Reduction of breast lymphoedema secondary to breast cancer: a randomised controlled exercise trial.

BACKGROUND: Breast lymphoedema can occur following surgical treatment for breast cancer. We investigated whether an exercise program reduced breast lymphoedema symptoms compared to a non-exercise control group. METHODS: A single-blinded randomised controlled trial was conducted in which women with stable breast lymphoedema (n = 89) were randomised into an exercise (n = 41) or control (n = 47) group. The intervention comprised a 12-week combined aerobic and resistance training program, supervised weekly by an accredited exercise physiologist. All participants completed a weekly symptoms diary and were assessed monthly to ensure that there was no exacerbation of their lymphoedema. Changes in the breast were captured physically with ultrasound and bioimpedance spectroscopy and changes in symptoms were captured using European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer (BR23) and Lymphoedema Symptom Intensity and Distress questionnaires. RESULTS: The exercise group reported a greater reduction in breast-related symptoms than the control group, assessed by the EORTC BR23 breast symptom questions. Measures of extracellular fluid, assessed with bioimpedance spectroscopy ratio, decreased in the exercise group compared to the control group. No significant difference was detected in dermal thickness in the breast, assessed by ultrasound. Session attendance in the exercise sessions was high, with two musculoskeletal adverse events reported, but no exacerbations of lymphoedema observed. CONCLUSION: Combined resistance and aerobic exercise training is safe for women living with breast lymphoedema. Preliminary data suggest exercise training can reduce breast lymphoedema symptoms to a greater extent than usual care.

Screening for breast cancer-related lymphoedema: self-assessment of symptoms and signs.

INTRODUCTION: In the absence of monitoring programs, those at risk of developing breast cancer-related lymphoedema (BCRL) must detect its development. However, the efficacy of self-assessment for BCRL has not been widely investigated. This study will determine if symptoms and signs of BCRL are associated with lymphoedema detected by bioimpedance spectroscopy (BIS) and whether those with and without BCRL can accurately assess the signs of its presence. METHODS AND RESULTS: Participants with a history of breast cancer (n = 100) reported the presence/absence of symptoms associated with upper limb BCRL and underwent assessment for pitting oedema and differences in tissue texture between their arms (pinch). BIS detected BCRL in 48 women. Women were more likely to have BIS-detected BCRL if they reported swelling (odds ratio (OR), 58.8; 95% CI, 4.9 to 709.4; p = 0.001) or had inter-limb tissue texture differences in their forearm (OR, 73.5; 95% CI, 7.3 to 736.9; p = < 0.001) or upper arm (OR, 23.9; 95% CI, 2.8 to 201.7; p = 0.003). Agreement between therapist and self-assessment of signs of BCRL was almost perfect (kappa, 0.819 to 0.940). A combination of self-reported swelling and/or self-assessed forearm tissue texture difference identified all cases of BIS-detected BCRL. CONCLUSION: Participants accurately identified the presence or absence of physical signs of BCRL in their arm. Perceived swelling and differences in tissue texture in the affected arm were associated with, and sensitive to, BIS-detected BCRL. These findings support the use of self-assessment to determine if BCRL is developing, indicating the need for professional assessment.

Diagnosis of upper limb lymphedema: development of an evidence-based approach.

