Whole blood interleukin-2 release test to detect and characterize rare circulating gluten-specific T cell responses in coeliac disease.

Whole blood cytokine release assays (CRA) assessing cellular immunity to gluten could simplify the diagnosis and monitoring of coeliac disease (CD). We aimed to determine the effectiveness of electrochemiluminescence CRA to detect responses to immunodominant gliadin peptides. HLA-DQ2·5+ CD adults (cohort 1, n = 6; cohort 2, n = 12) and unaffected controls (cohort 3, n = 9) were enrolled. Cohort 1 had 3-day gluten challenge (GC). Blood was collected at baseline, and for cohort 1 also at 3 h, 6 h and 6 days after commencing 3-day GC. Gliadin peptide-stimulated proliferation, interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and 14- and 3-plex electrochemiluminescence CRA were performed. Poisson distribution analysis was used to estimate responding cell frequencies. In cohort 1, interleukin (IL)-2 dominated the gliadin peptide-stimulated cytokine release profile in whole blood. GC caused systemic IL-2 release acutely and increased gliadin peptide-stimulated IFN-γ ELISPOT and whole blood CRA responses. Whole blood CRA after GC was dominated by IL-2, but also included IFN-γ, C-X-C motif chemokine ligand 10/IFN-γ-induced protein 10 (CXCL10/IP-10), CXCL9/monokine induced by IFN-γ (MIG), IL-10, chemokine (C-C motif) ligand 3/macrophage inflammatory protein 1-alpha (CCL3/MIP-1α), TNF-α and IL-8/CXCL8. In cohorts 2 and 3, gliadin peptide-stimulated whole blood IL-2 release was 100% specific and 92% sensitive for CD patients on a gluten-free diet; the estimated frequency of cells in CD blood secreting IL-2 to α-gliadin peptide was 0·5 to 11 per ml. Whole blood IL-2 release successfully mapped human leucocyte antigen (HLA)-DQ2·5-restricted epitopes in an α-gliadin peptide library using CD blood before and after GC. Whole blood IL-2 release assay using electrochemiluminescence is a sensitive test for rare gliadin-specific T cells in CD, and could aid in monitoring and diagnosis. Larger studies and validation with tetramer-based assays are warranted.

Evaluation of Polysaccharide Typhim Vi Antibody Response as a predictor of Humoral Immunodeficiency in Haematological Malignancies.

An increasing healthcare challenge in the management of haematological malignancy (HM) is secondary immunodeficiency. From January 2019, the EMA included the evaluation of specific antibody (Ab) responses to better select patients for immunoglobulin replacement therapy (IgRT). We evaluated Ab responses to pneumococcal and Salmonella typhi pure polysaccharide immunization in a cohort of 42 HM patients and 24 healthy-controls. Pre-post specific Ab concentrations were measured by ELISA at 4 weeks. Globally, significantly lower Typhim Vi (TV) seroprevalence (9%) compared to 23-valent pneumococcal polysaccharide vaccine (PPV) (76%) (p <0.001) was observed. TV non responders (88%) were higher than PPV non responders (62%) (p <0.0001) and correlated better to infectious history. By ROC analysis, pre-post 5-fold TV increase was the best cut-off to discriminate HM with recurrent infections and controls (sensitivity 91%, specificity 100%). Despite the small sample cohort, our results suggest that specific anti-S typhi Ab response is a useful complementary assay in the diagnosis and management decision of SID to HM.

Serum cytokines elevated during gluten-mediated cytokine release in coeliac disease.

