Assessing the effects of parthenolide on inflammation, bone loss, and glial cells within a collagen antibody-Induced arthritis mouse model

Rheumatoid arthritis is characterised by a chronic inflammatory response resulting in destruction of the joint and significant pain. Although a range of treatments are available to control disease activity in RA, bone destruction and joint pain exist despite suppression of inflammation. This study is aimed at assessing the effects of parthenolide (PAR) on paw inflammation, bone destruction, and pain-like behaviour in a mild collagen antibody-induced arthritis (CAIA) mouse model. CAIA was induced in BALB/c mice and treated daily with 1 mg/kg or 4 mg/kg PAR. Clinical paw inflammation was scored daily, and mechanical hypersensitivity was assessed on alternate days. At end point, bone volume and swelling in the paws were assessed using micro-CT. Paw tissue sections were assessed for inflammation and pre-/osteoclast-like cells. The lumbar spinal cord and the periaqueductal grey (PAG) and rostral ventromedulla (RVM) regions of the brain were stained for glial fibrillary acidic protein (GFAP) and ionised calcium-binding adaptor molecule 1 (IBA1) to assess for glial reactivity. Paw scores increased in CAIA mice from days 5-10 and were reduced with 1 mg/kg and 4 mg/kg PAR on days 8-10. Osteoclast-like cells on the bone surface of the radiocarpal joint and within the soft tissue of the hind paw were significantly lower following PAR treatment (p < 0.005). GFAP- and IBA1-positive cells in the PAG and RVM were significantly lower following treatment with 1 mg/kg (p < 0.0001 and p = 0.0004, respectively) and 4 mg/kg PAR (p < 0.0001 and p = 0.001, respectively). In the lumbar spinal cord, IBA1-positive cells were significantly lower in CAIA mice treated with 4 mg/kg PAR (p = 0.001). The findings indicate a suppressive effect of both low- and moderate-dose PAR on paw inflammation, osteoclast presence, and glial cell reactivity in a mild CAIA mouse model.B. Williams, F. Lees, H. Tsangari, M. R. Hutchinson, E. Perilli and T. N. Crott

Sample size considerations for trials using cerebral white matter hyperintensity progression as an intermediate outcome at 1 year after mild stroke: Results of a prospective cohort study

Background: White matter hyperintensities (WMHs) are commonly seen on in brain imaging and are associated with stroke and cognitive decline. Therefore, they may provide a relevant intermediate outcome in clinical trials. WMH can be measured as a volume or visually on the Fazekas scale. We investigated predictors of WMH progression and design of efficient studies using WMH volume and Fazekas score as an intermediate outcome. Methods: We prospectively recruited 264 patients with mild ischaemic stroke and measured WMH volume, Fazekas score, age and cardiovascular risk factors at baseline and 1 year. We modelled predictors of WMH burden at 1 year and used the results in sample size calculations for hypothetical randomised controlled trials with different analysis plans and lengths of follow-up. Results: Follow-up WMH volume was predicted by baseline WMH: a 0.73-ml (95% CI 0.65-0.80, p < 0.0001) increase per 1-ml baseline volume increment, and a 2.93-ml increase (95% CI 1.76-4.10, p < 0.0001) per point on the Fazekas scale. Using a mean difference of 1 ml in WMH volume between treatment groups, 80% power and 5% alpha, adjusting for all predictors and 2-year follow-up produced the smallest sample size (n = 642). Other study designs produced samples sizes from 2054 to 21,270. Sample size calculations using Fazekas score as an outcome with the same power and alpha, as well as an OR corresponding to a 1-ml difference, were sensitive to assumptions and ranged from 2504 to 18,886. Conclusions: Baseline WMH volume and Fazekas score predicted follow-up WMH volume. Study size was smallest using volumes and longer-term follow-up, but this must be balanced against resources required to measure volumes versus Fazekas scores, bias due to dropout and scanner drift. Samples sizes based on Fazekas scores may be best estimated with simulation studies

Trabecular bone modeling and subcapital femoral fracture

Fragility fractures, including neck of femur fractures, result from reductions in the amount, quality and architecture of bone. The aim of this study was to compare the cancellous bone structure, and static indices of bone turnover, in female patients who had sustained fragility fracture at the femoral neck, with age-matched females without fragility fracture. Bone samples were taken from the intertrochanteric region of the proximal femur of female patients undergoing hip arthroplasty surgery for a subcapital fragility fracture of the femoral neck (#NOF) or from age-matched female control individuals at routine autopsy. The histomorphometric data, which were normally distributed, indicated no difference between the mean values for any of the structural parameters in control and fracture samples. In particular, the BV/TV values were not different and did not change significantly with age in these cohorts of individuals aged >65 years. The static indices of bone turnover, eroded surface (ES/BS) and osteoid surface (OS/BS), were positively correlated with age in the >65-year-old control group (p65-year-old controls compared with a group of younger females aged <65 years, suggesting an increase in bone formation in older females in the proximal femur after 65 years of age. When the data were further interrogated, a reduction in the percentage osteoid surface to eroded surface quotient (OS/ES) was found for the fracture group compared with the age-matched control group. These data indicate that perturbations in bone formation and/or resorption surface are potentially important in producing bone in the proximal femur with increased propensity to fracture. These data also support the concept that trabecular bone modeling may be a factor influencing bone strength in addition to bone mass.H. Tsangari, J.S. Kuliwaba, N.L. Fazzalar

Structural and remodeling indices in the cancellous bone of the proximal femur across adulthood

Copyright © 2006 Published by Elsevier Inc.Fragility fractures, including fractures of the femoral neck, result from reductions in the amount, quality and architecture of bone. However, investigations of the underlying structural changes that might predispose to fracture have been largely limited to skeletal sites that do not fracture, such as the iliac crest (IC). The aim of this study was to use histomorphometry to map changes in the architecture and the static remodeling indices of cancellous bone, as a function of age and sex, in bone samples taken from the intertrochanteric (IT) region of the proximal femur at routine autopsy (18-88 years of age). Bone samples for histology were processed from 10-mm cubes of IT cancellous bone. Histomorphometry was performed using an ocular-mounted 10 x 10 graticule at a magnification of x100. An age-dependent decrease in trabecular bone volume was observed in both females and males, as expected (r=-0.75 and r=-0.63, p<0.001, respectively). The underlying mechanisms for bone turnover appeared to be different between males and females. Thus, while the static index of bone resorption (ES/BV) was positively age-dependent in males and females (p<0.001, p<0.03, respectively), the index of bone formation (OS/BV) correlated positively with age in the female group only (p<0.001 vs. NS). Perhaps reflecting an increase in bone formation in older females, the OS/ES ratio was greater in older females than younger females or males. Surprisingly, while resorption indices increased in older males compared with their younger counterparts, bone formation indices increased only in the older female cohort. The IT region in the proximal femur is adjacent to the site commonly involved in fragility fracture. With the limitation that these results describe cross-sectional data, they provide useful insights into changes in the cancellous bone structure and at the bone surface of females and males over the age range of 20-90 years, at a clinically relevant skeletal site.http://www.elsevier.com/wps/find/journaldescription.cws_home/525233/description#descriptio

Increased expression of IL-6 and RANK mRNA in human trabecular bone from fragility fracture of the femoral neck

Copyright © 2004 Elsevier Inc.Previous studies have implicated pro-inflammatory cytokines in the bone loss of estrogen deficiency. The aim of this study was to investigate the expression of key regulatory molecules of bone remodeling in the trabecular bone microenvironment in osteoporosis. Bone samples were taken from the intertrochanteric region of the proximal femur of patients undergoing total hip arthroplasty for a subcapital fragility fracture of the femoral neck (#NOF). For comparison, samples were taken from age-matched control individuals at routine autopsy. Expression of RANKL, RANK, osteoprotegerin (OPG), IL-6, IL-11, osteocalcin (OCN), and calcitonin receptor (CTR) messenger RNA (mRNA) species were analyzed and the data were nonparametrically distributed. The median expression of the proresorptive genes, RANK and IL-6, were significantly elevated in the fracture group compared to an age-matched control group (2.2 [1.9–2.9; 25th–75th percentiles] > 1.0 [0.4–2.1], P 0.8 [0.7–1.5], P 3.2 [2.1–4.0], P < 0.05). IL-6 mRNA levels associated strongly with RANKL mRNA levels in the #NOF group (r = 0.77, P < 0.001), but not in the control group. A strong positive association was found between IL-11 mRNA levels and RANKL mRNA levels in the #NOF group (r = 0.81, P < 0.001), consistent with the apparent coordinated regulation of IL-6 and IL-11 in bone samples from the #NOF group (r = 0.93, P < 0.0001). These data suggest a relative increase in the expression of the molecular promoters of osteoclast formation and activity in #NOF bone, which may lead to the imbalance between bone formation and resorption associated with fragility fracture.Helen Tsangaria, David M. Findlayb, Julia S. Kuliwabaa, Gerald J. Atkinsb and Nicola L. Fazzalarihttp://www.elsevier.com/wps/find/journaldescription.cws_home/525233/description#descriptio

Caring for a relative with dementia: Family caregiver burden

Aim. This paper is a report of part of a study to investigate the burden experienced by families giving care to a relative with dementia, the consequences of care for the mental health of the primary caregiver and the strategies families use to cope with the care giving stressors. Background. The cost of caring for people with dementia is enormous, both monetary and psychological. Partners, relatives and friends who take care of patients experience emotional, physical and financial stress, and care giving demands are central to decisions on patient institutionalization. Method. A volunteer sample of 172 caregiver/care recipient dyads participated in the study in Cyprus in 2004-2005. All patients were suffering from probable Alzheimer&apos;s type dementia and were recruited from neurology clinics. Data were collected using the Memory and Behaviour Problem Checklist, Burden Interview, Center for Epidemiological Studies-Depression scale and Ways of Coping Questionnaire. Findings. The results showed that 68·02% of caregivers were highly burdened and 65% exhibited depressive symptoms. Burden was related to patient psychopathology and caregiver sex, income and level of education. There was no statistically significant difference in level of burden or depression when patients lived in the community or in institutions. High scores in the burden scale were associated with use of emotional-focused coping strategies, while less burdened relatives used more problem-solving approaches to care-giving demands. Conclusion. Caregivers, especially women, need individualized, specific training in how to understand and manage the behaviour of relatives with dementia and how to cope with their own feelings. © 2007 The Authors. Journal compilation 2007 Blackwell Publishing Ltd

Influence of pre-fatigue microdamage on the fracture of human cortical bone

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An extended Canvas business model: A tool for sustainable technology transfer and adoption

The rise of new agricultural technologies represents an opportunity for agricultural development, especially to achieve the 2030 Sustainable Development Goal. However, farmers in developing countries struggle with adopting new agricultural technologies due to several socio-economic factors. This study proposes a service-based business for transfer and sustainable scaling of new technologies to increase household resilience. Two segments, (i) cost-benefit and (ii) sensitivity analysis was added to the original Canvas business model. We used two innovative technologies: a personalised extension application and a rice threshing machine to apply the business model. Quantitative data from 700 randomly selected rice farmers in Kano State, and qualitative data collected using the Delphi method were used. The adapted Canvas business model is profitable when both technologies are used separately, with an Internal Rate of Return (IRR) of 23 and 28% for the threshing machine and the application, respectively. However, higher profitability is observed when both technologies are combined in one business model. In this case, the business has an IRR of 33%. Moreover, the study shows that the combined business model is vulnerable to the service price. Therefore, we recommend re-evaluating the business model to determine a fair price and payment method for both the service recipient and the provide