BACKGROUND: The diagnosis of secondary upper limb lymphedema (LE) is complicated by the lack of an agreed-upon measurement tool and diagnostic threshold. The aim of this study was to determine which of the many commonly used and normatively determined clinical diagnostic thresholds has the best diagnostic accuracy of secondary upper limb LE, when compared to diagnosis by an appropriate reference standard, lymphoscintigraphy. MATERIAL AND METHODS: The arms of women treated for breast cancer with and without a previous diagnosis of LE, as well as healthy controls, were assessed using lymphoscintigraphy, bioimpedance spectroscopy (BIS) and perometry. Dermal backflow score determined from lymphoscintigraphy imaging assessment (reference standard) was compared with diagnosis by both commonly used and normatively determined diagnostic thresholds for volume and circumference measurements as well as BIS. RESULTS: For those with established dermal backflow, all commonly used and normatively determined diagnostic thresholds accurately identified presence of LE compared with lymphoscintigraphy diagnosis. In participants with mild to moderate changes in dermal backflow, only a normatively determined diagnostic threshold, set at two standard deviations above the norm, for arm circumference and full arm BIS were found to have both high sensitivity (81% and 76%, respectively) and specificity (96% and 93%, respectively). For this group, strong, and clinically useful, positive (23 and 10, respectively) and negative likelihood (0.2 and 0.3) ratios were found for both the circumference and bioimpedance diagnostic thresholds. CONCLUSION: For the first time, evidence-based clinical diagnostic thresholds have been established for secondary LE. With mild LE, normatively determined circumference and BIS thresholds are superior to the commonly used thresholds.

Measuring body composition in dogs using bioelectrical impedance spectroscopy.

Assessment of body composition is an essential aspect of veterinary canine care, particularly as prevalence of overweight and obesity in dogs is increasing. Few quantitative objective methods for body composition measurement are available for routine clinical use. Bioelectrical impedance analysis is widely used in human medicine and nutritional assessment and although it has shown promise in production animals it has not yet been adopted for companion animals. The present study validated bioimpedance spectroscopy (BIS) against the reference method of dual-energy X-ray absorptiometry. Resistivity coefficients for use in BIS were determined: ρe = 444.8 and ρi = 1477.8 ohm.cm and used to predict fat-free mass (FFM) in a cohort of 35 mixed breed dogs. Overall, FFM was predicted to within 3.5% of reference values. At an individual level, FFM was predicted within 2 standard deviations (95% confidence) of 10%. BIS provides an objective quantitative alternative to the widely used semi-quantitative body condition scoring. In addition, BIS provides estimates of body water volumes (total, extra-and intracellular), information that can be useful in fluid management. BIS is inexpensive, and simple to perform but does require brief (<5 min) sedation of the animal.

KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study.

BACKGROUND: Inhibitors of the epidermal growth factor (EGFR) signaling pathway have a major role in the treatment of KRAS wild-type colorectal cancer patients. The EGFR pathway has been shown to be activated in gastric cancer (GC). However, published data on KRAS and BRAF mutation status is limited in GC and has not been compared between GC from different geographic regions. METHODS: The prevalence of KRAS and BRAF mutations was established in 712 GC: 278 GC from the United Kingdom, 230 GC from Japan and 204 GC from Singapore. The relationship between KRAS/BRAF mutation status, DNA mismatch repair (MMR) status, clinicopathological variables and overall survival was analysed. RESULTS: Overall, 30 (4.2%) GC carried a KRAS mutation. In total, 5.8% of the UK GC, 4% of Japan GC and 1.5% of Singapore GC were KRAS mutant. KRAS mutant GC had fewer lymph node metastases in the UK cohort (P=0.005) and were more frequent in elderly patients in the Japan cohort (P=0.034). KRAS mutations were more frequent in MMR-deficient GC in the UK and the Japanese cohort (P<0.05). A BRAF mutation was only detected in a single Japanese GC. CONCLUSIONS: This large multicentre study demonstrated that KRAS mutations and DNA MMR deficiency have a role in a small subgroup of GC irrespective of country of origin, suggesting that this subgroup of GC may have developed along a common pathway. Further studies need to establish whether concomitant mutations or amplifications of other EGFR signalling pathway genes may contribute to the activation of this pathway in GC.

Low urinary iodine postpartum is associated with hypothyroid postpartum thyroid dysfunction and predicts long-term hypothyroidism.

