Microglial recruitment of IL-1ß-producing monocytes to brain endothelium causes stress-induced anxiety.

Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine interleukin-1ß (IL-1ß). Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1+ neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1ß signaling by caspase-1KO specifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1ß. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1ß-producing monocytes, which stimulated brain endothelial IL-1R1. Thus, monocyte IL-1ß production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders.

Peripheral and central effects of repeated social defeat stress: monocyte trafficking, microglial activation, and anxiety.

The development and exacerbation of depression and anxiety are associated with exposure to repeated psychosocial stress. Stress is known to affect the bidirectional communication between the nervous and immune systems leading to elevated levels of stress mediators including glucocorticoids (GCs) and catecholamines and increased trafficking of proinflammatory immune cells. Animal models, like the repeated social defeat (RSD) paradigm, were developed to explore this connection between stress and affective disorders. RSD induces activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis activation, increases bone marrow production and egress of primed, GC-insensitive monocytes, and stimulates the trafficking of these cells to tissues including the spleen, lung, and brain. Recently, the observation that these monocytes have the ability to traffic to the brain perivascular spaces and parenchyma have provided mechanisms by which these peripheral cells may contribute to the prolonged anxiety-like behavior associated with RSD. The data that have been amassed from the RSD paradigm and others recapitulate many of the behavioral and immunological phenotypes associated with human anxiety disorders and may serve to elucidate potential avenues of treatment for these disorders. Here, we will discuss novel and key data that will present an overview of the neuroendocrine, immunological and behavioral responses to social stressors.

Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain.

Repeated social defeat (RSD) in mice causes myeloid cell trafficking to the brain that contributes to the development of prolonged anxiety-like behavior. Myeloid cell recruitment following RSD occurs in regions where neuronal and microglia activation is observed. Thus, we hypothesized that crosstalk between neurons, microglia, and endothelial cells contributes to brain myeloid cell trafficking via chemokine signaling and vascular adhesion molecules. Here we show that social defeat caused an exposure- and brain region-dependent increase in several key adhesion molecules and chemokines involved in the recruitment of myeloid cells. For example, RSD induced distinct patterns of adhesion molecule expression that may explain brain region-dependent myeloid cell trafficking. VCAM-1 and ICAM-1 mRNA expression were increased in an exposure-dependent manner. Furthermore, RSD-induced VCAM-1 and ICAM-1 protein expression were localized to the vasculature of brain regions implicated in fear and anxiety responses, which spatially corresponded to previously reported patterns of myeloid cell trafficking. Next, mRNA expression of additional adhesion molecules (E- and P-selectin, PECAM-1) and chemokines (CXCL1, CXCL2, CXCL12, CCL2) were determined in the brain. Social defeat induced an exposure-dependent increase in mRNA levels of E-selectin, CXCL1, and CXCL2 that increased with additional days of social defeat. While CXCL12 was unaffected by RSD, CCL2 expression was increased by six days of social defeat. Last, comparison between enriched CD11b(+) cells (microglia/macrophages) and enriched GLAST-1(+)/CD11b(-) cells (astrocytes) revealed RSD increased mRNA expression of IL-1ß, CCL2, and CXCL2 in microglia/macrophages but not in astrocytes. Collectively, these data indicate that key mediators of leukocyte recruitment were increased in the brain vasculature following RSD in an exposure- and brain region-dependent manner.

A randomised trial to evaluate the self-administered standardised chronic respiratory questionnaire.

