxis. Follistatin treatment also increased body weight and survival of β-ENaC mice, with no evidence of local or systemic toxicity. Our findings demonstrate that activin A levels are elevated in CF and provide proof-of-concept for the use of the activin A antagonist, follistatin, as a therapeutic in the long-term management of lung disease in CF patients.

Importance: The breakdown of previously inserted intravascular devices can lead to microemboli that can clinically mimic the symptoms of common disorders, such as senile purpura, and have subtle histologic findings. However, device failure can occur gradually and start months after placement. If not identified early, microemboli to noncutaneous sites can cause significant morbidity and mortality., Observations: A woman in her 70s presented 6 months after a complex aortic aneurysm repair with several large ecchymoses radiating from firm subcutaneous nodules on the buttocks, arms, and thighs. Skin biopsy specimens revealed extensive hemorrhage and a panniculitis with sparse, subtle, intra-arteriole, gray amorphous deposits that, on analysis by scanning electron microscopy with energy-dispersive radiography analysis and infrared spectrometry, were most consistent with a hydrophilic polymer. This type of hydrophilic polymer coats catheters and stents such as those used in aortic aneurysm repair., Conclusions and Relevance: This is an unusual case of microemboli from the polymer coating intra-arterial stents starting months after placement and causing a panniculitis. Prior observations show that polymers coating intravascular devices have the potential to break down gradually and long after the device's placement, but clinical consideration for delayed microembolization is underrecognized until catastrophic impairment or death.

Engineered nanoparticles (ENP), which could be composed of inorganic metals, metal oxides, metalloids, organic biodegradable and inorganic biocompatible polymers, are being used as carriers for vaccine and drug delivery. There is also increasing interest in their application as delivery agents for the treatment of a variety of lung diseases. Although many studies have shown ENP can be effectively and safely used to enhance the delivery of drugs and vaccines in the periphery, there is concern that some ENP could promote inflammation, with unknown consequences for lung immune homeostasis. In this study, we review research on the effects of ENP on lung immunity, focusing on recent studies using diverse animal models of human lung disease. We summarize how the inflammatory and immune response to ENP is influenced by the diverse biophysical and chemical characteristics of the particles including composition, size and mode of delivery. We further discuss newly described unexpected beneficial properties of ENP administered into the lung, where biocompatible polystyrene or silver nanoparticles can by themselves decrease susceptibility to allergic airways inflammation. Increasing our understanding of the differential effects of diverse types of nanoparticles on pulmonary immune homeostasis, particularly previously underappreciated beneficial outcomes, supports rational ENP translation into novel therapeutics for prevention and/or treatment of inflammatory lung disorders.

There is increasing interest in the use of engineered particles for biomedical applications, although questions exist about their proinflammatory properties and potential adverse health effects. Lung macrophages and dendritic cells (DC) are key regulators of pulmonary immunity, but little is known about their uptake of different sized particles or the nature of the induced immunological imprint. We investigated comparatively the immunological imprints of inert nontoxic polystyrene nanoparticles 50 nm in diameter (PS50G) and 500 nm in diameter (PS500G). Following intratracheal instillation into naive mice, PS50G were preferentially taken up by alveolar and nonalveolar macrophages, B cells, and CD11b(+) and CD103(+) DC in the lung, but exclusively by DC in the draining lymph node (LN). Negligible particle uptake occurred in the draining LN 2 h postinstillation, indicating that particle translocation does not occur via lymphatic drainage. PS50G but not PS500G significantly increased airway levels of mediators that drive DC migration/maturation and DC costimulatory molecule expression. Both particles decreased frequencies of stimulatory CD11b(+)MHC class II(hi) allergen-laden DC in the draining LN, with PS50G having the more pronounced effect. These distinctive particle imprints differentially modulated induction of acute allergic airway inflammation, with PS50G but not PS500G significantly inhibiting adaptive allergen-specific immunity. Our data show that nanoparticles are taken up preferentially by lung APC stimulate cytokine/chemokine production and pulmonary DC maturation and translocate to the lung-draining LN via cell-associated transport. Collectively, these distinctive particle imprints differentially modulate development of subsequent lung immune responses. These findings support the development of lung-specific particulate vaccines, drug delivery systems, and immunomodulators.