Cytokines have been extensively studied in coeliac disease, but cytokine release related to exposure to gluten and associated symptoms has only recently been described. Prominent, early elevations in serum interleukin (IL)-2 after gluten support a central role for T cell activation in the clinical reactions to gluten in coeliac disease. The aim of this study was to establish a quantitative hierarchy of serum cytokines and their relation to symptoms in patients with coeliac disease during gluten-mediated cytokine release reactions. Sera were analyzed from coeliac disease patients on a gluten free-diet (n = 25) and from a parallel cohort of healthy volunteers (n = 25) who underwent an unmasked gluten challenge. Sera were collected at baseline and 2, 4 and 6 h after consuming 10 g vital wheat gluten flour; 187 cytokines were assessed. Confirmatory analyses were performed by high-sensitivity electrochemiluminescence immunoassay. Cytokine elevations were correlated with symptoms. Cytokine release following gluten challenge in coeliac disease patients included significant elevations of IL-2, chemokine (C-C motif) ligand 20 (CCL20), IL-6, chemokine (C-X-C motif) ligand (CXCL)9, CXCL8, interferon (IFN)-γ, IL-10, IL-22, IL-17A, tumour necrosis factor (TNF)-α, CCL2 and amphiregulin. IL-2 and IL-17A were earliest to rise. Peak levels of cytokines were generally at 4 h. IL-2 increased most (median 57-fold), then CCL20 (median 10-fold). Cytokine changes were strongly correlated with one another, and the most severely symptomatic patients had the highest elevations. Early elevations of IL-2, IL-17A, IL-22 and IFN-γ after gluten in patients with coeliac disease implicates rapidly activated T cells as their probable source. Cytokine release after gluten could aid in monitoring experimental treatments and support diagnosis.

Repurposing a fracture risk calculator (FRAX) as a screening tool for women at risk for sarcopenia.

Osteoporosis and sarcopenia share risk profiles, so we tested a fracture risk assessment tool (FRAX) as a screening tool for sarcopenia. FRAX probabilities without bone mineral density predicted sarcopenia with high sensitivity and reasonable specificity. There is potential to use this FRAX as a screening tool for sarcopenia. PURPOSE: There is a need for simple screening tools for sarcopenia. As osteoporosis and sarcopenia share risk profiles, we tested the performance of a fracture risk assessment tool for discriminating individuals at risk for sarcopenia. METHODS: In this longitudinal study, FRAX (Australia) probabilities were calculated for 354 women (ages 40-90 years) in the Geelong Osteoporosis Study. Sarcopenia was assessed a decade later using DXA-derived low appendicular lean mass (Lunar; ALM/height2 < 5.5 kg/m2) and low handgrip strength (Jamar; HGS < 16 kg), according to EWGSOP2. We determined FRAX probabilities (%) for hip fracture (HF-FRAX) and major osteoporotic fracture (MOF-FRAX), with and without BMD. Area under the receiver operator characteristic (AUROC) curves quantified the performance of FRAX for predicting sarcopenia. RESULTS: Baseline median (IQR) values for HF-FRAX without BMD were 0.4 (0.1-1.3) and for MOF-FRAX without BMD, 2.4 (1.2-5.2); comparable figures for HF-FRAX with BMD were 0.2 (0.0-0.7) and for MOF-FRAX with BMD, 2.1 (1.1-4.4). At follow-up, sarcopenia was identified for 11 (3.1%) women. When FRAX was calculated without BMD, the AUROC was 0.90 for HF-FRAX and 0.88 for MOF-FRAX. Optimal thresholds were 0.9 for HF-FRAX (sensitivity 90.9%, specificity 62.4%) and 5.3 for MOF-FRAX (sensitivity 81.8%, specificity 71.7%). Calculating FRAX with BMD did not improve the predictive performance of FRAX for sarcopenia. CONCLUSION: Here we provide preliminary evidence to suggest that FRAX probabilities without BMD might predict sarcopenia with high sensitivity and reasonable specificity. Given that FRAX clinical risk factors are identified without equipment, there is potential to use this or a modified version of the FRAX tool to screen for individuals at risk of sarcopenia.

Inorganic particulate matter modulates non-typeable Haemophilus influenzae growth: a link between chronic bacterial infection and geogenic particles.