The original chronic respiratory questionnaire (CRQ), one of the most widely used measures of health-related quality of life (HRQL) in chronic respiratory disease (CRD), is traditionally interviewer administered (IA) and includes an individualised dyspnoea domain. The present authors studied the impact of self-administered (SA) and standardised dyspnoea questions on CRQ measurement properties. In a factorial design multicentre trial, 177 patients with CRD (mean age 67.7 yrs; mean forced expiratory volume in one second per cent predicted 44.6%) were randomised to CRQ-IA (n = 86) or CRQ-SA (n = 91), and to initially complete the standardised or individualised items before and after respiratory rehabilitation. While maintaining validity, the CRQ-SA proved more responsive to changes in HRQL than the CRQ-IA in all domains. Compared with the standardised dyspnoea domain, the individualised dyspnoea domain indicated greater responsiveness. The correlations of baseline scores and change scores with other HRQL instruments indicated good validity of the CRQ-SA. In conclusion, self-administration and standardisation of the chronic respiratory questionnaire maintains validity and responsiveness relative to the interviewer-administered chronic respiratory questionnaire. These results challenge the assumption that interviewer-administered questionnaires are superior to self-administered questionnaires in older patients with chronic respiratory disease.

Development and testing of formal protocols for oxygen prescribing.

The absence of standardized assessment protocols with well- defined measurement properties limits comparison of outcomes among those receiving long-term oxygen therapy (LTOT). We describe simple protocols for a hospital test, a simulated home test, and an actual home test, their reliability and relationship to each other. Stable patients with exercise hypoxemia participated. In 74 patients who completed four exercise tests, correlations between tests ranged from 0.85 to 0.78. Of these 27.0% had the same prescription from all four tests. In 46% prescriptions were within 1 L/ min and in 27% within 2 L/min. During exercise the hospital tests suggested slightly higher oxygen prescriptions than did the simulated home tests (2.5 L/min versus 2.0 L/min, p < 0.001). In 23 patients who participated in actual home assessments, the correlations between the home test, the hospital, and the simulated home tests were 0.22 (95% CI -0.24 to 0.67) and 0.27 (95% CI -0.18 to 0.72). In conclusion, standardizing tests for the assessment of LTOT is important. We describe simple hospital and simulated home tests that are reproducible, easy to carry out, and correlate well with each other.

Appropriateness of domiciliary oxygen delivery.

OBJECTIVE: Almost every country in the developed world has a domiciliary oxygen program. Whether recipients meet program criteria has not been rigorously studied. DESIGN: Cross-sectional survey. PARTICIPANTS: Two hundred thirty-seven patients receiving domiciliary oxygen in the Ontario Ministry of Health Home Oxygen Program (HOP). METHODS: A respiratory therapist visited the patients' homes and administered questionnaires, obtained resting arterial blood gas measurements, and conducted a standardized home exercise test while monitoring oxygen saturation using an oximeter. MEASURES OF OUTCOME: We evaluated the extent to which patients met HOP criteria that are based on the inclusion criteria of randomized trials showing the life-prolonging effects of domiciliary oxygen. We also assessed the extent to which the patients' oxygen prescription was consistent with the results of rest and exercise testing. RESULTS: Ninety-six of 237 participants (40.5%; 95% confidence interval, 34.3 to 46.8) did not meet criteria for home oxygen. Patients aged < or = 70 years were more likely to meet criteria (71 of 105 patients; 67.9%) than those > 70 years old (70 of 132 patients; 53.0%). The proportion of patients meeting criteria was similar whether the referring physician was a specialist (71 of 112 patients; 62.5%) or a primary-care physician (69 of 123 patients; 56. 1%). A very important health benefit from oxygen was identified among 82% of those who met criteria and 88% of those who did not. Patients received higher flow rates than our criteria suggested were appropriate. Agreement between the independently assessed oxygen prescription at rest and the patients' report of oxygen use was extremely poor (chance-corrected agreement [kappa], 0.17), as was agreement concerning optimal exercise flow rates (kappa, 0.26). CONCLUSIONS: Current procedures for administration and reimbursement of home oxygen result in a large proportion of recipients not meeting criteria, as well as the prescription of excessive oxygen flow rates. These results are likely to apply to many jurisdictions and suggest a large potential for more efficient resource allocation.