Nanoparticles (NP) possess remarkable adjuvant and carrier capacity, therefore are used in the development of various vaccine formulations. Our previous studies demonstrated that inert non-toxic 40-50 nm polystyrene NP (PS-NP) can promote strong CD8 T cell and antibody responses to the antigen, in the absence of observable inflammatory responses. Furthermore, instillation of PS-NP inhibited the development of allergic airway inflammation by induction of an immunological imprint via modulation of dendritic cell (DC) function without inducing oxidative stress in the lungs in mice. This is in contrast to many studies which show that a variety of ambient and man-made NP promote lung immunopathology, raising concerns generally about the safe use of NPs in biomedicine. Most NPs are capable of inducing inflammatory pathways in DC largely mediated by signalling via the extracellular signal-regulated kinase 1/2 (ERK). Herein, we investigate whether PS-NPs also activate ERK in DC in vitro. Our data show that PS-NP do not induce ERK activation in two different types of bone marrow derived (BM) DC cultures (expanded with GM-CSF or with GM-CSF together with IL-4). The absence of such signalling was not due to lack of PS-NP uptake by BM-DC as confirmed by confocal microscopy and flow cytometry. The process of NP uptake by DC usually initiates ERK signalling, suggesting an unusual uptake pathway may be engaged by PS-NPs. Indeed, data herein showns that uptake of PS-NP by BM-DC was substantially inhibited by phorbol myristate acetate (PMA) but not cytochalasin D (CCD), suggesting an uptake pathway utilising caveole for PS-NP. Together these data show that BM-DC take up PS-NP via a caveole-dependent pathway which does not trigger ERK signalling which may explain their efficient uptake by DC, without the concomitant activation of conventional inflammatory pathways., (Copyright © 2013. Published by Elsevier Inc.)

Background: Current pharmacotherapy is highly effective in the clinical management of the majority of patients with stable asthma, however severe asthma remains inadequately treated. Prevention of airway remodelling is a major unmet clinical need in the management of patients with chronic severe asthma and other inflammatory lung diseases. Accumulating evidence convincingly demonstrates that activin A, a member of the transforming growth factor (TGF)-β superfamily, is a key driver of airway inflammation, but its role in chronic asthmatic airway remodelling is ill-defined. Follistatin, an endogenously produced protein, binds activin A with high affinity and inhibits its bioactivity. The aim of this study was to test the potential of follistatin as a therapeutic agent to inhibit airway remodelling in an experimental model of chronic allergic airway inflammation., Methods: BALB/c mice were systemically sensitised with ovalbumin (OVA), and challenged with OVA intranasally three times a week for 10 weeks. Follistatin was instilled intranasally during allergen challenge., Results: Chronic allergen challenge induced mucus hypersecretion and subepithelial collagen deposition which persisted after cessation of challenge. Intranasal follistatin (0.05, 0.5, 5 µg) inhibited the airway remodelling and dose-dependently decreased airway activin A and TGF-β1, and allergen-specific T helper 2 cytokine production in the lung-draining lymph nodes. Follistatin also impaired the loss of TGF-β1 and activin RIB immunostaining in airway epithelium which occurred following chronic allergen challenge., Conclusions: These data demonstrate that follistatin attenuates asthmatic airway remodelling. Our findings point to the potential of follistatin as a therapeutic for prevention of airway remodelling in asthma and other inflammatory lung diseases.