Australian Aboriginal populations have unacceptably high rates of bronchiectasis. This disease burden is associated with high rates of detection of pathogenic bacteria, particularly non-typeable Haemophilus influenzae (NTHi). While there is evidence to suggest that exposure to inorganic particulate matter (PM) is associated with worse respiratory infections, no studies have considered the direct effect of this PM on bacterial growth. Nine clinical isolates of pathogenic NTHi were used for this study. Isolates were exposed to two common iron oxides, haematite (Fe2O3) or magnetite (Fe3O4), or quartz (SiO2), as the main constituents of environmental inorganic PM. NTHi isolates were exposed to PM with varying levels of heme to identify whether the response to PM was altered by iron availability. The maximal rate of growth and maximum supported growth were assessed. We observed that inorganic PM was able to modify the maximal growth of selected NTHi isolates. Magnetite and quartz were able to increase maximal growth, while haematite could both increase and suppress the maximal growth. However, these effects varied depending on iron availability and on the bacterial isolate. Our data suggest that inorganic PM may directly alter the growth of pathogenic NTHi. This observation may partly explain the link between exposure to high levels of crustal PM and chronic bacterial infection in Australian Aboriginals.

The Inflammatory Effect of Iron Oxide and Silica Particles on Lung Epithelial Cells.

PURPOSE: Our understanding of the respiratory health consequences of geogenic (earth-derived) particulate matter (PM) is limited. Recent in vivo evidence suggests that the concentration of iron is associated with the magnitude of the respiratory response to geogenic PM. We investigated the inflammatory and cytotoxic potential of silica and iron oxide particles alone, and in combination, on lung epithelial cells. METHODS: Bronchial epithelial cells (BEAS-2B) were exposed to silica (quartz, cristobalite) and/or iron oxide (hematite, magnetite) particles. Cytotoxicity and cytokine production (IL-6, IL-8, IL-1ß and TNF-α) were assessed by LDH assay and ELISA, respectively. In subsequent experiments, the cytotoxic and inflammatory potential of the particles was assessed using alveolar epithelial cells (A549). RESULTS: After 24 h of exposure, iron oxide did not cause significant cytotoxicity or production of cytokines, nor did it augment the response of silica in the BEAS2-B cells. In contrast, while the silica response was not augmented in the A549 cells by the addition of iron oxide, iron oxide particles alone were sufficient to induce IL-8 production in these cells. There was no response detected for any of the outcomes at the 4 h time point, nor was there any evidence of IL-1ß or TNF-α production. CONCLUSIONS: While previous studies have suggested that iron may augment silica-induced inflammation, we saw no evidence of this in human epithelial cells. We found that alveolar epithelial cells produce pro-inflammatory cytokines in response to iron oxide particles, suggesting that previous in vivo observations are due to the alveolar response to these particles.

Differences in all-cause hospitalisation by ethnic group: a data linkage cohort study of 4.62 million people in Scotland, 2001-2013.

OBJECTIVES: Immigration into Europe has raised contrasting concerns about increased pressure on health services and equitable provision of health care to immigrants or ethnic minorities. Our objective was to find out if there were important differences in hospital use between the main ethnic groups in Scotland. STUDY DESIGN: A census-based data linkage cohort study. METHODS: We anonymously linked Scotland's Census 2001 records for 4.62 million people, including their ethnic group, to National Health Service general hospitalisation records for 2001-2013. We used Poisson regression to calculate hospitalisation rate ratios (RRs) in 14 ethnic groups, presented as percentages of the White Scottish reference group (RR = 100), for males and females separately. We adjusted for age and socio-economic status and compared those born in the United Kingdom or the Republic of Ireland (UK/RoI) with elsewhere. We calculated mean lengths of hospital stay. RESULTS: 9.79 million hospital admissions were analysed. Compared with the White Scottish, unadjusted RRs for both males and females in most groups were about 50-90, e.g. Chinese males 49 (95% confidence interval [CI] = 45-53) and Indian females 76 (95% CI 71-81). The exceptions were White Irish, males 120 (95% CI 117-124) and females 115 (95% CI 112-119) and Caribbean females, 103 (95% CI 85-126). Adjusting for age increased the RRs for most groups towards or above the reference. Socio-economic status had little effect. In many groups, those born outside the UK/RoI had lower admission rates. Unadjusted mean lengths of stay were substantially lower in most ethnic minorities. CONCLUSIONS: Use of hospital beds in Scotland by most ethnic minorities was lower than by the White Scottish majority, largely explained by their younger average age. Other countries should use similar methods to assess their own experience.

Randomized open-label phase II study comparing oxycodone-naloxone with oxycodone in early return of gastrointestinal function after laparoscopic colorectal surgery.