Intubation and mechanical ventilation for COPD: development of an instrument to elicit patient preferences.

BACKGROUND: Whether to simply provide palliative care or to intubate and use mechanical ventilation (MV) in a patient with severe COPD in acute respiratory failure is a difficult decision. The outcome of MV cannot be accurately predicted. Some patients cannot be weaned from the ventilator; those who are weaned often return to chronic severe respiratory disability. It is important that patients participate in this decision, but assistance is required. To address these issues, we developed and pilot-tested an aid to assist patients with MV decisions. METHODS: A scenario-based decision aid was developed consisting of an audiocassette and a booklet describing intubation and MV and its possible outcomes. We used a probability tradeoff technique to elicit the patients' preferences and a decisional conflict scale to evaluate satisfaction. RESULTS: With the assistance of the decision aid, all patients (10 men and 10 women) reached a decision. Two men and all 10 women declined MV. Mean decisional conflict was low (2.2 of a possible 5; SD, 0.9). At 1 year, only two patients (11%) had changed their decision. The agreement between physicians and patients was 65%; between next-of-kin and patients, there was uniform disagreement. CONCLUSION: With the decision aid, stable decisions were made with satisfaction and confidence. Proxy decisions were incongruent, especially when made by family members. The strong gender effect should be further investigated. We suggest that the COPD decision aid be further tested in a community clinical setting.

Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice.

STUDY OBJECTIVE: To compare quality of life and exercise capacity (primary aim), and drug usage (secondary aim), between groups of patients with irreversible chronic airflow limitation (CAL) who were undergoing theophylline Theo-Dur; Key Pharmaceuticals; Kenilworth, NJ) therapy guided by n of 1 trials or standard practice. DESIGN: Randomized study of n of 1 trials vs standard practice. SETTING: Outpatient departments in two tertiary care centers. PATIENTS: Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators, and who were unsure whether theophylline was helping them following open treatment, were randomized into n of 1 trials (N=34) or standard practice. INTERVENTIONS: The n of 1 trials (single-patient, randomized, double-blind, multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo) followed published guidelines. Standard practice patients stopped taking theophylline but resumed it if their dyspnea worsened. If their dyspnea then improved, theophylline was continued. In both groups, a decision about continuing or stopping the use of theophylline was made within 3 months of randomization. MEASUREMENTS AND RESULTS: The primary outcomes (the chronic respiratory disease questionnaire [CRQ] and 6-min walk) were measured at baseline, 6 months, and 12 months by personnel blinded to treatment group allocation. No between-group differences (n of 1 minus standard practice) were seen in within-group changes over time (1 year minus baseline) in the CRQ Physical Function score (point estimate on the difference, -2.8; 95% confidence limits [CLs], -8.2, 2.5), CRQ Emotional Function score (point estimate on the difference, 0.5; 95% CLs, -4.7, 5.7), or 6-min walk (point estimate on the difference, 8 m; 95% CLs, -26, 44 m). No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months. In 7 of 34 n of 1 trial patients (21%), dyspnea improved during theophylline treatment compared with placebo treatment. CONCLUSIONS: Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity, or reduce drug usa e, over 1 year compared to standard practice. Under the objective conditions of an n of 1 trial, 21% of patients with CAL responded to theophylline. There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators, but the use of n of 1 trials to guide this decision did not yield clinically important advantages over standard practice.

Superior vena cava obstruction secondary to mediastinal lymphadenopathy in a patient with cystic fibrosis.

Superior vena cava (SVC) obstruction most often is a complication of malignant tumors such as lung cancer or lymphoma. The common use of long-term indwelling central venous catheters also has added to the prevalence of SVC obstruction. This report describes the first case of SVC obstruction in a patient with cystic fibrosis due to extrinsic compression from benign reactive mediastinal lymphadenopathy. Although in these circumstances intravascular thrombosis should be ruled out, extrinsic compression from mediastinal lymphadenopathy should be considered.

