George W. Reed

Identification of a key pathway required for the sterile inflammatory response triggered by dying cells

Dying cells stimulate inflammation, and this response is thought to contribute to the pathogenesis of many diseases. Very little has been known, however, about how cell death triggers inflammation. We found here that the acute neutrophilic inflammatory response to cell injury requires the signaling protein myeloid differentiation primary response gene 88 (Myd88). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor 2 (Tlr2) and Tlr4 and normal responses in mice lacking Tlr1, Tlr3, Tlr6, Tlr7, Tlr9, Tlr11 or the interleukin-18 receptor (IL-18R). However, mice lacking IL-1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL-1α, and IL-1R function was required on non–bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL-1R–Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggest that inhibiting the IL-1R–Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.

MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals

While it is known that monosodium urate (MSU) crystals cause the disease gout, the mechanism by which these crystals stimulate this inflammatory condition has not been clear. Here we find that the Toll/IL-1R (TIR) signal transduction adaptor myeloid differentiation primary response protein 88 (MyD88) is required for acute gouty inflammation. In contrast, other TIR adaptor molecules, TIRAP/Mal, TRIF, and TRAM, are not required for this process. The MyD88-dependent TLR1, -2, -4, -6, -7, -9, and -11 and IL-18 receptor (IL-18R) are not essential for MSU-induced inflammation. Moreover, MSU does not stimulate HEK cells expressing TLR1-11 to activate NF-kappaB. In contrast, mice deficient in the MyD88-dependent IL-1R showed reduced inflammatory responses, similar to those observed in MyD88-deficient mice. Similarly, mice treated with IL-1 neutralizing antibodies also showed reduced MSU-induced inflammation, demonstrating that IL-1 production and IL-1R activation play essential roles in MSU-triggered inflammation. IL-1R deficiency in bone marrow-derived cells did not affect the inflammatory response; however, it was required in non-bone marrow-derived cells. These results indicate that IL-1 is essential for the MSU-induced inflammatory response and that the requirement of MyD88 in this process is primarily through its function as an adaptor molecule in the IL-1R signaling pathway.

Evaluation of a Live, Cold-Passaged, Temperature-Sensitive, Respiratory Syncytial Virus Vaccine Candidate in Infancy

A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.

Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis

Objective To examine the association of cardiovascular events with tumour necrosis factor (TNF) α antagonist use compared with non-biological disease-modifying antirheumatic drug (DMARD) utilisation in patients with rheumatoid arthritis (RA). Methods The study population included 10 156 patients enrolled in the Consortium of Rheumatology Researchers of North America RA registry. Three study cohorts were defined based on three mutually exclusive drug use categories, including TNF antagonists, methotrexate and other non-biological DMARDs. HR were calculated adjusting for cardiovascular risk factors, RA disease characteristics and prednisone use. The primary study outcome was a composite of non-fatal myocardial infarction (MI), transient ischaemic attack (TIA) or stroke and cardiovascular-related death. Results There were 88 cardiovascular events, including 26 MI, 45 TIA/strokes and 17 cardiovascular-related deaths. After adjusting for age, gender, cardiovascular risk factors and RA disease characteristics, patients using a TNF antagonist experienced a reduced risk of the primary composite cardiovascular endpoint (HR 0.39, 95% CI 0.19 to 0.82) compared with users of non-biological DMARDs. Methotrexate was not associated with a reduced risk (HR 0.94, 95% CI 0.49 to 1.80). Prednisone use was associated with a dose-dependent increased risk (p=0.04). The risk reduction associated with TNF antagonists was also observed for non-fatal cardiovascular events (HR 0.35, 95% CI 0.16 to 0.74). Conclusion TNF antagonist use was associated with a reduced risk of cardiovascular events in patients with RA.

Mindfulness, spirituality, and health-related symptoms.