BACKGROUND: Postpartum thyroid dysfunction (PPTD) is characterized by an early hyperthyroid phase followed, with peak prevalence at 6 months, by a hypothyroid phase which carries a risk of long-term hypothyroidism. Iodine has a major effect on thyroid function. Western Australia has previously been shown to be iodine replete. OBJECTIVE: To examine the iodine status of women with and without PPTD and the relationship of iodine status postpartum with long-term hypothyroidism. DESIGN: Case-control with follow-up. PATIENTS: A total of 149 women at 6 months postpartum (74 PPTD, 75 controls) with 98 (46 PPTD, 52 controls) followed up at 12 years. MEASUREMENTS: Urinary iodine concentration (UIC) and thyroid function at 6 months postpartum; thyroid function at 12-year follow-up. RESULTS: At 6 months postpartum, median UIC (quartiles) for observed TSH ranges were: for TSH < 0·4 mU/l 130·0 µg/l (82·0, 170·0); for TSH 0·4-4·0 mU/l 123·0 µg/l (80·5, 168·0); for TSH > 4·0 mU/l 85·0 µg/l (40·0, 141·5), P = 0·018. The odds ratio (OR) of hypothyroid PPTD with each unit of decreasing log iodine was 2·54, (95%CI: 1·47, 4·35), and with UIC < 50 µg/l, OR 4·22, (95%CI: 1·54, 11·55). In the long term, decreased log UIC significantly predicted hypothyroidism at 12-year follow-up (P = 0·002); as did UIC < 100 µg/l (P = 0·03) and UIC < 50 µg/l (P = 0·02). The association was independent of antibody status. CONCLUSION: Low UIC measured at 6 months postpartum is associated with hypothyroid PPTD and independently predicts long-term hypothyroidism. We believe that it results from more severe preceding destructive thyroiditis, with discharge of thyroidal iodine, and thereby predicts a greater risk of long-term hypothyroidism.

Use of bioelectrical impedance spectroscopy to provide a measure of body composition in sows.

The ability to accurately estimate fat mass and fat-free mass (FFM) has the potential to improve the way in which sow body condition can be managed in a breeding herd. Bioelectrical impedance spectroscopy (BIS) has been evaluated as a practical technique for assessment of body composition in several livestock species, but similar work is lacking in sows. Bioelectrical impedance uses population-specific algorithms that require values for the apparent resistivities of body fluids and body proportion factors. This study comprised three major aims: (i) to derive apparent resistivity coefficients for extracellular water (ECW) and intracellular water (ICW) required for validation of BIS predictions of total body water (TBW) in live sows against standard reference tracer dilution methods; (ii) to develop predictions of TBW to body composition prediction algorithms, namely FFM, by developing a body geometry correction factor (Kb) and (iii) to compare the BIS predictions of FFM against existing impedance predictors and published prediction equations for use in sows, based on physical measurements of back-fat depth and BW (P2-based predictors). Whole body impedance measurements and the determination of TBW by deuterium dilution and ECW by bromide dilution were performed on 40 Large White x Landrace sows. Mean apparent resistivity coefficients of body fluids were 431.1 Ω.cm for ECW and 1827.8 Ω.cm for ICW. Using these coefficients, TBW and ECW were over-estimated by 6.5 and 3.3%, respectively, compared to measured reference values, although these differences were not statistically different (P > 0.05). Mean Kb was 1.09 ±â€¯0.14. Fat-free mass predictions were 194.9 kg, which equates to 60.9% of total sow weight, and 183.0 kg for BIS and the deuterium dilution method, respectively. Mean differences between the predicted and measured FFM values ranged from -8.2 to 32.7%, but were not statistically different (P > 0.05). Method validation (leave-one-out procedure) revealed that mean differences between predicted and measured values were not statistically significant (P > 0.05). Of the impedance-based predictors, equivalence testing revealed that BIS displayed the lowest test bias of 11.9 kg (8.2%), although the P2-based prediction equations exhibited the lowest bias and percentage equivalence, with narrow limits of agreement. Results indicate although differences between mean predicted and measured values were not significantly different, relatively wide limits of agreement suggest BIS as an impractical option for assessing body composition in individual sows compared to the use of existing prediction equations based on BW and back fat.