Deciding about mechanical ventilation in end-stage chronic obstructive pulmonary disease: how respirologists perceive their role.

OBJECTIVE: To determine when respirologists approach patients with end-stage chronic obstructive pulmonary disease (COPD) to decide about the use of mechanical ventilation, what information they provide to patients and how they provide it. DESIGN: Self-administered national survey. PARTICIPANTS: All Canadian specialists in respiratory medicine; of 401 eligible respirologists, 279 (69.6%) returned a completed questionnaire. OUTCOME MEASURES: Timing and content of doctor-patient discussions regarding mechanical ventilation; physicians' perception of their level of involvement in the decision-making process; and patient and physician characteristics that may influence decisions. RESULTS: Discussions were reported to occur most often at advanced stages of COPD: when the patient's dyspnea was severe (reported by 235 [84.2%] of the respondents) or when the patient's forced expiratory volume in the first second was 30% or less than predicted value (reported by 210 [75.3%]). A total of 120 respondents (43.0%) stated that they discuss mechanical ventilation with 40% or less of their COPD patients before an exacerbation necessitates ventilatory support. Most (154 [55.2%]) described the decision-making process as a collaboration between patient and physician; 83 (29.7%) reported that the patient decides after he or she has considered the physician's opinion. Over half (148 [53.0%]) of the respondents indicated that they occasionally, often or always modify the information provided to patients in order to influence their decision about mechanical ventilation. CONCLUSIONS: Discussions with COPD patients concerning end-of-life decisions about mechanical ventilation are reported to occur in advanced stages of the disease or not at all, with patients' input where possible. Information presented to patients is often modified in order to influence the decision. Future studies should explore ways to involve patients further in the decision-making process and to improve the process for both patients and physicians.

Role of central respiratory muscle fatigue in endurance exercise in normal subjects.

The role of central respiratory muscle fatigue in determining endurance time (ET) of steady-state ergometry, ventilation (VE), and breathing pattern during exhaustive submaximal exercise is not known. Six normal subjects exercised on a cycle ergometer to exhaustion at 72-82% of maximal power output on three occasions. During the second test, inspiratory muscle load was reduced (approximately 50% of baseline load) for all but the last 3 min of exercise. ET was determined, and VE, tidal volume (VT), respiratory rate (f), and sense of breathing effort (Borg scale) were assessed at different points during the assisted exercise and compared with the values obtained at the same time in identical tests without assist, carried out before and after the assisted test (different days). Borg scale rating was less and there was a nonsignificant trend for VT and VE to be higher and for f to be lower when the assist was in place than at the same time during the unassisted runs. In the last 3 min of exercise, when the respiratory load was comparable (assist removed) but ventilatory work history was different, there were no significant differences in sense of respiratory effort, VE, VT, or f between the experimental and control tests, and ET was also similar. We conclude that central respiratory muscle fatigue plays no role in determining ET, sense of respiratory effort, or breathing pattern in normal subjects during exhaustive submaximal exercise.

Orbital panniculitis as the initial manifestation of systemic lupus erythematosus.

Inflammation of the fat in lupus erythematosus also known as lupus erythematosus profundus (panniculitis) is a rare clinical entity. As the presenting feature of lupus, it is even more unusual. In this report, we describe an elderly woman who presented with an orbital mass infiltrate as the initial manifestation of lupus that had the classical histological features of lupus panniculitis.

Phylogenetic implications of comparative primate growth rates.

Growth data from a number of species of Old and New World primates have been analyzed by calculating instantaneous relative growth rates. Species discussed are the New World species Saimiri sciureus and Saguinus nigricollis, and the Old World species Pan troglodytes and Macaca mulatta. The analysis of the perinatal growth data indicated that differences in relative growth rates are present during early periods of growth. More specifically, it was found that the closer taxonomically a species is to man the greater the deceleration of growth during the first postnatal year. It is suggested that this may be a general primate trend.