Summary
Background
Cytokines and chemokines produced by allergen‐reactive T‐helper type 2 (Th2) cells may be pivotal to the pathophysiology of allergic disorders.
Objective
This study was performed ...to assess the effect of 7 days of topical corticosteroid on nasal allergen challenge (NAC) in terms of eosinophils, cytokines and chemokines obtained by nasal lavage and filter paper methods.
Methods
Patients with grass pollen seasonal‐allergic rhinitis (n=13) out of season received nasal challenge following matched placebo (twice daily into each nostril for 7 days) and fluticasone propionate (100 μg twice daily into each nostril for 7 days). Chemokine and cytokine levels were analysed using a sensitive automated bead immunoassay system at intervals up to 8 h after NAC.
Results
Levels of cytokines and chemokines from filter paper were generally higher than from nasal lavage. Fluticasone propionate caused a reduction in symptoms, total leukocyte counts and eosinophils, and abrogation of IL‐4, IL‐5, IL‐6 and IL‐13 responses in the filter paper taken in the late phase (P<0.05 for IL‐4 and IL‐13, P<0.01 for IL‐5 and IL‐6). Levels of chemokines (eotaxin, RANTES, MCP‐1, MIP‐1α, IL‐8 and IP‐10) were also reduced in the late phase (P<0.01 at 8 h). However, levels of IL‐2, IL‐3, IL‐7, IL‐12 (p40 and p70), ‐15, TNF‐α, IFN‐γ and GM‐CSF were not affected.
Conclusion
Fluticasone propionate has selective inhibitory effects on Th2 cytokine synthesis following nasal challenge, while also decreasing release of chemokines, but not affecting levels of Th1 cytokines.
A phase-locked, self-referenced frequency comb generated by a mode-locked fiber soliton laser with a tunable repetition rate is presented. The spacing of the frequency comb is set by the laser's ...repetition rate, which can be scanned from 49.3 MHz to 50.1 MHz while one tooth of the comb is held phase-locked to a stable RF source. This variable repetitionrate frequency comb should be useful for wavelength and length metrology, synchronization of different fiber laser-based frequency combs, and the generation of precise swept wavelength sources.
Abstract Emerging evidence indicates that early life exposures influence adult health outcomes and there is cause to hypothesise a role for physical activity (PA) in childhood as a protective factor ...in adult depression. This study aimed to investigate the association between self-reported levels of PA in childhood and self-reported depressive illness. Lifetime depression and levels of physical activity (low/high) in childhood (<15 yr) were ascertained by self-report in 2152 adults (20–97 yr) participating in an ongoing epidemiological study in south-eastern Australia. Data were collected between 2000 and 2006. In this sample, 141 women (18.9%) and 169 men (12.0%) reported ever having a depressive episode. Low PA in childhood was associated with an increased risk of reporting depression in adulthood (OR = 1.70, 95%CI = 1.32–2.17, p < 0.001). Adjustment for age, gender and adult PA attenuated the relationship somewhat (OR = 1.35, 95%CI = 1.01–1.78, p = 0.04), however further adjustment for SES or country of birth did not affect this relationship. In this community-based study, lower levels of self-reported PA in childhood were associated with a 35% increase in odds for self-reported depression in adulthood. These results are consistent with the hypothesis that lower levels of PA in childhood may be a risk factor for adult depression.
Abstract Introduction The association between osteoporosis and osteoarthritis (OA) is controversial. Although previous studies have shown total body, lower limb, spinal and knee BMD and knee ...cartilage volume to be positively associated, the relationship between other distant site-specific measures of BMD and other knee structures is unknown. The aim of this study was to determine the associations between BMD at eight skeletal sites, and knee structure in asymptomatic young to middle-aged females without any clinical signs of OA. Methods One hundred and sixty healthy, asymptomatic females (29–50 yr) underwent magnetic resonance imaging of the knee. BMD was measured at the spine, hip, total body and forearm by dual energy X-ray absorptiometry, and at the calcaneus by quantitative ultrasound. BMD was tested for an association with cartilage volume, defects, and bone marrow lesions (BMLs). Results Medial cartilage volume was positively associated with BMD at the spine, total body, femoral neck, and Ward's triangle (all p < 0.05), with non-significant associations in the same direction at the trochanter (p = 0.07). Findings in the lateral compartment were similar. The presence of medial cartilage knee defects were also associated with BMD at the spine; defects in the lateral compartment were associated with BMD at the forearm (both p = 0.05). BMD was not associated with the presence of BMLs. No associations were observed with calcaneus BMD. Conclusions Site-specific BMD is associated with cartilage volume at the knee in asymptomatic young to middle-aged adults, with the direction and effects trending in the same direction. The magnitude of changes correlates with clinically relevant changes. QUS defined calcaneus BMD, showed no associations with knee structure. Although systemic factors may underlie the association between knee cartilage volume and axial/lower limb BMD, these data suggest that common local, possibly biomechanical factors may also play a role.