Activin A, a member of the transforming growth factor-β superfamily of cytokines, is a critical controller of inflammation, immunity and fibrosis. It is rapidly released into the blood following a lipopolysaccharide challenge in experimental animals, through activation of the Toll-like receptor 4 signalling pathway. Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality. Likewise, high serum levels of activin A are predictive of death in patients with septicaemia. However, activin A has complex immunomodulatory actions. It is produced by inflammatory macrophages, but can regulate either pro- or anti-inflammatory responses in these cells, depending on their prior activation status. Activin A is also produced by Th2 cells, and stimulates antibody production by B cells and the development of regulatory T cells. Production of activin A during inflammatory responses stimulates fibrosis and tissue remodelling, and follistatin inhibits these actions of activin A. The modulation of activin by follistatin may represent an important therapeutic target for the modulation and amelioration of inflammatory and fibrotic disorders., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Nanoparticles are being developed for diverse biomedical applications, but there is concern about their potential to promote inflammation, particularly in the lung. Although a variety of ambient, anthropogenic and man-made nanoparticles can promote lung inflammation, little is known about the long-term immunomodulatory effects of inert noninflammatory nanoparticles. We previously showed polystyrene 50-nm nanoparticles coated with the neutral amino acid glycine (PS50G nanoparticles) are not inflammatory and are taken up preferentially by dendritic cells (DCs) in the periphery. We tested the effects of such nanoparticles on pulmonary DC function and the development of acute allergic airway inflammation. Surprisingly, exposure to PS50G nanoparticles did not exacerbate but instead inhibited key features of allergic airway inflammation including lung airway and parenchymal inflammation, airway epithelial mucus production, and serum allergen-specific IgE and allergen-specific Th2 cytokines in the lung-draining lymph node (LN) after allergen challenge 1 mo later. PS50G nanoparticles themselves did not induce lung oxidative stress or cardiac or lung inflammation. Mechanistically, PS50G nanoparticles did not impair peripheral allergen sensitization but exerted their effect at the lung allergen challenge phase by inhibiting expansion of CD11c(+)MHCII(hi) DCs in the lung and draining LN and allergen-laden CD11b(hi)MHCII(hi) DCs in the lung after allergen challenge. PS50G nanoparticles further suppressed the ability of CD11b(hi) DCs in the draining LN of allergen-challenged mice to induce proliferation of OVA-specific CD4(+) T cells. The discovery that a defined type of nanoparticle can inhibit, rather than promote, lung inflammation via modulation of DC function opens the door to the discovery of other nanoparticle types with exciting beneficial properties.

Introduction: Rural residence may reduce access to specialized mental health services. The objective of this study was to examine the role of rural residence in relation to service utilization. Using Canadian data collected in 2002, service use was examined as a function of the presence of anxiety or mood disorders and rural/urban residence. Use of four different types of professional mental health services was examined in relation to rural residence and additional demographic, social, and health status factors known to predict use of services., Methods: Data were obtained from Statistics Canada's Canadian Mental Health Survey Cycle 1.2. Rural residence was defined as living in a rural community with a population of 1000 or less. For all participants, associations between the presence of anxiety or mood disorders, rural/urban residence, and any service use or use of specialized mental health services (psychiatry and psychology) were examined. For participants who had used professional services, associations were examined between 17 predictor variables, including location of residence, and the use of four types of service providers (family doctor or GP; nurse, social worker, counsellor, or psychotherapist; psychiatrist; or psychologist). Predictors included demographic, social, and health status variables. Cross-tabulated counts and adjusted odds ratios with 99% confidence intervals based on bootstrapped variance estimates were used to evaluate predictors., Results: Among the total sample (n = 35 140), 7.9% had used professional mental health services in the previous year. Among people who were likely to have had anxiety or mood disorders, rural or urban residence was not differentially related to past-year use of any professional services or specialized mental health services. Multivariate logistic regression was used to model factors predicting past year use of four different types of professional services. Location of residence was not a significant predictor of service utilization. Age, sex, race, level of education, degree of psychological distress, chronicity of distress, and the presence of anxiety or mood disorders predicted type of service used., Conclusions: The notion that rural residence limits access to mental health services was not supported. Other demographic and health status indicators such as age, sex, race, education, distress, and type of illness were more important predictors of service utilization. However, null findings related to geographic residence must be interpreted cautiously due to the small sample of rural residents who sought mental health services. The mental health system in Canada must provide a variety of professional services in order to meet the preferences of diverse groups, and mental health specialists must find ways to adequately support general practice physicians and counsellors who provide mental health services.