BACKGROUND: Combined oral modified-release oxycodone-naloxone may reduce opioid-induced postoperative gut dysfunction. This study examined the feasibility of a randomized trial of oxycodone-naloxone within the context of enhanced recovery for laparoscopic colorectal resection. METHODS: In a single-centre open-label phase II feasibility study, patients received analgesia based on either oxycodone-naloxone or oxycodone. Primary endpoints were recruitment, retention and protocol compliance. Secondary endpoints included a composite endpoint of gut function (tolerance of solid food, low nausea/vomiting score, passage of flatus or faeces). RESULTS: Eighty-two patients were screened and 62 randomized (76 per cent); the attrition rate was 19 per cent (12 of 62), leaving 50 patients who received the allocated intervention with 100 per cent follow-up and retention (modified intention-to-treat cohort). Protocol compliance was more than 90 per cent. Return of gut function by day 3 was similar in the two groups: 13 (48 per cent) of 27 in the oxycodone-naloxone group and 15 (65 per cent) of 23 in the control group (95 per cent c.i. for difference -10·0 to 40·7 per cent; P = 0·264). However, patients in the oxycodone-naloxone group had a shorter time to first bowel movement (mean(s.d.) 87(38) h versus 111(37) h in the control group; 95 per cent c.i. for difference 2·3 to 45·4 h, P = 0·031) and reduced total (oral plus parenteral) opioid consumption (mean(s.d.) 78(36) versus 94(56) mg respectively; 95 per cent c.i. for difference -10·2 to 42·8 mg, P = 0·222). CONCLUSION: High participation, retention and protocol compliance confirmed feasibility. Potential benefits of oxycodone-naloxone in reducing time to bowel movement and total opioid consumption could be tested in a randomized trial. Registration number: NCT02109640 (https://www.clinicaltrials.gov/).

Citalopram and sertraline exposure compromises embryonic bone development.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.

Pooled long-term outcomes from two randomized trials of axillary node sampling with axillary radiotherapy versus axillary node clearance in patients with operable node-positive breast cancer.

BACKGROUND: The aim was to determine long-term overall, breast cancer-specific and metastasis-free survival as well as axillary relapse rate from a pooled analysis of two randomized trials in women with operable breast cancer. These trials compared axillary node sampling (ANS), combined with axillary radiotherapy (AXRT) if the sampled nodes were involved, with axillary node clearance (ANC). METHODS: Data from two clinical trials at the Edinburgh Breast Unit that randomized patients between 1980 and 1995 were pooled. Long-term survival was analysed using Kaplan-Meier curves and Cox regression, with separate analyses for patients with node-positive (ANS + AXRT versus ANC) and node-negative (ANS versus ANC) disease. RESULTS: Of 855 women randomized, 799 were included in the present analysis after a median follow-up of 19·4 years. Some 301 patients (37·7 per cent) had node-positive disease. There was no evidence of a breast cancer survival advantage for ANS versus ANC in patients with node-negative disease (hazard ratio (HR) 0·88, 95 per cent c.i. 0·58 to 1·34; P = 0·557), or for ANS + AXRT versus ANC in those with node-positive breast cancer (HR 1·07, 0·77 to 1·50; P = 0·688). There was no metastasis-free survival advantage for ANS versus ANC in patients with node-negative tumours (HR 1·03, 0·70 to 1·51; P = 0·877), or ANS + AXRT versus ANC in those with node-positive disease (HR 1·03, 0·75 to 1·43; P = 0·847). Node-negative patients who underwent ANS had a higher risk of axillary recurrence than those who had ANC (HR 3·53, 1·29 to 9·63; P = 0·014). Similarly, among women with node-positive tumours, the risk of axillary recurrence was greater after ANS + AXRT than ANC (HR 2·64, 1·00 to 6·95; P = 0·049). CONCLUSION: Despite a higher rate of axillary recurrence with ANS combined with radiotherapy to the axilla, ANC did not improve overall, breast cancer-specific or metastasis-free survival. Axillary recurrence is thus not a satisfactory endpoint when comparing axillary treatments.