Postpartum thyroid dysfunction and the long-term risk of hypothyroidism: results from a 12-year follow-up study of women with and without postpartum thyroid dysfunction.

BACKGROUND: The long-term risk of hypothyroidism following postpartum thyroid dysfunction (PPTD) is uncertain. Most previous studies have been small, short-term or have lacked a control group. OBJECTIVE: To ascertain the long-term risk of hypothyroidism in women following PPTD. Design and participants A 12-year longitudinal study of 409 women (including 71 with PPTD) who previously participated in a PPTD prevalence study. MEASUREMENTS: The primary outcome measure was hypothyroidism (defined as TSH greater than 4 mU/l or on thyroxine replacement) at follow-up. Outcomes in women with and without PPTD were compared by logistic regression. Receiver operating characteristic analysis was used to determine the optimal cut-off for baseline TSH as a predictor of hypothyroidism in the cohort. RESULTS: At follow-up, hypothyroidism was present in 27 of 71 women who had PPTD at baseline (38%) and 14 of 338 women without PPTD (4%). From multivariate analysis, odds ratios (with 95% confidence intervals) for hypothyroidism were - 4.8 (1.6, 14.1) for PPTD; 8.2 (2.8, 24.6) for positive thyroid peroxidase antibodies (TPOAb); 9.7 (2.6, 37.0) for the hypothyroid phase of PPTD and 51.4 (19.2, 137.5) for hypothyroid PPTD with positive TPOAb. A baseline TSH above 2.6 mU/l was the optimal cut-off for predicting hypothyroidism (sensitivity 76%, specificity 86%). CONCLUSIONS: PPTD is a strong predictor of hypothyroidism in the long-term. Women who present with postpartum hypothyroidism or have positive TPOAb are at particularly high risk, suggesting that close long-term follow-up is advisable if thyroxine replacement is not instituted at an early stage.

Assessment of breast cancer-related arm lymphedema--comparison of physical measurement methods and self-report.

PURPOSE: To determine the relationship between physical methods of measuring lymphedema and self-reported swelling, their reliability, and standard error of measurement. METHOD: Lymphedema in each arm of women with (n = 33) and without (n = 18) unilateral arm lymphedema, secondary to breast cancer was measured by self-report, bioimpedance spectroscopy (BIS), perometer, and the truncated cone method. RESULTS: The physical measurement tools were highly reliable (ICC((2,1)): 0.94 to 1.00) with high concordance (r(c): 0.89 to 0.99). Self-report correlated moderately with physical measurements (r = 0.65 to 0.71) and was moderately reliable (ICC((2,1)): 0.70). CONCLUSIONS: Lymphedema assessment methods are concordant and reliable but not interchangeable.

A randomized trial to examine the mechanisms of cognitive, behavioral and mindfulness-based psychosocial treatments for chronic pain: Study protocol.

This randomized trial will evaluate the mechanisms of three chronic pain treatments: cognitive therapy (CT), mindfulness meditation (MM), and activation skills (AS). We will determine the extent to which late-treatment improvement in primary outcome (pain interference) is predicted by early-treatment changes in cognitive content, cognitive process, and/or activity level. The shared versus specific role of these mechanisms across the three treatments will be evaluated during treatment (Primary Aim), and immediately post-treatment to examine relapse mechanisms (Secondary Aim). We will enroll 300 individuals with chronic pain (with low back pain as a primary or secondary condition), with 240 projected to complete the study. Participants will be randomly assigned to eight, 1.5 h telehealth group sessions of CT, MM, or AS. Mechanisms and outcomes will be assessed twice daily during 2-week baseline, 4-week treatment period, and 4-week post-treatment epoch via random cue-elicited ecological momentary assessment (EMA); activity level will be monitored during these time epochs via daily monitoring with ActiGraph technology. The primary outcome will be measured by the PROMIS 5-item Pain Interference scale. Structural equation modeling (SEM) will be used to test the primary aims. This study is pre-registered on clinicaltrials.gov (Identifier: NCT03687762). This study will determine the temporal sequence of lagged mediation effects to evaluate rates of change in outcome as a function of change in mediators. The findings will provide an empirical basis for enhancing and streamlining psychosocial chronic pain interventions. Further, results will guide future efforts towards optimizing maintenance of gains to effectively reduce relapse risk.

Quantitative bioimpedance spectroscopy for the assessment of lymphoedema.

The aim was to make bioimpedance spectroscopy (BIS) quantitative for assessment of lymphoedema. Apparent resistivity coefficients were determined for the intra- and extracellular water of arms in a control cohort of women (n = 66). These coefficients were used to predict water volumes in the arms of women with lymphoedema (n = 23) and a separate control group without lymphoedema (n = 13) and to compare these with total arm size measured by perometry. Total arm volume was highly correlated (r = 0.80-0.90) with arm fluid volumes predicted by BIS and the proportional increase in arm size predicted by BIS was not significantly different to that measured by perometry. BIS predicted that the increased volume in the women with lymphoedema was predominantly (60%) due to increase in extracellular fluid. BIS is capable of quantifying the volume increase in limb size seen in lymphoedema.

Single frequency versus bioimpedance spectroscopy for the assessment of lymphedema.

BACKGROUND: The aims were to determine (i) whether single frequency bioimpedance analysis (SFBIA) is as accurate as bioimpedance spectroscopy (BIS) in measurement of extracellular fluid and (ii) whether change in extracellular fluid was specific to only the limb directly affected by surgery. METHODS: Arms of the control (n = 28) and arm lymphedema group (n = 28) and legs of the leg lymphedema group (n = 16) were assessed with SFBIA. All four limbs in all participants were assessed with BIS. All measurements occurred in a single session. RESULTS: BIS-measured ratios were highly concordant with those obtained with SFBIA (r (c) = 0.99, P < 0.001). Repeated measures ANOVA revealed that the ratio involving the lymphedema limb was different to the ratio of the non-oedematous limbs which was not significantly different to the arm or leg ratios of the control group. CONCLUSIONS: SFBIA is a simple accurate alternative to BIS for the clinical assessment of unilateral lymphedema. BIS discriminates those with clinical diagnosis of unilateral lymhoedema from those without the diagnosis.

Airplane travel and lymphedema: a case study.

A single subject prospective study of the relationship between air travel and lymphedema is reported. This proof of concept study was aimed at assessing the feasibility of using self-measured, inter-limb impedance ratios as a quantitative measure of lymphedema immediately prior to and following flying. The participant, a breast cancer survivor with lymphedema, measured whole arm impedance prior to and following air travel on 20 occasions, varying in duration of between 1 and 9 h, over a 12-month period. Although the inter-arm impedance ratio fluctuated over this time, it generally increased and worsened following flying. Impedance measurements were easily performed by the participant and could be obtained as close to the start and cessation of flying as is practicably possible. These data, when associated with self-assessment of lymphedema-related symptoms, could provide a comprehensive evidence base for an assessment of the risks associated with air travel and the provision of appropriate advice to prospective travelers. Further large-scale studies are recommended.

Optimal designs for studying bioimpedance.

D-optimal designs for nonlinear fixed and mixed effects models are explored, and the theory is applied to the measurement and analysis of bioelectrical impedance. Bioimpedance is known to vary more at extreme frequencies than others. D-optimal designs that account for this variation, and also possible mis-specification of initial parameter estimates, are considered in an attempt to find designs that will provide good parameter estimates in practice.

Body composition assessment in horses using bioimpedance spectroscopy.

Assessment of equine body composition using objective measurements is difficult owing to the large size of the animals and the costs involved. Bioelectrical impedance spectroscopy (BIS), a technique widely used for the assessment of body composition in humans, was investigated for practicality of use in horses. BIS uses algorithms that require values for the apparent resistivities of body fluids and body proportion factors (Kb), currently not available for horses. Aims of the present study were to derive resistivity coefficients and body proportion factors and to validate their use for prediction of body composition horses. Validation of coefficients and predictive power using a split-sample agreement study design using correlation and limits of agreement analysis. Whole body impedance measurements were performed on 35 standardbred horses, yearlings to 14 yr, concurrently with determination of total body water volume (TBW) by deuterium dilution and extracellular water volume (ECW) by bromide dilution. Kb was determined in an independent group of 38 mixed-breed, age, and sex horses. Mean apparent resistivity coefficients were 511.4 and 1415.9 ohm.cm for intracellular water and TBW, respectively. Mean Kb was 1.52 ± 0.1. Using these coefficients, TBW and fat-free mass could be predicted with limits of agreement (2SD) of ± 11.6%; mean fat-free mass and fat mass were under- and overestimated by 3.1% and 14.1%, respectively, compared to measured reference values although these differences were not statistically significant. BIS is a practical technique for the assessment of body composition in equids, but the relatively wide limits of agreement, particularly for fat mass, may limit its usefulness for predicting body composition in individual horses.

Bioimpedance spectroscopy in the infant: effect of milk intake and extracellular fluid reservoirs on resistance measurements in term breastfed infants.

BACKGROUND/OBJECTIVES: Bioimpedance spectroscopy is an accurate non-invasive method for measuring body composition in adults, but in infants it requires further testing and validation. Of the few studies of bioimpedance conducted in infants, none have comprehensively investigated the effect of milk intake volume. This study assessed the effect of the milk intake, feed duration and the volume of the infant's stomach and bladder on the resistance values pre-/post-feed to establish the feasibility of using these values interchangeably during data collection. SUBJECTS/METHODS: Forty-eight breastfeeding infants were measured at 2, 5, 9 and/or 12 months (n=62 sessions) within 1-2 min before the start and after the end of breastfeed. Median (IQR) time between measurements was 24 (20.0-30.0) min. Resistance measurements at 0 and 50 kHz, and infinite frequency (R0, R50 and Rinf) and resistance of intracellular water (Ricw) were analysed with customised infant settings. Milk intake was measured by test weights. Free-water volumes and free-water change were determined from stomach and bladder volumes calculated from ultrasound images. RESULTS: Small pre-to-post-feed changes (median (IQR): R0 -3.7 (-14.8, 14.3); R50 0.3 (-10.4, 15.0); Rinf 2.8 (-13.3, 35.5); Ricw 20.8 (-98.1, 290.9)) were not significantly different from zero (R0: P=0.92; R50: P=0.48; Rinf: P=0.32; Ricw: P=0.097). No significant effect of milk intake or free-water change was detected. CONCLUSIONS: The lack of consistent change in resistance across a breastfeed provides flexibility in the timing of measurements of infants in the research setting, such that typically pre- and post-feed measures of resistance can be used interchangeably.

Measuring body composition in dogs using multifrequency bioelectrical impedance analysis and dual energy X-ray absorptiometry.

Thirty-five healthy, neutered, mixed breed dogs were used to determine the ability of multifrequency bioelectrical impedance analysis (MFBIA) to predict accurately fat-free mass (FFM) in dogs using dual energy X-ray absorptiometry (DXA)-measured FFM as reference. A second aim was to compare MFBIA predictions with morphometric predictions. MFBIA-based predictors provided an accurate measure of FFM, within 1.5% when compared to DXA-derived FFM, in normal weight dogs. FFM estimates were most highly correlated with DXA-measured FFM when the prediction equation included resistance quotient, bodyweight, and body condition score. At the population level, the inclusion of impedance as a predictor variable did not add substantially to the predictive power achieved with morphometric variables alone; in individual dogs, impedance predictors were more valuable than morphometric predictors. These results indicate that, following further validation, MFBIA could provide a useful tool in clinical practice to objectively measure FFM in canine patients and help improve compliance with prevention and treatment programs for obesity in dogs.

Risk factors for lymphoedema in women with breast cancer: A large prospective cohort.

A prospective study was conducted to identify women at increased risk for lymphoedema (LE) based on axillary surgery. Assessment occurred prior to surgery, within 4 weeks, and at 6, 12 and 18 months following surgery. Following post-surgery assessment, women were asked to complete weekly diaries regarding events that occurred in the previous week. Risk factors were grouped into demographic, lifestyle, breast cancer treatment-related, arm swelling-related, and post-surgical activities. Bioimpedance spectroscopy thresholds were used to determine presence of LE. At 18-months, 241 women with <5 nodes removed and 209 women with ≥5 nodes removed were assessed. For those with <5 nodes removed, LE was present in 3.3% compared with 18.2% for those with ≥5 nodes removed. There were insufficient events to identify risk factors for those with <5 nodes removed; for those with >5 nodes removed, independent risk factors included presence of arm swelling at 12-months (Odds Ratio (OR): 13.5, 95% CI 4.8, 38.1; P < 0.01), at 6-months (5.6 (2.0, 16.9); P < 0.01), and radiotherapy to the axilla (2.6 (0.7, 8.9); P = 0.14). Arm swelling at 6 and 12 months was associated with taxane-based chemotherapy, high body weight at diagnosis and arm swelling within 4 weeks post-surgery. Of the post-surgical events assessed in a sub-group of women with >5 nodes removed and who maintained weekly diaries, only blood drawn from the 'at-risk' arm was identified as a potential risk (OR 2.0; 0.8, 5.2). For women with ≥5 nodes removed, arm swelling in the first year poses a very strong risk for presence of LE at 18-months.

Pediatric post-thrombotic syndrome in children: Toward the development of a new diagnostic and evaluative measurement tool.

OBJECTIVE: Our goal was to conduct the item generation and piloting phases of a new discriminative and evaluative tool for pediatric post-thrombotic syndrome. METHODS: We followed a formative model for the development of the tool, focusing on the signs/symptoms (items) that define post-thrombotic syndrome. For item generation, pediatric thrombosis experts and subjects diagnosed with extremity post-thrombotic syndrome during childhood nominated items. In the piloting phase, items were cross-sectionally measured in children with limb deep vein thrombosis to examine item performance. RESULT: Twenty-three experts and 16 subjects listed 34 items, which were then measured in 140 subjects with previous diagnosis of limb deep vein thrombosis (70 upper extremity and 70 lower extremity). The items with strongest correlation with post-thrombotic syndrome severity and largest area under the curve were pain (in older children), paresthesia, and swollen limb for the upper extremity group, and pain (in older children), tired limb, heaviness, tightness and paresthesia for the lower extremity group. CONCLUSION: The diagnostic properties of the items and their correlations with post-thrombotic syndrome severity varied according to the assessed venous territory. The information gathered in this study will help experts decide which item should be considered for inclusion in the new tool.

The kinetics of myofibrillar protein breakdown in perfused rat skeletal muscle.

Nt-Methylhistidine, a non-reutilised amino acid present in some myofibrillar proteins, was radioactively labelled in vivo with [Me-3H]methionine. The specific radioactivities of protein-bound methylhistidine and free methylhistidine in perfusate after perfusion of rat hind limbs taken from prelabelled rats was determined. The decrease in urinary methylhistidine activity with time was determined for rats similarly labelled. Comparison of the specific activities of free and bound methylhistidine and the non-linear semilogarithmic plot of urinary methylhistidine activity suggest that the myofibrillar protein catabolism, as indicated by methylhistidine release, may not be a simple exponential process. The possibility of non-random decay is discussed and an alternative model proposed.