Activin A is a member of the TGF-beta superfamily and plays a role in allergic inflammation and asthma pathogenesis. Recent evidence suggests that activin A regulates proinflammatory cytokine production and is regulated by inflammatory mediators. In a murine model of acute allergic airway inflammation, we observed previously that increased activin A concentrations in bronchoalveolar lavage (BAL) fluid coincide with Th2 cytokine production in lung-draining lymph nodes and pronounced mucus metaplasia in bronchial epithelium. We therefore hypothesized that IL-13, the key cytokine for mucus production, regulates activin A secretion into BAL fluid in experimental asthma. IL-13 increased BAL fluid activin A concentrations in naive mice and dose dependently induced activin A secretion from cultured human airway epithelium. A key role for IL-13 in the secretion of activin A into the BAL fluid during allergic airway inflammation was confirmed in IL-13-deficient mice. Eosinophils were not involved in this response because there was no difference in BAL fluid activin A concentrations between wild-type and eosinophil-deficient mice. Our data highlight an important role for IL-13 in the regulation of activin A intraepithelially and in BAL fluid in naive mice and during allergic airway inflammation. Given the immunomodulatory and fibrogenic effects of activin A, our findings suggest an important role for IL-13 regulation of activin A in asthma pathogenesis.

Success of hematopoietic cell transplantation (HCT) can vary by race, but the impact of socioeconomic status (SES) is not known. To evaluate the role of race and SES, we studied 6207 unrelated-donor myeloablative (MA) HCT recipients transplanted between 1995 and 2004 for acute or chronic leukemia or myelodysplastic syndrome (MDS). Patients were reported by transplant center to be White (n = 5253), African American (n = 368), Asian/Pacific-Islander (n = 141), or Hispanic (n = 445). Patient income was estimated from residential zip code at time of HCT. Cox regression analysis adjusting for other significant factors showed that African American (but not Asian or Hispanic) recipients had worse overall survival (OS) (relative-risk [RR] 1.47; 95% confidence interval [CI] 1.29-1.68, P < .001) compared to Whites. Treatment-related mortality (TRM) was higher in African Americans (RR 1.56; 95% CI 1.34-1.83, P < .001) and in Hispanics (RR 1.30; 95% CI 1.11-1.51, P = .001). Across all racial groups, patients with median incomes in the lowest quartile (<$34,700) had worse OS (RR 1.15; 95% CI 1.04-1.26, P = .005) and higher risks of TRM (RR 1.21; 1.07-1.36, P = .002). Inferior outcomes among African Americans are not fully explained by transplant-related factors or SES. Potential other mechanisms such as genetic polymorphisms that have an impact on drug metabolism or unmeasured comorbidities, socioeconomic factors, and health behaviors may be important. Low SES, regardless of race, has a negative impact on unrelated donor HCT outcomes.

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8 x 10(-5)), establishing a novel phenotype for this genetic variant., Competing Interests: The authors have declared that no competing interests exist.

Immunotherapy and preventative cancer vaccines offer the hope of controlling cancer in humans with few of the undesirable side effects associated with current chemotherapy-based methods. Particulate vaccines are effectively taken up by dendritic cells, inducing both T-cell and antibody responses. Virus-like particles (VLPs) have shown preventive efficacy against cervical cancer. Herein we review a range of leading particle-based vaccine approaches: VLPs, immunostimulating complexes, liposomes, synthetic nanoparticles and microparticles (both biocompatible and biodegradable, such as polylactide-co-glycolides and poly[D,L-lactic-co-glycolic] acid). Immune efficacy, regulatory and safety issues, as well the application of immunotherapeutics to immunosuppressed patients with high levels of Tregs are also discussed. We argue that developmental issues (cost and intellectual property lifespan) and the lack of reliable preclinical animal models, rather than the lack of innovative vaccine approaches, currently present a major obstacle to rapid and effective vaccine development.

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped across >or= 1322 single nucleotide polymorphisms that were pre-selected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p < 10(-12)). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained approximately 20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications.

Three experimental studies examined the relationship between altruistic behavior and the emergence of status hierarchies within groups. In each study, group members were confronted with a social dilemma in which they could either benefit themselves or their group. Study 1 revealed that in a reputation environment when contributions were public, people were more altruistic. In both Studies 1 and 2, the most altruistic members gained the highest status in their group and were most frequently preferred as cooperative interaction partners. Study 3 showed that as the costs of altruism increase, the status rewards also increase. These results support the premise at the heart of competitive altruism: Individuals may behave altruistically for reputation reasons because selective benefits (associated with status) accrue to the generous.