Association between underestimation of tumour size by imaging and incomplete excision in breast-conserving surgery for breast cancer.

BACKGROUND: Completeness of excision is the most important factor influencing local recurrence after breast-conserving surgery (BCS). The aim of this case-control study was to determine factors influencing incomplete excision in patients undergoing BCS. METHODS: Women with invasive breast cancer treated by BCS between 1 June 2008 and 31 December 2009 were identified from a prospectively collected database in the Edinburgh Breast Unit. The maximum size of the tumour, measured microscopically, was compared with the size estimated before operation by mammography and ultrasound imaging. A multivariable analysis was performed to investigate factors associated with incomplete excision. RESULTS: The cohort comprised 311 women, of whom 193 (62·1 per cent) had a complete (CE group) and 118 (40·7 per cent) an incomplete (IE group) excision. Mammography underestimated tumour size in 75·0 per cent of the IE group compared with 40·7 per cent of the CE group (P < 0·001). Ultrasound imaging underestimated tumour size in 82·5 per cent of the IE group compared with 56·5 per cent of the CE group (P < 0·001). The risk of an incomplete excision was greater when mammography or ultrasonography underestimated pathological size: odds ratio (OR) 4·38 (95 per cent c.i. 2·59 to 7·41; P < 0·001) for mammography, and OR 3·64 (2·03 to 6·54; P < 0·001) for ultrasound imaging. For every 1-mm underestimation of size by mammography and ultrasonography, the relative odds of incomplete excision rose by 10 and 14 per cent respectively. CONCLUSION: Underestimation of tumour size by current imaging techniques is a major factor associated with incomplete excision in women undergoing BCS.

Prior fracture as a risk factor for future fracture in an Australian cohort.

SUMMARY: This study investigated the influence of prior fracture on the risk of subsequent fracture. There was a higher risk of subsequent fracture in both young and older adult age groups when Australian males or females had already sustained a prior fracture. Fracture prevention is important throughout life for both sexes. INTRODUCTION: The purpose of this study was to determine the impact of prior fracture on the risk of subsequent fracture across the adult age range in Australian males and females. METHODS: All-cause fractures were grouped into age categories for males and females enrolled in the Geelong Osteoporosis Study (Australia) using retrospective self-report data and prospective radiology-confirmed data. For all age categories, the relative risk (RR and 95% confidence interval (CI)) of subsequent fracture in a later age category was compared between those with prior fracture and those without. RESULTS: For both sexes, childhood fracture increased the risk of subsequent fracture in adolescence (males: RR 21.7; 95% CI 16.0, 27.4; females: RR 8.1; 3.5, 12.8). Males with adolescent fracture had increased risk of subsequent fracture in early adulthood (RR 11.5; 5.7, 17.3) and mid-adulthood (RR 13.0; 6.3, 19.7). Additionally, males with young adulthood or mid-adulthood fracture had increased risk of subsequent fracture in the following age group (RR 11.2; 4.4, 17.9, and RR 6.2; 0.8, 11.7, respectively). Mid-adult fractures increased the risk of subsequent fracture in older adulthood (RR 6.2; 0.8, 11.7). Females with childhood or adolescent fracture had an increased risk of fracture in young adulthood (RR 4.3; 0.7, 7.9, and RR 10.5; 4.4, 16.6), and prior fracture in older adult life increased the risk of subsequent fracture in old age (RR 14.9; 6.4. 23.3). CONCLUSIONS: Fracture prevention strategies may be more effective if attention is directed towards individuals with prior fracture at any age as they have a higher likelihood of sustaining a subsequent fracture later in life.

The social gradient of fractures at any skeletal site in men and women: data from the Geelong Osteoporosis Study Fracture Grid.

UNLABELLED: Age-specific and age-standardized associations between socioeconomic status (SES) and fractures in adults showed a social gradient of fracture, irrespective of fracture site. Compared to the highest SES, males in the lowest SES group had a sixfold increased odds for any fracture, whilst females had a twofold increased odds. INTRODUCTION: The effective identification of predisposing risk factors for fracture requires understanding any association with SES. These investigations should consider both sexes, span the adult age range and include any fractures. We investigated age- and sex-specific and age-standardized associations between SES and fractures at any skeletal site in Australians aged ≥ 50 years. METHODS: Incident fractures that occurred 2006-2007 for adults aged ≥ 50 years were identified from radiological reports extracted for the Barwon Statistical Division, in south-eastern Australia. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics census data and then categorized in quintiles. We compared frequencies of observed vs. expected fractures for SES quintiles using χ (2) comparison, calculated age-specific fracture incidence across SES and compared age-standardized fracture rates in SES quintile 1 to quintile 5. RESULTS: We identified 3943 incident fractures (69.4 % female); 47.4 % had occurred at major osteoporotic fracture (MOF) sites (hip, humerus, spine and forearm/wrist). Differences existed in observed vs. expected fractures across SES quintiles (p ≤ 0.001, sexes combined); all fractures showed an inverse association with SES (p ≤ 0.001, sexes combined). Compared to the highest SES quintile, individuals from the lowest SES quintile had between two to six times greater standardized fracture rates. CONCLUSIONS: Disadvantaged men and women have an increased fracture incidence compared to their less disadvantaged counterparts. The large differences in fracture rates between SES groups warrant further research into designing appropriate, targeted interventions for those demographics at most risk.

The association between major depressive disorder, use of antidepressants and bone mineral density (BMD) in men.

OBJECTIVE: Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men. METHODS: Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression. RESULTS: Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and -2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75-110 kg depending on bone site). CONCLUSIONS: Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men.

Long-term life satisfaction in ageing women with work disability due to mental and musculoskeletal disorders.

BACKGROUND: Mental disorders (MDs) and musculoskeletal disorders (MSDs) are the major causes of global disability and increase in prevalence with age. AIMS: To support healthy ageing, we studied how work disability due to MDs or MSDs is related to life satisfaction (LS) cross-sectionally and in 5- and 10-year follow-ups among ageing women. METHODS: In the population-based OSTPRE cohort (women aged 58-67 in 1999), data on lifetime permanent work disability pensions (DPs) due to 'MDs only' (n = 337), 'MSDs only' (n = 942) and 'MDs + MSDs' (n = 212) and 'no DP' (n = 6322) until 1999 was obtained from the Finnish national register. The OSTPRE postal enquiry included a four-item life satisfaction (LS) scale (range 4-20: satisfied 4-6, intermediate 7-11, dissatisfied 12-20) at 5-year intervals, in 1999-2004 (n = 6548) and in 1999-2009 (n = 5562). RESULTS: In 1999, the risks of belonging to the dissatisfied LS group (score 12-20) vs. the satisfied group (score 4-6) were higher in 'MDs only' (OR = 4.30; 95%CI 2.95-6.28), 'MSDs only' (OR = 2.69; 2.12-3.40) and 'MDs + MSDs' (OR = 2.72; 1.77-4.16) groups than in the 'no DP' group. In the follow-ups, these risks were OR5yr = 5.59 (3.54-8.84) and OR10yr = 4.94 (2.80-8.73) for 'MDs only', OR5yr = 3.36 (2.58-4.37) and OR10yr = 3.18 (2.40-4.21) for 'MSDs only', and OR5yr = 4.70 (2.75-8.05) and OR10yr = 6.84 (3.53-13.27) for 'MDs + MSDs' (all: p ≤ 0.001). Adjusting for baseline LS did not change the pattern (all p ≤ 0.001). CONCLUSION: Work disability due to MDs and MSDs undermines healthy ageing among women via life dissatisfaction.

Comorbidity of mental and musculoskeletal disorders in ageing women: A data linkage study using national registries.

BACKGROUND: Mental disorders (MDs) and musculoskeletal disorders (MSDs) are the main causes of disability. Yet, their comorbidity has not received the deserved attention. OBJECTIVE: To investigate the extent of the comorbidity between MDs and MSDs in ageing women using national registries on prescription medications and work disability pensions (DPs). METHODS: The study included 7,809 Finnish women, born during 1932-41, from the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) cohort, established in 1989. Lifetime permanent DPs due to: 1) 'MDs only' (n = 359), 2) 'MSDs only' (n = 954), 3) 'MDs + MSDs' (n = 227), were recorded till 2003. The reference group was 'no DP' (n = 6,269). Data from the OSTPRE questionnaires was obtained in 1994. Use of medications was recorded in 1995 and 2003. The use of musculoskeletal or psychotropic medications by women having a DP or medication due to MD, or MSD diagnoses, respectively, was considered as an indicator of comorbidity. RESULTS: In 1995, all DP groups had used psychotropic and musculoskeletal medications more often than the referents. Use of musculoskeletal medications was associated with a higher use of psychotropic medications, and vice versa (OR=2.45; 95% CI 2.17-2.77), compared with non-use. The 'MSDs only' group was more likely to use psychotropic (OR=1.79; 95% CI 1.50-2.12), and the 'MDs only' group musculoskeletal medications (OR=1.38; 95% CI 1.09-1.74), compared with those without DPs. The proportions of medication users were similar in 1995 and 2003; however, the amounts used increased. CONCLUSIONS: There was strong evidence for comorbidity between MDs and MSDs in ageing women. Further research concerning their longitudinal relationships is warranted.

An automatic algorithm for the segmentation and morphological analysis of microvessels in immunostained histological tumour sections.

A fully automatic segmentation and morphological analysis algorithm for the analysis of microvessels from CD31 immunostained histological tumour sections is presented. Development of the algorithm exploited the distinctive hues of stained vascular endothelial cells, cell nuclei and background, to provide the seeds for a 'region-growing' method for object segmentation in the 3D hue, saturation, value (HSV) colour model. The segmented objects, identified as microvessels by CD31 immunostaining, were post-processed with three morphological tasks: joining separate objects that were likely to belong to a single vessel, closing objects that had a narrow gap around their periphery, and splitting objects with multiple lumina into individual vessels. The automatic segmentation was validated against a hand-segmented set of 44 images from three different SW1222 human colorectal carcinomas xenografted into mice. 96.3 ± 0.9% of pixels were found to be correctly classified. Automated segmentation was carried out on a further 53 images from three histologically distinct mouse fibrosarcomas (MFs) for morphological comparison with the SW1222 tumours. Four morphometric measurements were calculated for each segmented vessel: vascular area (VA), ratio of lumen area to vascular area (lu/VA), eccentricity (e), and roundness (ro). In addition, the total vascular area relative to tumour tissue area (rVA) was calculated. lu/VA, e and ro were found to be significantly smaller in MF tumours than in SW1222 tumours (p < 0.05; unpaired t-test). The algorithm is available through the website http://www.caiman.org.uk where images can be uploaded, processed and sent back to users. The output from CAIMAN consists of the original image with boundaries of segmented vessels overlaid, the calculated parameters and a Matlab file, which contains the segmentation that the user can use to derive further results.

Improving stable isotopic interpretations made from human hair through reduction of growth cycle error.

A recent trend in stable isotopic analysis involves the reconstruction of short-term variations in diet using hair segments. However, bulk hair samples typically contain a growth cycle error, which may conceal or confound the most recently incorporated isotopic information. It is assumed that, at any given time, ∼85-90% of scalp hairs are actively growing, while the remaining 10-15% have transitioned into a resting or inactive phase, which lasts up to 4 months before hairs are shed. This study uses growth phase to determine the effects of age, sex, and health status on carbon and nitrogen isotopic ratios of hair analyzed in sequential segments. For this study, we selected archaeological hair samples from 10 individuals from Dakhleh Oasis, Egypt. Isotopic analyses of actively growing hair segments were compared to those for mixed growth phase segments from each individual. These data demonstrate the presence of growth cycle error and show that an understanding of structural-functional relationships is essential for interpreting normal versus pathological changes in hair follicle and fiber production. In situations where diet change and mobility produce variations in an individual's isotopic composition, elimination of positional-temporal error in sequential segment hair analyses can facilitate greater understanding of intraindividual metabolic reactions and changes in hair growth cycles. Phase identification may aid in determining the presence of pathological conditions in individuals, especially in those lacking skeletal indications, and provide a more precise estimation of seasonal dietary patterns, access to changing food resources, and metabolic equilibration to a new locality.