Background: Urban and rural communities differ in the incidence of several diseases including coronary heart disease and some cancers. Lower hip fracture rates among rural than urban populations have ...been reported but few studies have compared rural and urban fractures at sites other than the hip. Objective: To compare total and site specific fracture rates among adult residents of rural and urban communities within the same population. Design and setting: This is a population based study on osteoporosis in Australia. All fractures occurring in adult residents over a two year period were ascertained using radiological reports. The rural and urban areas are in close proximity, with the same medical, hospital, and radiological facilities permitting uniform fracture ascertainment. Main outcome measures: All fracture rates were age adjusted and sex adjusted to the Australian population according to the 1996 census of the Australian Bureau of Statistics and described as the rate per 10 000 person years. The p values refer to the adjusted rate difference. Results: The hip fracture rate (incidence per 10 000 person years) was 32% lower (39 v 57, p<0.001), and the total fracture rate 15% lower (160 v 188, p=0.004) among rural than urban residents, respectively. The lower fracture rates in the rural population were also apparent for pelvic fractures. Conclusion: In the older rural population, lower fracture rates at sites typically associated with osteoporosis suggest environmental factors may have a different impact on bone health in this community. If the national rate of hip fracture could be reduced to that of the rural population, the projected increase in hip fracture number attributable to aging of the population could be prevented.
Persin is a plant toxin that displays synergistic cytotoxicity with tamoxifen in human breast cancer cell lines. Here, we examined the ability of persin to circumvent tamoxifen resistance and ...delineated the intracellular signalling pathways involved.
The induction of apoptosis in tamoxifen-resistant and -sensitive breast cancer cells was measured by flow cytometry following treatment with persin±tamoxifen. Markers of endoplasmic reticulum stress (ERS) were analysed following treatment, and their causal role in mediating persin-induced apoptosis was determined using chemical inhibitors and RNA interference.
Cells that were resistant to an apoptotic concentration of tamoxifen maintained an apoptotic response to persin. Persin-induced apoptosis was associated with an increase in markers of ERS, that is, CHOP expression and XBP-1 splicing and was decreased by CHOP siRNA. The CASP-4 inhibitor Z-YVAD-FMK markedly inhibited persin-induced apoptosis in both tamoxifen-sensitive and -resistant cells.
The cytotoxic effects of persin are CASP-4 dependent and mediated by CHOP-dependent and -independent ERS signalling cascades. Increased ERS signalling contributes to persin-induced reversal of tamoxifen resistance.
High‐dose corticosteroids, used for many medical conditions, are associated with rapid bone loss from sites such as the vertebrae, and compression fractures can be observed within months. Recent ...trials suggest treatment with bisphosphonates or active vitamin D analogs can reduce bone loss and the risk of fracture associated with glucocorticoids, but few studies have directly compared such agents. We conducted a randomized, multicenter, open‐label trial to compare the efficacy of alendronate, calcitriol, and simple vitamin D in prevention and treatment of glucocorticoid‐induced bone loss. A total of 195 subjects (134 females and 61 males) commencing or already taking glucocorticoids were randomized to one of three groups: calcitriol, 0.5 to 0.75 μg/day; simple vitamin D (ergocalciferol, 30,000 IU weekly) plus calcium carbonate (600 mg daily); or alendronate, 10 mg/day plus calcium carbonate (600 mg daily). Over 2 years, mean lumbar bone mineral density change was +5.9% with alendronate, −0.5% with ergocalciferol, and −0.7% with calcitriol (p < 0.001). At the femoral neck, there was no significant difference in bone mineral density change between the treatments over 2 years: alendronate (+0.9%), ergocalciferol (−3.2%), and calcitriol (−2.2%). Lumbar bone loss varied according to whether patients were starting or receiving chronic glucocorticoids, and there was a significant treatment × prior glucocorticoid use interaction effect. Six of 66 calcitriol subjects, 1 of 61 ergocalciferol subjects, and 0 of 64 alendronate subjects sustained new vertebral fractures. These data do not suggest any difference between simple vitamin D and calcitriol but do show that alendronate was superior to either treatment for glucocorticoid induced bone loss.
Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain. Functional and structural analysis showed that disease severity was related to the type of ...mutation but was unrelated to the polyubiquitin‐binding properties of the mutant UBA domain peptides.