Background: Activin A is a member of the transforming growth factor-beta superfamily which is directly implicated in airway structural change and inflammation in asthma. In vitro, the biological effects of activin A are neutralized by the soluble binding protein follistatin., Objective: To determine the potential of endogenous follistatin to suppress activin A in vivo by analysing their relative tissue and kinetic compartmentalization during the effector phase of subchronic Th2-driven mucosal inflammation in a murine model of allergic asthma., Methods: Eosinophilic mucosal inflammation was elicited by triggering Th2 recall responses by antigen challenge in ovalbumin-sensitized BALB/c mice. The kinetics and distribution of activin A and follistatin protein were assessed in lung tissue and bronchoalveolar lavage fluid and measured in relation to airway eosinophilia, goblet cell metaplasia and Th2 cytokine production in mediastinal lymph nodes., Results: Follistatin was released concurrently with activin A suggesting it acts as an endogenous regulator: peak BAL concentrations coincided with maximal airway eosinophilia, and frequency of IL-4, IL-5 and IL-13 producing cells in mediastinal lymph nodes but induction lagged behind the onset of inflammation. Follistatin and activin A immunoreactivity were lost in airway epithelial cells in parallel with goblet cell metaplasia. Exogenous follistatin inhibited the allergen-specific Th2 immune response in mediastinal lymph nodes and mucus production in the lung., Conclusion: Follistatin is preformed in the normal lung and released in concert with activin A suggesting it serves as an endogenous regulator. Disturbance of the fine balance between activin A and its endogenous inhibitor follistatin may be a determinant of the severity of allergic inflammation or tissue phenotypic shift in asthma.

Intranasal infection of mice with murine gammaherpesvirus 68 causes a dramatic increase in numbers of activated CD8(+) T cells in the blood, analogous in many respects to EBV-induced infectious mononucleosis in humans. In the mouse model, this lymphocytosis has two distinct components: an early, conventional virus-specific CD8(+) T cell response, and a later response characterized by a dramatic increase among CD8(+) T cells that bear Vbeta4(+) TCRs. We previously demonstrated that Vbeta4(+)CD8(+) T cells recognize an uncharacterized ligand expressed on latently infected B cells in an MHC-independent manner. The frequency of Vbeta4(+)CD8(+) T cells increases dramatically following the peak of viral latency in the spleen. In the current studies, we show that elevated Vbeta4(+)CD8(+) T cell levels are sustained long-term in persistently infected mice, apparently a consequence of continued ligand expression. In addition, we show that Vbeta4(+)CD8(+) T cells can acquire effector functions, including cytotoxicity and the capacity to secrete IFN-gamma, although they have an atypical activation profile compared with well-characterized CD8(+) T cells specific for conventional viral epitopes. The characteristics of Vbeta4(+)CD8(+) T cells (potential effector function, stimulation by latently infected B cells, and kinetics of expansion) suggested that this dominant T cell response plays a key role in the immune control of latent virus. However, Ab depletion and adoptive transfer studies show that Vbeta4(+)CD8(+) T cells are not essential for this function. This murine model of infection may provide insight into the role of unusual populations of activated T cells associated with persistent viral infections.

Chronic myelomonocytic leukemia (CMML) is a relatively rare, heterogeneous syndrome classified as a myelodysplastic syndrome according to the French-American-British classification system. The patient's presenting symptom was a pigmented skin nodule that, although common for cases of acute monoblastic leukemia, is peculiar for CMML. This case should increase awareness of the inclusion of CMML in the differential diagnosis of a discolored nodule and highlight the clinicopathologic considerations and therapeutic challenges consistent with the diagnosis of CMML.