OBJECTIVE Although the relationship between religious practice and health is well established, the relationship between spirituality and health is not as well studied. The objective of this study was to ascertain whether participation in the mindfulness-based stress reduction (MBSR) program was associated with increases in mindfulness and spirituality, and to examine the associations between mindfulness, spirituality, and medical and psychological symptoms. METHODS Forty-four participants in the University of Massachusetts Medical Schools MBSR program were assessed preprogram and postprogram on trait (Mindful Attention and Awareness Scale) and state (Toronto Mindfulness Scale) mindfulness, spirituality (Functional Assessment of Chronic Illness Therapy--Spiritual Well-Being Scale), psychological distress, and reported medical symptoms. Participants also kept a log of daily home mindfulness practice. Mean changes in scores were computed, and relationships between changes in variables were examined using mixed-model linear regression. RESULTS There were significant improvements in spirituality, state and trait mindfulness, psychological distress, and reported medical symptoms. Increases in both state and trait mindfulness were associated with increases in spirituality. Increases in trait mindfulness and spirituality were associated with decreases in psychological distress and reported medical symptoms. Changes in both trait and state mindfulness were independently associated with changes in spirituality, but only changes in trait mindfulness and spirituality were associated with reductions in psychological distress and reported medical symptoms. No association was found between outcomes and home mindfulness practice. CONCLUSIONS Participation in the MBSR program appears to be associated with improvements in trait and state mindfulness, psychological distress, and medical symptoms. Improvements in trait mindfulness and spirituality appear, in turn, to be associated with improvements in psychological and medical symptoms.

Altruistic social interest behaviors are associated with better mental health

Objective This study investigated whether altruistic social interest behaviors such as engaging in helping others were associated with better physical and mental health in a stratified random sample of 2016 members of the Presbyterian Church throughout the United States. Methods Mailed questionnaires evaluated giving and receiving help, prayer activities, positive and negative religious coping, and self-reported physical and mental health. Results Multivariate regression analysis revealed no association between giving or receiving help and physical functioning, although the sample was highly skewed toward high physical functioning. Both helping others and receiving help were significant predictors of mental health, after adjusting for age, gender, stressful life events, income, general health, positive and negative religious coping, and asking God for healing (R2 = .27). Giving help was a more important predictor of better reported mental health than receiving help, and feeling overwhelmed by others’ demands was an independent predictor of worse mental health in the adjusted model. Significant predictors of giving help included endorsing more prayer activities, higher satisfaction with prayer life, engaging in positive religious coping, age, female gender, and being a church elder. Frequency of prayer and negative religious coping were not related to giving help. Conclusions Helping others is associated with higher levels of mental health, above and beyond the benefits of receiving help and other known psychospiritual, stress, and demographic factors. The links between these findings and response shift theory are discussed, and implications for clinical interventions and future research are described.

Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity

Background Cardiovascular (CV) disease has a major impact on patients with rheumatoid arthritis (RA), however, the relative contributions of traditional CV risk factors and markers of RA severity are unclear. The authors examined the relative importance of traditional CV risk factors and RA markers in predicting CV events. Methods A prospective longitudinal cohort study was conducted in the setting of the CORRONA registry in the USA. Baseline data from subjects with RA enrolled in the CORRONA registry were examined to determine predictors of CV outcomes, including myocardial infarction, stroke or transient ischemic attack. Possible predictors were of two types: traditional CV risk factors and markers of RA severity. The discriminatory value of these variables was assessed by calculating the area under the receiver operating characteristic curve (c-statistic) in logistic regression. The authors then assessed the incidence rate for CV events among subjects with an increasing number of traditional CV risk factors and/or RA severity markers. Results The cohort consisted of 10 156 patients with RA followed for a median of 22 months. The authors observed 76 primary CV events during follow-up for a composite event rate of 3.98 (95% CI 3.08 to 4.88) per 1000 patient-years. The c-statistic improved from 0.57 for models with only CV risk factors to 0.67 for models with CV risk factors plus age and gender. The c-statistic improved further to 0.71 when markers of RA severity were also added. The incidence rate for CV events was 0 (95% CI 0 to 5.98) for persons without any CV risk factors or markers of RA severity, while in the group with two or more CV risk factors and three or more markers of RA severity the incidence was 7.47 (95% CI 4.21 to 10.73) per 1000 person-years. Conclusions Traditional CV risk factors and markers of RA severity both contribute to models predicting CV events. Increasing numbers of both types of factors are associated with greater risk.

Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry

Objective: To examine the association of methotrexate (MTX) and tumour necrosis factor (TNF) antagonists with the risk of infectious outcomes including opportunistic infections in patients with rheumatoid arthritis (RA). Methods: Patients with RA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) registry prescribed MTX, TNF antagonists or other disease-modifying antirheumatic drugs (DMARDs) were included. The primary outcomes were incident overall and opportunistic infections. Incident rate ratios were calculated using generalised estimating equation Poisson regression models adjusted for demographics, comorbidities and RA disease activity measures. Results: A total of 7971 patients with RA were followed. The adjusted rate of infections per 100 person-years was increased among users of MTX (30.9, 95% CI 29.2 to 32.7), TNF antagonists (40.1, 95% CI 37.0 to 43.4) and a combination of MTX and TNF antagonists (37.1, 95% CI 34.9 to 39.3) compared with users of other non-biological DMARDs (24.5, 95% CI 21.8 to 27.5). The adjusted incidence rate ratio (IRR) was increased in patients treated with MTX (IRR 1.30, 95% CI 1.12 to 1.50) and TNF antagonists (IRR 1.52, 95% CI 1.30 to 1.78) compared with those treated with other DMARDs. TNF antagonist use was associated with an increased risk of opportunistic infections (IRR 1.67, 95% CI 0.95 to 2.94). Prednisone use was associated with an increased risk of opportunistic infections (IRR 1.63, 95% CI 1.20 to 2.21) and an increased risk of overall infection at doses >10 mg daily (IRR 1.30, 95% CI 1.11 to 1.53). Conclusions: MTX, TNF antagonists and prednisone at doses >10 mg daily were associated with increased risks of overall infections. Low-dose prednisone and TNF antagonists (but not MTX) increased the risk of opportunistic infections.

Epidemiology and Clinical Impact of Parainfluenza Virus Infections in Otherwise Healthy Infants and Young Children < 5 Years Old

Over a 20-year period in a population of otherwise healthy children, respiratory viruses have been cultured from nasal wash specimens from each child with a clinically significant respiratory illness. Since efforts are underway to develop vaccines for prevention of illness due to parainfluenza virus (PIV) type 3, the epidemiologic characteristics of PIVs were reviewed, and the population size necessary to demonstrate vaccine efficacy was estimated. A population of 1429 children was followed through early childhood. PIVs were isolated from 286 samples, 17.4% of positive viral cultures. PIV-3 was the most common: 10% of the children had at least one symptomatic, culture-proven PIV-3 infection. PIV-3 was endemic during the study period, while the other two PIVs, PIV-1 and -2, caused biennial flu epidemics. Only four PIV-related hospitalizations were seen. The efficacy of a PIV-3 vaccine could be demonstrated in a trial of 600 carefully monitored children vaccinated by 3 months and followed to 15 months of age.

Long-term Visual Results and Complications in Children with Aphakia: A Function of Cataract Type

PURPOSE Previous studies of outcome in children with aphakia have approached the data by grouping patients according to features such as age at surgery, type of procedure, or some other common attribute. The purpose of this study is to identify factors predictive for visual outcome and complications in pediatric patients with cataracts. METHOD One hundred seventy-four eyes in 118 patients underwent lensectomy and anterior vitrectomy for congenital or juvenile cataracts. All received early optical correction, occlusion therapy when necessary, and follow-up for at least 6 months. Visual outcome and complications were analyzed statistically to determine predictive factors. Features analyzed included cataract type, laterality, age at onset, follow-up, and corneal size. RESULTS Statistical analysis showed that the most important predictor of long-term visual outcome and complications is cataract type. Visual outcome differed significantly by cataract type, with best results in the lamellar and posterior lentiglobus groups. Unilateral cases had a mean acuity lower than bilateral cases. Other factors, such as age at surgery and corneal size, were less predictive but closely linked to cataract type. Complications, such as aphakic glaucoma, also were more closely linked to the type of cataract than to other variables. CONCLUSION The results indicate that an important determinant of long-term outcome and complications in aphakic children is cataract type. Other features were found to be closely correlated to cataract type and were not independently significant.