Introduction: Mutations affecting the ubiquitin‐associated (UBA) domain of Sequestosome 1 (SQSTM1) gene have recently been identified as a common cause of familial Paget's disease of bone (PDB), but the mechanisms responsible are unclear. We identified three novel SQSTM1 mutations in PDB, conducted functional and structural analyses of all PDB‐causing mutations, and studied the relationship between genotype and phenotype.
Materials and Methods: Mutation screening of the SQSTM1 gene was conducted in 70 kindreds with familial PDB. We characterized the effect of the mutations on structure of the UBA domain by protein NMR, studied the effects of the mutant UBA domains on ubiquitin binding, and looked at genotype‐phenotype correlations.
Results and Conclusions: Three novel missense mutations affecting the SQSTM1 UBA domain were identified, including a missense mutation at codon 411 (G411S), a missense mutation at codon 404 (M404V), and a missense mutation at codon 425 (G425R). We also identified a deletion leading to a premature stop codon at 394 (L394X). None of the mutations were found in controls. Structural analysis showed that M404V and G425R involved residues on the hydrophobic surface patch implicated in ubiquitin binding, and consistent with this, the G425R and M404V mutants abolished the ability of mutant UBA domains to bind polyubiquitin chains. In contrast, the G411S and P392L mutants bound polyubiquitin chains normally. Genotype‐phenotype analysis showed that patients with truncating mutations had more extensive PDB than those with missense mutations (bones involved = 6.05 ± 2.71 versus 3.45 ± 2.46; p < 0.0001). This work confirms the importance of UBA domain mutations of SQSTM1 as a cause of PDB but shows that there is no correlation between the ubiquitin‐binding properties of the different mutant UBA domains and disease occurrence or extent. This indicates that the mechanism of action most probably involves an interaction between SQSTM1 and a hitherto unidentified protein that modulates bone turnover.
Both serum leptin and bone mineral density are positively correlated with body fat, generating the hypothesis that leptin may be a systemic and/or local regulator of bone mass. We investigated 214 ...healthy, nonobese Australian women aged 20-91 yr. Bone mineral content, projected bone area, and body fat mass were measured by dual energy x-ray absorptiometry and fasting serum leptin levels by RIA. Associations between bone mineral content (adjusted for age, body weight, body fat mass, and bone area) and the natural logarithm of serum leptin concentrations were analyzed by multiple regression techniques. There was a significant positive association at the lateral spine, two proximal femur sites (Ward's triangle and trochanter), and whole body (partial r(2) = 0.019 to 0.036; all P < 0.05). Similar trends were observed at the femoral neck and posterior-anterior-spine. With bone mineral density the dependent variable (adjusted for age, body weight, and body fat mass), the association with the natural logarithm of leptin remained significant at the lateral spine (partial r(2) = 0.030; P = 0.011), was of borderline significance at the proximal femur sites (partial r(2) = 0.012 to 0.017; P = 0.058 to 0.120), and was not significant at the other sites. Our results demonstrate an association between serum leptin levels and bone mass consistent with the hypothesis that circulating leptin may play a role in regulating bone mass.
There is little population-based data concerning fracture rates in Australia. We ascertained all fractures occurring during 2 years in adults aged 35 years and over residing within a defined region ...(population 218 000), representative of the Australian population. The major strength of this study is the comprehensive ascertainment of fractures, which was ensured by regular searches of the only two radiologic providers in the Geelong Osteoporosis Study region. Nevertheless, vertebral fractures are likely to be underestimated since our ascertainment relied on a clinical indication for a medical imaging procedure. Among those aged 35-55 years, the fracture rate (persons per 10,000/year) in men was about double the rate in women (65 vs 35). The fracture rate was almost 7 times higher in women over 60 years versus women less than 55 years of age. In contrast, the fracture rate in men over 60 years was only 50% higher than in men less than 55 years of age (72 vs 104). Fracture rates in women and men were highest at the hip (28 and 10 respectively), spine (21 and 7), distal forearm (Colles') (18 and 4) and humerus (11 and 3), and were 3-4 times higher in women than men. These fractures accounted for 63% of all fractures in women and 32% in men. By contrast, the rate of lower leg and ankle fractures was less than 10 per 10,000 in both women and men and did not increase to the same extent with age. Hip fracture rates appear high, particularly among the older age strata, compared with retrospective ascertainment in other populations. In Australia, as in many other countries, there is an increasing longevity of the population. The number of women aged 90 years and over increased by 32% and the number of men of this age increased by 48% in the 5 years between the Australian national census of 1991 and 1996. Given stable fracture rates, the substantial health burden imposed by age-related fractures, particularly hip fractures, will continue to escalate in both women and men.
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