Allergen-specific immunotherapy is a clinically proven effective treatment for many allergic diseases, including asthma; however, it is not currently available for latex allergy because of the high risk of anaphylaxis. There is, therefore, a crucial need for an animal model of latex allergy in which to develop effective immunotherapy. Previous mouse models of latex allergy either did not characterize the allergic pulmonary immune response or used crude latex extracts, making it difficult to quantify the contribution of individual proteins and limiting their usefulness for developing specific immunotherapy. We immunized mice with recombinant Hev b 5, a defined major latex allergen, or latex glove protein extract, representing the range of occupationally encountered processed latex allergens. The immune response was compared with that seen in ovalbumin-immunized mice. Immunization with Hev b 5 or glove extract elicits hallmarks of allergic pulmonary Th2-type immune responses, comparable to those for ovalbumin, including (1) serum antigen-specific IgE, (2) an eosinophilic inflammatory infiltrate in the lung, (3) increased interleukin-5 in lung bronchoalveolar lavage fluid, and (4) mucus hypersecretion by epithelial cells in the lung airways. This mouse model will aid the development of potentially curative treatments for latex-sensitized individuals, including those with occupational asthma.

Objective: To evaluate predictors of somatization and pain reactivity in childhood., Methods: Facial expressions of children undergoing inoculation were scored for pain reactivity. Measures of temperament, pain experience, pain models, parental behavior, and parental ability to decode pain were examined for their ability to predict pain reactivity and somatization in a structural modeling analysis., Results: Pain reactivity was associated positively with parental reports of their child's somatization. Child temperament, previous negative experiences with medical procedures, and maternal responses to their children's pain were positively associated with pain reactivity., Conclusions: Temperament and pain experience may play a role in children's pain reactivity, and reactivity may contribute to the development of somatization. Although the model that guided the analysis proved to be a reasonable description of the outcomes, several anticipated relationships were not significant. We discuss implications for a refined model of somatization and for early identification and prevention.

The involvement of glucocorticoid receptor (GR) signaling in T cell development is highly controversial, with several studies for and against. We have previously demonstrated that GR(-/-) mice, which usually die at birth because of impaired lung development, exhibit normal T cell development, at least in embryonic mice and in fetal thymus organ cultures. To directly investigate the role of GR signaling in adult T cell development, we analyzed the few GR(-/-) mice that occasionally survive birth, and irradiated mice reconstituted with GR(-/-) fetal liver precursors. All thymic and peripheral T cells, as well as other leukocyte lineages, developed and were maintained at normal levels. Anti-CD3-induced cell death of thymocytes in vitro, T cell repertoire heterogeneity and T cell proliferation in response to anti-CD3 stimulation were normal in the absence of GR signaling. Finally, we show that metyrapone, an inhibitor of glucocorticoid synthesis (commonly used to demonstrate a role for glucocorticoids in T cell development), impaired thymocyte development regardless of GR genotype indicating that this reagent inhibits thymocyte development in a glucocorticoid-independent fashion. These data demonstrate that GR signaling is not required for either normal T cell development or peripheral maintenance in embryonic or adult mice.

Epstein-Barr virus (EBV) is known to be involved in the majority of patients who develop post-transplant lymphoproliferative disorder after solid organ transplant. We conducted a retrospective study to determine the utility of qualitative and quantitative Epstein-Barr virus polymerase chain reaction (PCR) for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Peripheral blood leukocytes obtained from 35 adult solid organ transplant patients consecutively referred for evaluation of possible post-transplant lymphoproliferative disorder, were tested by EBV PCR at the time of initial evaluation and at time points thereafter. Eighteen of 35 (51%) patients were ultimately diagnosed with post-transplant lymphoproliferative disorder by tissue biopsy. Fifteen of 18 (83%) patients were found to have EBER-1 positive tumors by in situ hybridization. EBV PCR was positive in 7 of 15 patients, suggesting a sensitivity of 39%. Seventeen patients without post-transplant lymphoproliferative disorder and three with EBER-1 negative post-transplant lymphoproliferative disorder all had negative EBV PCR tests, suggesting a specificity of 100%. We observed that declines in EBV DNA load were associated with response to therapeutic interventions, such as reduction in immunosuppression, rituximab therapy and chemotherapy. We conclude that peripheral blood EBV PCR may have a role in the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients.