Evaluation of a disease specific rheumatoid arthritis self-management education program, a single group repeated measures study.

BACKGROUND: Rheumatoid Arthritis is a progressive and disabling disease, predicted to increase in prevalence over the next 50 years. Self-management is acknowledged as an integral part in the management of chronic disease. The rheumatoid arthritis specific self-management program delivered by health professionals was developed by Arthritis Western Australia in 2006. The purpose of this study was to determine whether this program would achieve early benefits in health related outcomes, and whether these improvements would be maintained for 12 months. METHODS: Individuals with rheumatoid arthritis were referred from rheumatologists. Participants with co-existing inflammatory musculoskeletal conditions were excluded. All participants completed a 6-week program. Assessments occurred at baseline (8 weeks prior to intervention), pre-intervention, post-intervention, and 6 and 12 month follow ups. Outcomes measured included pain and fatigue (numerical rating scale, 0-10), depression and anxiety (hospital anxiety and depression questionnaire), health distress, and quality of life (SF-36 version 2). RESULTS: There were significant improvements in mean [SD] fatigue (5.7 [2.4] to 5.1 [2.6]), depression (6.3 [4.3] to 5.6 [3.9]) and SF-36 mental health (44.5 [11.1] to 46.5 [9.5]) immediately following intervention, with long term benefits for depression (6.3 [4.3] to 4.9 [3.9]), and SF-36 subscales mental health (44.5 [11.1] to 47.8 [10.9]), role emotional (41.5 [13.2] to 46.5 [11.8]), role physical (35.0 [11.0] to 40.2 [12.1]) and physical function (34.8 [11.5] to 38.6 [10.7]). CONCLUSION: Participants in the program recorded significant improvements in depression and mental health post-intervention, which were maintained to 12 months follow up.

The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.

OBJECTIVE: To determine the effectiveness of subsensory, pulsed electrical stimulation (PES) in the symptomatic management of osteoarthritis (OA) of the knee. METHODS: This was a double-blind, randomized, placebo-controlled, repeated-measures trial in 70 participants with clinical and radiographically diagnosed OA of the knee who were randomized to either PES or placebo. The primary outcome was change in pain score over 26 weeks measured on a 100-mm visual analog scale (VAS). Other measures included pain on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), function on the WOMAC, patient's global assessment of disease activity (on a 100-mm VAS), joint stiffness on the WOMAC, quality of life on the Medical Outcomes Study Short-Form 36 (SF-36) health survey, physical activity (using the Human Activity Profile and an accelerometer), and global perceived effect (on an 11-point scale). RESULTS: Thirty-four participants were randomized to PES and 36 to placebo. Intent-to-treat analysis showed a statistically significant improvement in VAS pain score over 26 weeks in both groups, but no difference between groups (mean change difference 0.9 mm [95% confidence interval -11.7, 13.4]). Similarly, there were no differences between groups for changes in WOMAC pain, function, and stiffness scores (-5.6 [95% confidence interval -14.9, 3.6], -1.9 [95% confidence interval -9.7, 5.9], and 3.7 [95% confidence interval -6.0, 13.5], respectively), SF-36 physical and mental component summary scores (1.7 [95% confidence interval -1.5, 4.8] and 1.2 [95% confidence interval -2.9, 5.4], respectively), patient's global assessment of disease activity (-2.8 [95% confidence interval -13.9, 8.4]), or activity measures. Fifty-six percent of the PES-treated group achieved a clinically relevant 20-mm improvement in VAS pain score at 26 weeks compared with 44% of controls (12% [95% confidence interval -11%, 33%]). CONCLUSION: In this sample of subjects with mild-to-moderate symptoms and moderate-to-severe radiographic OA of the knee, 26 weeks of PES was no more effective than placebo.

A bundle of infection control measures reduces postoperative sternal wound infection due to Staphylococcus aureus but not Gram-negative bacteria: a retrospective analysis of 6903 patient episodes.

BACKGROUND: Prevention of cardiac surgical site infection has largely focused on reducing infection due to Staphylococcus aureus, although other bacteria also play an important role in this complication. AIM: To assess the impact of an evolving infection control programme on the incidence of sternal wound infection (SWI), and the changing incidence of non-staphylococcal infections. METHODS: A retrospective cohort study of all patients who underwent primary sternotomy at a single UK centre between September 2010 and May 2018 was undertaken. Data were collated from the 2 years preceding the stepwise introduction of a broad-ranging infection control programme, including S. aureus decolonization. FINDINGS: In total, 6903 primary sternotomies were performed, of which 2.6% (N=178) were complicated by SWI. Gram-negative bacteria (GNB) and S. aureus were most commonly identified as causative pathogens (45.5% and 30.3%, respectively). Following programme introduction, there was a reduction in the rate of SWI from 3.9 to 1.8 cases/100 patients/month. This was mainly due to a sustained reduction in cases of S. aureus infection, with no discernible impact on GNB. Multi-variable logistic regression analysis identified coronary artery bypass grafting, procedural urgency, and procedures performed in the third quarter of the calendar year (July to September) as independent risk factors for postoperative infection. CONCLUSION: A multi-faceted infection control programme was successful at reducing the rate of SWI, primarily due to a reduction in S. aureus infections. GNB also play an important role in SWI, and traditional preventative measures fail to address these. Future intervention and impact assessments should consider GNB infections when measuring effectiveness.

Self-management for osteoarthritis of the knee: does mode of delivery influence outcome?

BACKGROUND: Self-management has become increasingly popular in the management of chronic diseases. There are many different self-management models. Meta analyses of arthritis self-management have concluded that it is difficult to recommend any one program in preference to another due to inconsistencies in the study designs used to evaluate different programs.The Stanford Arthritis Self-Management Program (ASMP), most commonly delivered by trained lay leaders, is a generic program widely used for people with rheumatological disorders. We have developed a more specific program expressly for people with osteoarthritis of the knee (OAKP). It includes information designed to be delivered by health professionals and results in improvements in pain, function and quality of life. AIM: To determine whether, for people with osteoarthritis (OA) of the knee, the OAKP implemented in a primary health care setting can achieve and maintain clinically meaningful improvements in more participants than ASMP delivered in the same environment. METHODS/DESIGN: The effectiveness of the programs will be compared in a single-blind randomized study. PARTICIPANTS: 146 participants with established OA knee will be recruited. Volunteers with coexistent inflammatory joint disease or serious co-morbidities will be excluded. INTERVENTIONS: Participants will be randomised into either OAKP or ASMP groups and followed for 6 months. MEASUREMENTS: Assessments will be immediately before and after the intervention and at 6 months. Primary outcome measures will be WOMAC and SF-36 questionnaires and a VAS for pain. Secondary outcomes will include balance, tested using a timed single leg balance test and a timed step test and self-efficacy. Data will be analysed using repeated measures ANOVA. DISCUSSION: With an aging population the health care costs for people with arthritis are ever increasing. Although cost analysis is beyond the scope of this study, it is reasonable to expect that costs will be greater when health professionals deliver self-management programs as opposed to lay leaders. Consequently it is critical to examine the relative effectiveness of the primary care management strategies available for OA. TRIAL REGISTRATION: This study is registered with the Australian New Zealand Clinical Trials Registry: 12607000031460.

Effects of self-management, education and specific exercises, delivered by health professionals, in patients with osteoarthritis of the knee.

BACKGROUND: An education self-management program for people with osteoarthritis (OA) of the knee was designed to be delivered by health professionals, incorporating their knowledge and expertise. Improvement in quality of life, health status and pain in response to this program has previously been demonstrated in an uncontrolled pilot study. To more rigorously test the effectiveness of the program we will undertake a randomised controlled trial of people with OA of the knee offering specific self-administered exercises and education, in accordance with the principles of self-management. AIM: To determine whether an education self management program for subjects with Osteoarthritis (OA) of the knee (OAK program) implemented by health professionals in a primary health care setting can achieve and maintain clinically meaningful improvements compared standard medical management in a control group. METHODS: The effects of standard medical management will be compared with the effects of the OAK program in a single-blind randomized study. PARTICIPANTS: 146 male and female participants with established OA knee will be recruited. Volunteers with coexistent inflammatory joint disease or serious co-morbidities will be excluded. INTERVENTIONS: Participants will be randomized into either intervention or control groups (delayed start). The intervention group will complete the OA knee program and both groups will be followed for 6 months. MEASUREMENTS: Assessments will be at baseline, 8 weeks and 6 months. SF-36, WOMAC and VAS pain questionnaires will be completed. Isometric quadriceps and hamstring strength will be measured using a dynamometer; knee range of movement using a goniometer; and physical function will be determined by a modified timed up and go test. Data will be analysed using repeated measures ANOVA. DISCUSSION: While there is evidence to support the effectiveness of SM programs for people with hypertension, diabetes and asthma, the evidence available for treatment of arthritis remains equivocal. The aim of this study is to determine the effectiveness of a disease specific self-management program for people with OA knee.The study design includes all the important features of a clinical experimental study to minimize bias so the results of the study will provide a high level of evidence. People with OA of the knee have identified pain and problems with daily activities as the most important problems associated with their condition. The outcome measures selected specifically address these issues and have demonstrated validity and are responsive within the range of change expected in response to the intervention. Hence the results of the study will reflect their priorities.The results of the study will provide evidence to guide clinicians and funding bodies seeking to establish priorities regarding the provision of this disease specific program. TRIAL REGISTRATION: ACTR number: 12607000080426.

The effectiveness of pulsed electrical stimulation (E-PES) in the management of osteoarthritis of the knee: a protocol for a randomised controlled trial.

BACKGROUND: Osteoarthritis (OA) of the knee is one of the main causes of musculoskeletal disability in the western world. Current available management options provide symptomatic relief (exercise and self-management, medication and surgery) but do not, in general, address the disease process itself. Moreover, adverse effects and complications with some of these interventions (medication and surgery) and the presence of co-morbidities commonly restrict their use. There is clearly a need to investigate treatments that are more widely applicable for symptom management and which may also directly address the disease process itself. In two randomised controlled trials of four and 12 weeks duration, pulsed electrical stimulation was shown to be effective in managing the symptoms of OA of the knee. Laboratory and animal studies demonstrate the capacity of externally applied electric and electromagnetic fields to positively affect chondrocyte proliferation and extracellular matrix protein production. This latter evidence provides strong theoretical support for the use of electrical stimulation to maintain and repair cartilage in the clinical setting and highlights its potential as a disease-modifying modality. METHODS/DESIGN: A double-blind, randomised, placebo-controlled, repeated measures trial to examine the effectiveness of pulsed electrical stimulation in providing symptomatic relief for people with OA of the knee over 26 weeks. Seventy people will be recruited and information regarding age, gender, body mass index and medication use will be recorded. The population will be stratified for age, gender and baseline pain levels. Outcome measures will include pain (100 mm VAS and WOMAC 3.1), function (WOMAC 3.1), stiffness (WOMAC 3.1), patient global assessment (100 mm VAS) and quality of life (SF-36). These outcomes will be measured at baseline, four, 16 and 26 weeks. Activity levels will be measured at baseline and 16 weeks using accelerometers and the Human Activity Profile questionnaire. A patient global perceived effect scale (11-point Likert) will be completed at 16 and 26 weeks. DISCUSSION: This paper describes the protocol for a randomised, double-blind, placebo-controlled trial that will contribute to the evidence regarding the use of sub-sensory pulsed electrical stimulation in the management of OA of the knee. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN12607000492459.

Probiotic containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophiles (ACTIMEL) for the prevention of Clostridium difficile associated diarrhoea in the elderly with proximal femur fractures.

The incidence of Clostridium difficile associated diarrhoea (CDAD) is greater in elderly patients. Probiotics may have a beneficial effect in the prevention of CDAD. However, their effect in elderly orthopaedic patients has not been previously reported. Between April 2013 and April 2014, 105 patients admitted with femoral neck fractures, and who required 3days of antibiotics for infection of any cause, were prescribed the probiotic ACTIMEL until 3days after the last antibiotic dose. The incidence of CDAD was compared with historical controls (April 2011￢ﾀﾓApril 2012). There was no significant reduction in the incidence of CDAD in patients receiving probiotics (OR: 0.9; 95% CI 0.27￢ﾀﾓ2.91; p=0.8) and therefore we cannot recommend the use of ACTIMEL containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophiles for this purpose in this patient group.

Geometric indices of bone strength are associated with physical activity and dietary calcium intake in healthy older women.

UNLABELLED: A population-based study on 1008 postmenopausal women identified that the 24% of women achieving high levels of PA and CI had 3.4-4.4% higher femoral bone strength in axial compression and 1.7-5.2% in bending than those achieving low levels, indicating that lifestyle factors influence bone strength in the proximal femur. INTRODUCTION: Extensive research has shown that increased physical activity (PA) and calcium intake (CI) decrease the rate of bone loss; however, there is little research on how these lifestyle variables affect bone geometry. This study was designed to investigate the effects of modifiable lifestyle variables, habitual PA and dietary CI, on femoral geometry in older women. MATERIALS AND METHODS: Femoral geometry, habitual PA, and dietary CI were measured in a population-based sample of 1008 women (median age+/-interquartile range, 75+/-4years) enrolled in a randomized controlled trial (RCT) of calcium supplementation. Baseline PA and CI were assessed by validated questionnaires, and 1-year DXA scans (Hologic 4500A) were analyzed using the hip structural analysis technique. Section modulus (Z), an index of bending strength, cross-sectional area (CSA), an index of axial compression strength, subperiosteal width (SPW), and centroid position, the position of the center of mass, were measured at the femoral neck (NN), intertrochanter (IT), and femoral shaft (FS) sites. These data were divided into tertiles of PA and CI, and the results were compared using analysis of covariance (ANCOVA), with corrections for age, height, weight, and treatment (calcium/placebo). RESULTS AND CONCLUSIONS: PA showed a significant dose-response effect on CSA all hip sites (p<0.03) and Z at the narrow neck and intertrochanter sites (p<0.02). For CI, there was a dose-response effect for centroid position at the intertrochanter (p=0.03). These effects were additive, such that the women (n=240) with PA in excess of 65.5 kcal/day and CI in excess of 1039 mg/day had significantly greater CSA (NN, 4.4%; IT, 4.3%; FS, 3.4%) and Z (NN, 3.9%; IT, 5.2%). These data show a favorable association between PA and aspects of bone structural geometry consistent with better bone strength. Association between CI and bone structure was only evident in 1 of 15 variables tested. However, there was evidence that there may be additive effects, whereby women with high levels of PA and CI in excess of 1039 mg/day had significantly greater CSA (NN, 0.4%; FS, 2.1%) and Z (IT, 3.0%) than women with high PA but low CI. These data show that current public health guidelines for PA and dietary CI are not inappropriate where bone structure is the health component of interest.

Dance training intensity at 11-14 years is associated with femoral torsion in classical ballet dancers.

OBJECTIVE: To examine in a cross sectional study the influence of femoral torsion (FT) and passive hip external rotation (PER) on turnout (TO). Starting age, years of classical ballet training, and current and past dance training intensity were assessed to determine their influence on FT, PER, and TO in pre-professional female dancers. METHODS: Sixty four dancers (mean (SD) age 18.16 (1.80) years) were recruited from four different dance training programmes. They completed a dance history questionnaire. FT was measured using a clinical method. PER was measured with the subjects prone, and TO was measured with the subjects standing. RESULTS: Mean TO was 136 degrees, mean unilateral PER was 49.4 degrees, and mean FT was 18.4 degrees. A positive correlation was observed between PER combined (PERC) and TO (r = 0.443, p < 0.001). A negative association was found between FT combined (FTC) and PERC (r = -0.402, p = 0.001). No association was found between starting age or years of classical ballet training and FTC, PERC, or TO. Dancers who trained for six hours a week or more during the 11-14 year age range had less FT than those who trained less (mean difference 6 degrees, 95% confidence interval 1.4 to 10.3). Students currently training for longer had higher levels of TO (p < 0.001) but comparable PERC and FTC. CONCLUSION: FT is significantly associated with PERC. Dancers who trained for six hours a week or more at 11-14 years of age had significantly less FT. FTC had a significant influence on PERC, but no influence on the execution of TO.

Do sleep problems or urinary incontinence predict falls in elderly women?

The objectives of this cross-sectional study were: (1) To determine if night-time sleep disturbance, daytime sleepiness, or urinary incontinence were associated with an increased risk of falling in older Australian women and (2) to explore the interrelationships between daytime sleepiness, night-time sleep problems, and urge incontinence. Participants were 782 ambulatory, community-dwelling women aged 75 to 86 recruited from within the existing Calcium Intake Fracture Outcome Study, in which women above 70 years were selected at random from the electoral roll. Daytime sleepiness, night-time sleep problems, urinary incontinence and falls data were collected via self-complete questionnaires. Thirty-five per cent of participants had fallen at least once in the past 12 months and 37.7% reported at least one night-time sleep problem. However, only 8.1% of the study sample experienced abnormal daytime sleepiness (Epworth Sleepiness Scale score > 10). Pure stress, pure urge, and mixed incontinence occurred in 36.8%, 3.7%, and 32.6% of participants respectively. In forward stepwise multiple logistic regression analysis, urge incontinence (OR 1.76; 95% CI 1.29 to 2.41) and abnormal daytime sleepiness (OR 2.05; 95% CI 1.21 to 3.49) were significant independent risk factors for falling after controlling for other falls risk factors (age, central nervous system drugs, cardiovascular drugs). As urge incontinence and abnormal daytime sleepiness were independently associated with an increased falls risk, effective management of these problems may reduce the risk of falling in older women.

Whole Arm Water Displacement Volumetry Is a Reliable and Sensitive Measure: A Pilot to Assess Acute Postburn Volume Change.

Water displacement volumetry (WDV) is a reliable method for measurement of wrist and hand volume in lymphedema patients. However, within session WDV reliability for the whole upper limb (UL) lacks comprehensive investigation, particularly in acute edema populations. This study aimed to confirm the reliability and investigate the impact of time between repeated trials on the sensitivity of WDV as a measure of whole UL volume change in an uninjured cohort and a burn injured pilot group. Within session, duplicate measures of whole UL WDV were recorded in two groups of noninjured volunteers and a group of burn patients. Each noninjured group differed only in the time between WDV repeats. The reliability trials were performed <10 minutes apart (T10) and 20 to 30 minutes apart (T20). The time between repetitions for burn patients was 20 to 30 minutes, based on the results of the noninjured participant trials. All trial groups demonstrated excellent correlation between trials (ICCT10 = 0.999, ICCT20 = 0.997). The minimum detectable difference calculated for WDV when measuring whole UL volume change of >50 ml for noninjured and >100 ml for burn patients. Despite this, a systematic bias was demonstrated between the T10 group means. The T20 group trials did not indicate such error on statistical testing (P = .297). The study confirms that WDV measurement of whole ULs is reliable and sensitive, if used at least 20 minutes apart. However, a significant and clinically relevant subject-by-method interaction was demonstrated. Researchers and clinicians are reminded to be aware of the performance of the technique when designing investigations in patient populations.

Reliability of palpation of humeral head position in asymptomatic shoulders.

The purpose of this study was to determine if, within a normal population: (1) palpation of the humeral head, relative to the acromion, in three static positions, was a reliable technique (2) there was a difference in humeral head position between the dominant and non-dominant shoulders in the three positions (3) there was a difference in humeral head position relative to the acromion between the arm at side (AS), the 90 degrees abduction/external rotation (AER) and 90 degrees abduction/internal rotation (AIR) positions. This test-retest study recorded palpation landmarks using a standardized protocol. Intra-tester reliability was above 0.8 for both AS and AER and all other ICCs were below 0.6. There was no systematic difference between dominant and non-dominant sides in any of the three positions (AS P=0.408, AER P=0.448, AIR P=0.233). There was a significant difference in measurements between each position (P<0.001). It can be concluded that, palpation of humeral head position in relation to the acromion is a reliable technique in the AS position. These normative data provide a baseline that can be used for future comparison if differences are found to exist in subgroups with pathological shoulder conditions where larger glenohumeral translations are thought to exist.

Effects of a water-based program on women 65 years and over: a randomised controlled trial.

The purpose of this study was to assess the effects of a water-based exercise and self-management program on balance, fear of falling, and quality of life in community-dwelling women 65 years of age or older with a diagnosis of osteopenia or osteoporosis. Fifty women with an average age of 73.3 years (range 65.5-82.4, SD 3.9) were randomised to intervention or control groups. The intervention group received a 10-week water-based exercise and self-management program compiled by Community Physiotherapy Services and conducted by a physiotherapist at an aquatic centre twice a week for one hour. The control group did not receive any instructions and were not encouraged to change their physical activity, activities of daily living or social habits during the study. Change in balance, measured using the step test, from baseline to follow-up differed between intervention and control groups, with mean (95% CI) between-group differences of 1.7 (0.9 to 2.6) and 2.1 (1.1 to 3.1) steps on the left and right sides respectively. Between-group differences in score changes were also significant in four of the eight domains of quality of life measured using the Short Form 36 questionnaire (SF36; physical function 8.6 (0.4 to 16.8), vitality 12.0 (2.3 to 21.8), social function, and 14.1 (0.6 to 27.7) mental health 10.2 (2.0 to 18.4)), but not fear of falling measured using the modified falls efficacy scale (0.25 (-0.3 to 0.81). It is concluded that a water-based exercise and self-management program produced significant changes in balance and quality of life, but not fear of falling, in this group of community-dwelling women 65 years of age or older with a diagnosis of osteopenia or osteoporosis.

Associations between turnout and lower extremity injuries in classical ballet dancers.

STUDY DESIGN: Descriptive correlational study. OBJECTIVES: To determine relationships between aspects of turnout and injury history in preprofessional classical ballet dancers, and to determine the clinical utility of various methods used to assess turnout. BACKGROUND: In Australia 50% of professional dancers currently have persistent or recurrent injuries, with 36% of these injuries commencing before 18 years of age (preprofessional level). Overuse or nontraumatic dance injuries are often attributed to faults in technique, with poor turnout and inappropriate compensatory strategies consistently cited as the main cause. METHODS AND MEASURES: Twenty-nine dancers (24 female), aged 15 to 22 years, were recruited from a preprofessional classical ballet program. Measurements were taken of passive and active hip external rotation (ER) range of motion (ROM) in supine, and functional turnout angles in standing. Three turnout variables were derived: active ER lag, compensated turnout, and static-dynamic turnout difference. Injury history over the previous 2 years was ascertained by interview. Pearson product moment and Spearman rank correlation coefficients were used to determine associations between turnout variables and injury history. RESULTS: All dancers reported a history of injury, with 93.1% reporting a history of nontraumatic injuries and 41.4% reporting a history of traumatic injuries. Number and severity of nontraumatic injuries were associated with reduced functional turnout (r or rho>0.38; P<.04), but not with hip ER ROM. Number and severity of traumatic injuries were not associated with turnout. No correlation was found between hip ER ROM and functional turnout. CONCLUSIONS: Functional measures of turnout are more relevant than hip ER ROM to prevalence of nontraumatic dance injuries. Control of turnout in classical ballet dancers should be assessed dynamically and in functional positions.

An opportunity in op-notes.

Operative notes in surgical practice are a vital source of information and communication between healthcare professionals as well as being a legal document. Errors and omissions can have serious effects on patient care and lead to confusion. We audited our compliance within trauma and orthopaedics at a busy district general hospital in South East England with the standard set by the Royal College of Surgeons (England) before and after the introduction of an operation note template. We achieved significant improvements in compliance across almost all of the standard's domains and recommend widespread implementation of similar templates nationally.

Lifestyle influences on 9-year changes in BMD in young women.

UNLABELLED: The effects of dietary calcium intake and physical activity on longitudinal changes in BMD over a mean of 9.4 years were examined in 62 healthy young women. Proximal femur BMD declined, lumbar spine BMD increased, and physical activity was associated with BMD change at intertrochanter and total hip sites. INTRODUCTION: Maximizing premenopausal BMD is an important strategy for the prevention of osteoporosis and resultant fractures later in life. MATERIALS AND METHODS: Young women who previously participated in a placebo-controlled 2-year calcium intervention study at a mean age of 18.5 +/- 0.3 years were remeasured at 27.8 +/- 1.0 years of age. DXA (Hologic QDR 1000W) was used to measure changes in BMD, and lifestyle factors were ascertained by questionnaire. RESULTS AND CONCLUSIONS: Early decline in BMD at the neck of femur (-3.3%/decade) and the converse gain in BMD at the lumbar spine (+4.3%/decade) and intertrochanter (+1.9%/decade) suggest site-specific changes in BMD in young premenopausal women. No effect of previous calcium supplementation was seen on current BMD or changes in BMD (p > 0.10). Lifestyle predictors of change in BMD were determined using hierarchical regression analysis after forced correction for the covariates baseline BMD and previous calcium supplementation. Physical activity was positively associated with change in BMD at total hip and intertrochanter sites (beta-coefficients, beta = 0.26 and 0.26 respectively; p < 0.05). Calcium intake was negatively associated with change in BMD at the lumbar spine (beta = -0.27, p < 0.05). Parity was negatively associated with change in BMD at all sites (beta = -0.40 to -0.26, p < 0.05). These data show that BMD is already declining at the proximal femur in these healthy young women. Physical activity assists in maintenance of BMD at some sites and thus may contribute to lifelong fracture prevention. There was no positive association between calcium intake and change in BMD.

Reduction of immunosuppressant therapy requirement in heart transplantation by calcitriol.

Calcitriol has been shown to have immunomodulatory effects. We examined whether heart transplant recipients, randomly assigned to receive calcitriol to reduce bone loss, required less immunosuppressive therapy or demonstrated different rejection and survival outcomes. Patients receiving low-dose calcitriol required substantially lower cumulative doses of cyclosporin (29% [95% confidence interval; 8%-50%] and 28% [7%-50%] for 1 and 2 years, respectively) for organ rejection without any detectable change in episodes of rejection, infection, or deaths. This major reduction of oral cyclosporine requirement, in addition to the skeletal benefits of calcitriol in those receiving immunosuppressive therapy, indicates a potential role for co-therapy with calcitriol or its analogues in the management of patients with solid-organ transplantation.

Combined immunosuppression with cyclosporine (neoral) and SDZ RAD in non-human primate lung transplantation: systematic pharmacokinetic-based trials to improve efficacy and tolerability.

BACKGROUND: We studied the efficacy and tolerability of combined immunosuppressive therapy with cyclosporine A microemulsion (Neoral) plus the macrolide SDZ RAD 40-0 (2-hydroxyethyl) rapamycin (RAD) in a stringent cynomolgus monkey lung graft model in comparison with cyclosporine or SDZ RAD monotherapy. METHODS: Thirty-nine cynomolgus monkeys received mixed lymphocyte reaction (MLR) mismatched unilateral lung transplants. Immunosuppressants were administered orally as single daily doses. The observation period was 28 days and follow-up included serial trough blood drug concentrations measured by high performance liquid chromatography/mass spectrometry, blood analyses, chest radiographs, open lung biopsies, as well as tissue drug concentrations and graft histology at necropsy. RESULTS: Graft biopsies in monkeys treated with vehicle (n=4), Neoral (day 1-7: 150 mg/kg/day; day 8-28: 100 mg/kg/day; n=6; mean +/- SE trough level (MTL): 292+/-17 ng/ml) or SDZ RAD monotherapy (1.5 mg/kg/day; n=6; MTL: 15+/-1 ng/ml) showed severe rejection. Coadministration in two transplant monkeys of Neoral (150/100 mg/kg/day) and SDZ RAD (1.5 mg/kg/day) caused their early death. In both animals, SDZ RAD blood levels were more than 5-fold higher than under monotherapy (MTL: 82+/-18 ng/ml). Simultaneous administration (n=6) of Neoral (150/100 mg/kg/day; MTL: 217+/-16 ng/ml) and SDZ RAD (0.3 mg/kg/day; MTL: 24+/-2 ng/ml) improved graft outcome (mild rejection). Side effects included renal failure (n=2) and seizures (n=1). Three monkeys survived to day 28. In this group the MTL for cyclosporin was 143+/-13 and for RAD 38+/-3. Staggered treatment completely prevented rejection in four of six grafts. However, five of six monkeys had moderate to severe diarrhea. In a concentration-controlled trial of simultaneously administered Neoral and SDZ RAD in transplant monkeys (target SDZ RAD MTL: 20-40 ng/ml; cyclosporine MTL: 100-200 ng/ml) all six monkeys survived with improved drug tolerability and an average biopsy score of mild rejection. CONCLUSION: Combination of orally administered SDZ RAD and Neoral showed excellent immunosuppressive efficacy in a stringent lung transplant model. The drug interaction and the narrow therapeutic index of this drug combination required careful dose adjustments to optimize tolerability and efficacy.

Multidimensional assessment of graft vascular disease (GVD) in aortic grafts by serial intravascular ultrasound in rhesus monkeys.

BACKGROUND: Graft vascular disease (GVD) is an incompletely understood process and the primary cause of late allograft failure. A nonhuman primate model was established to study the progression of GVD by using serial intravascular ultrasound (IVUS). METHODS: Aortic allografts were transplanted below the inferior mesenteric arteries (IMA) into 6 rhesus monkeys. Removed and re-implanted aortic segments between renal arteries, and the inferior mesenteric arteries served as autografts. IVUS was performed at days 0, 24, 52, 80, and 98 after transplantation. Vessel area (VA) and lumen area (LA) were measured from each cross-section at 0.5 mm intervals. Intimal index (II=100x (VA-LA/VA)) and corresponding vessel volumes were calculated for the whole grafts. Histologic features were assessed from autopsy samples using computerized morphometric method and a score from 0 to 3 for GVD (0=none, 3=severe). RESULTS: In allografts, vessel volume and luminal volume decreased significantly (P<0.05 for both) and the intimal index increased from 12% to 59% by day 98. These parameters remained unchanged in autografts. Histologic analysis of allografts showed concentric intimal hyperplasia and scattered mononuclear cell accumulations, whereas the autografts had only occasional eccentric intimal changes. The GVD-scores were significantly higher in allografts than in autografts (median 3 vs. 1, P=0.042). CONCLUSIONS: We introduce a nonhuman primate model of GVD that enables serial IVUS assessments of multiple parameters of GVD. Concentric intimal proliferation and decrease of vessel dimensions was observed in allografts as a consequence of alloimmunity. This is a potential new model for studying new therapies to prevent GVD or halt its progression.

The histology of subcutaneously implanted donor bronchial rings correlates with rejection scores of lung allografts in a primate lung transplant model.

BACKGROUND: The diagnosis of acute rejection in lung transplantation generally relies on transbronchial biopsies. This invasive procedure may be associated with bronchial bleeding or pneumothorax and may not be feasible in patients with severely compromised lung function. The hypothesis of the current study was that histopathological findings of donor bronchial segments implanted into the subcutaneous tissue of lung allograft recipients would predict lung tissue rejection scores, thus providing the clinician with an alternate source of information. METHODS: Unilateral left lung transplantation was performed in 34 cynomolgus monkeys as part of a drug efficacy study. After completion of the transplant procedure, 4 bronchial ring segments of the explanted recipient left lung and 4 bronchial ring segments of the non-transplanted right donor lung were implanted subcutaneously in the abdominal region. Lung allograft rejection was evaluated by open lung biopsies of the allograft performed on postoperative (PO) Day 14 and during sacrifice on PO Day 28. At the time of each biopsy, 2 donor and 2 recipient subcutaneous bronchial rings were explanted. Histologic evaluation of the lung tissue samples was performed according to the working formulation of the International Society for Heart and Lung Transplantation. Bronchial rings were independently evaluated by assessing the degree of airway narrowing; percentage of intact epithelial coverage as well as its specific histology (respiratory ciliated, flattened cuboidal, squamous); presence of lymphocytes, macrophages or spindle cells; and presence of peribronchial inflammation, luminal fibrosis, lymphocytic bronchitis or luminal mucous. Statistical analysis was performed by logistic regression. RESULTS: In the recipient bronchial rings, there was no evidence of airway narrowing. There was 98% epithelial coverage, 71% that were respiratory ciliated cells, and there was no inflammation. Donor bronchial rings showed no airway narrowing for monkeys with grade A0 to A2 rejection in tissue biopsies and a maximum narrowing (41.2%) with A4 rejection. Epithelial cell coverage was approximately 100% with grade A0-A2 and 44+/-11% with A4 rejection. Lymphocytic bronchitis was most severe in A4 rejection and minimal in A0 to A2 rejection. By logistic regression analysis, independent predictors of a likelihood of rejection were the degree of airway obliteration, the percentage of epithelial cell coverage, the degree of lymphocytic bronchitis and the product of respiratory and flattened cuboidal cell coverage. CONCLUSIONS: The current data show that histologic alterations of subcutaneously implanted donor bronchial rings correlate with lung tissue biopsy scores based on the ISHLT working formulation. Because subcutaneous bronchial rings can be explanted under local anesthesia, they may provide useful information for the diagnosis of acute allograft rejection in patients with impaired lung function, patients that obtaining lung tissue samples may not be feasible.