Offloading of Diabetic Neuropathic Plantar Ulcers: Secondary Analysis of Step Activity and Ulcer Healing.

OBJECTIVE: Although it is well-known that offloading devices facilitate healing in people with diabetes and neuropathic plantar ulcers, little is known about how step activity affects healing. The purposes of this study were to compare: (1) healing outcomes (time to healing, percentage of ulcers healed); (2) healing rates by ulcer location; and (3) step activity (daily step count, daily peak mean cadence) among patients using either total contact casts (TCCs) or removable cast walker boots (RCWs). METHODS: The study included 55 participants (TCC, 29; RCW, 26) with diabetes mellitus, peripheral neuropathy, and a Wagner grade 1 or 2 neuropathic plantar ulcer. Each participant wore an activity monitor for 14 consecutive days. Step activity and healing variables were assessed using independent t tests, Kruskal-Wallis, Kaplan-Meier, and Mantel-Cox log-rank tests. RESULTS: Mean participant age was 55 (SD, 11) years. The percentage of ulcers healed was lower in the RCW group versus the TCC group (65% vs 93%). If healed, average healing rate was 77 (SD, 48) days in the TCC group and 138 (SD, 143) days in the RCW group. Survival distribution by ulcer location was different for RCW forefoot than other locations (132 ± 13 days vs 91 ± 15, 75 ± 11, and 102 ± 36 days for TCC forefoot, TCC-midfoot/hindfoot, and RCW-midfoot/hindfoot, respectively; χ2 = 10.69, P = .014). Average step count was 2,597 in the RCW group versus 1,813 steps in the TCC group (P = .07). The daily peak mean cadence for 20-, 30-, or 60-minute periods was greater with RCW use. CONCLUSIONS: Step activity in participants with RCWs was increased compared with those with TCCs. Because of their potential to be easily removable, RCWs may impair ulcer healing by allowing greater step activity.

Remote Research: Resources, Intervention Needs, and Methods in People with Diabetes and Peripheral Neuropathy.

BACKGROUND: Stay-at-home orders associated with the SARS-CoV-2 (COVID-19) pandemic were particularly important for older adults with type 2 diabetes, at risk for severe COVID-19 complications. In response, research shifted to remote telehealth methodology. Study participant interests, equipment needs, and ability to adapt methods to the remote/telehealth environment were unknown. Study purposes to assess (1) resource needs (internet/devices accessibility), (2) future telehealth interests, and (3) ability to adapt common research and clinical measures of glycemic control, physical function, activity measures, and quality of life outcomes to a telehealth setting. METHOD: Twenty-one participants with type 2 diabetes and peripheral neuropathy were recruited from a longitudinal study (11 female; age: 66.3 ± 8.3 years; DM: 15.1 ± 8.7 years). Technology needs and future telehealth interests were assessed. A glycemic measure (HbA1c), a five-times chair rise, a one-week activity monitor, and surveys (self-efficacy, depression, and balance) were collected. All aspects of the study were completed remotely over email and video/phone call. RESULTS: Twelve participants used computers; nine used phones for study completion. Participants had the following resource needs: connectivity (n = 3), devices (n = 6), and technical support (n = 12). Twenty people expressed interest in participating in future telehealth studies related to balance, exercise, and diabetes management. Methodological considerations were primarily the need for assistance for participants to complete the home HbA1c test, five-time chair rise, wearable activity monitoring, and surveys. CONCLUSIONS: Older adults with type 2 diabetes and peripheral neuropathy would need technological and personal assistance (connection, device, guidance) to complete a long-term telehealth intervention. Despite technology needs, participants were interested in telehealth interventions. CLINICAL TRIAL: Parent study, "Metatarsal Phalangeal Joint Deformity Progression-R01 (NCT02616263) is registered at https://clinicaltrials.gov/.

Resistance exercise training with protein supplementation improves skeletal muscle strength and improves quality of life in late adolescents and young adults with Barth syndrome: A pilot study.

BACKGROUND: Muscle weakness and exercise intolerance contribute to reduced quality of life (QOL) in Barth syndrome (BTHS). Our group previously found that 12 weeks of resistance exercise training (RET) improved muscle strength, however, did not increase muscle (lean) mass or QOL in n = 3 young adults with BTHS. The overall objective of this pilot study was to examine the safety and effectiveness of RET plus daily protein supplementation (RET + protein) on muscle strength, skeletal muscle mass, exercise tolerance, cardiac function, and QOL in late adolescents/young adults with BTHS. METHODS: Participants with BTHS (n = 5, age 27 ± 7) performed 12 weeks of supervised RET (60 minutes per session, three sessions/week) and consumed 42 g/day of whey protein. Muscle strength, muscle mass, exercise capacity, cardiac function, and health-related QOL were assessed pre-post intervention. RESULTS: RET + protein was safe, increased muscle strength and quality of life, and tended to increase lean mass. CONCLUSIONS: RET + protein appears safe, increases muscle strength and quality of life and tends to increase lean mass. Larger studies are needed to confirm these findings and to fully determine the effects of RET + protein in individuals with BTHS.

Myocardial glucose and fatty acid metabolism is altered and associated with lower cardiac function in young adults with Barth syndrome.

BACKGROUND: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function. METHODS/RESULTS: Young adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15O-water and 1-11C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 µmol·g-1·min-1, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g-1·min-1, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS. CONCLUSIONS: Myocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663.

Arginine kinetics are altered in a pilot sample of adolescents and young adults with Barth syndrome.

Barth syndrome (BTHS) is a rare, X-linked cardiomyopathy that is characterized by abnormalities in glucose and lipid metabolism, with less known regarding amino acid metabolism. This pilot study characterized whole-body arginine kinetics and found lower arginine rate of appearance into plasma (0.69 ± 0.09 vs. 0.88 ± 0.06 µmol/kgFFM/min, p < 0.01) and arginine non-oxidative disposal rate (0.64 ± 0.11 vs. 0.80 ± 0.03 µmol/kgFFM/min, p < 0.02) in adolescents and young adults with BTHS compared to Controls. This study provides a foundation for more in-depth studies on how arginine and potentially other amino acid abnormalities contribute to the pathology and clinical manifestations of BTHS.

Relationships within and between lower and upper extremity dysfunction in people with diabetes.

INTRODUCTION: Diabetes mellitus (DM) is associated with systemic musculoskeletal system impairments suggesting concurrent development of lower and upper extremity musculoskeletal problems. This study aims to examine relationships between lower and upper extremity function in people with DM. METHODS: Sixty people with type 2 DM and peripheral neuropathy [mean (standard deviation); 67(6) years old, DM duration 14(10) yrs] completed the following measures: 1) Self-reports of function: Foot and Ankle Ability Measure (FAAM; higher = better function) and Shoulder Pain and Disability Index (SPADI; lower = better function), 2) Range of motion (goniometry): ankle dorsiflexion and shoulder flexion, and 3) Strength: unilateral heel rise power (UHR, 3D kinetics) and hand grip dynamometry. Pearson correlations examined associations between lower and upper extremity measures, p < .05. RESULTS: Forty of 60 (67%) reported pain/disability in both the foot/ankle and shoulder and 95% of study participants had some limitation in foot or shoulder function. Significant between extremity correlations: FAAM and SPADI (r = -0.39), ankle dorsiflexion and shoulder flexion range of motion (r = 0.35), and UHR and hand grip strength (r = 0.40). Significant within extremity correlations: FAAM and UHR (r = .47) and SPADI with shoulder flexion (r = -0.44). CONCLUSION: Upper and lower extremity inter- and intra-relationships indicate systemic musculoskeletal impairments in people with DM. Healthcare practitioners should consider the potential for concurrent and disabling musculoskeletal problems in people with DM.

Skeletal Muscle Regeneration in Advanced Diabetic Peripheral Neuropathy.

BACKGROUND: Decreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies. METHODS: Biopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture. RESULTS: Histological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology. CONCLUSION: DPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage). CLINICAL RELEVANCE: Restoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes.

Accelerated Cortical Osteolysis of Metatarsals in Charcot Neuroarthropathy: A Cross-Sectional Observational Study.

Metatarsals are frequent sites of stress and fragility fractures in younger athletic populations and aging older adults. Metatarsal fractures are particularly common in Charcot neuroarthropathy (CN), a complication of diabetes mellitus (DM) and peripheral neuropathy (PN). Neuropathic metatarsal fractures may be caused by an accelerated cortical bone osteolysis and may be reflected as geometric-derived strength estimates from standard foot radiographs. The purpose of this cross-sectional study was to determine geometry and strength-derived estimates of the metatarsals in individuals with DM, PN, and CN compared with younger and older adult controls who were nondiabetic and nonneuropathic. We studied 62 participants: 20 young adult controls (YACs), 22 older adult controls (OACs), and 20 diagnosed with DMPN&CN. From weight-bearing radiographs, we measured the outer diaphysis diameter and inner marrow diameter at the distal, middle, and proximal diaphysis sites of the second and fifth metatarsal. From these diameters, we derived strength estimates of combined cortical width (CCt.Wi), percent cortical area (%Ct.rA), buckling ratio (BR), moment of inertia (MOI), and section modulus (SM) at each site in both metatarsals. DMPN&CN participants had an accelerated cortical thinning, decreased %Ct.Ar, increased BR, and lower MOI and SM compared with OACs and YACs. The OACs showed age-related decreases in CCt.Wi and % Ct.Ar, and increased BR. The BR demonstrated significant group × bone × site interaction with the distal fifth metatarsal in the DMPN&CN group having the lowest bone strength. The BR in the distal fifth metatarsal of DMPN&CN participants was 36% and 49% greater than in the OAC and YAC groups, respectively. DMPN&CN participants have lower metatarsal bone strength estimates compared with younger and older adult controls. Standard foot radiographs demonstrate an accelerated cortical osteolysis in DMPN&CN individuals, particularly in the distal fifth metatarsal diaphysis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Blunted fat oxidation upon submaximal exercise is partially compensated by enhanced glucose metabolism in children, adolescents, and young adults with Barth syndrome.

Barth syndrome (BTHS) is a rare X-linked condition resulting in abnormal mitochondria, cardioskeletal myopathy, and growth delay; however, the effects of BTHS on substrate metabolism regulation and their relationships with tissue function in humans are unknown. We sought to characterize glucose and fat metabolism during rest, submaximal exercise, and postexercise rest in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardioskeletal energetics and function. Children/adolescents and young adults with BTHS (n = 29) and children/adolescent and young adult control participants (n = 28, total n = 57) underwent an infusion of 6'6'H2 glucose and U-13 C palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% V˙O2peak ), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, 31 P magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.2 ± 9.8 vs 27.2 ± 8.1 µmol/kgFFM/min, P < .01) and exercise (34.7 ± 11.2 vs 29.5 ± 8.8 µmol/kgFFM/min, P < .05) and tended to be higher postexercise (33.7 ± 10.2 vs 28.8 ± 8.0 µmol/kgFFM/min, P < .06) compared to controls. Increases in total fat (-3.9 ± 7.5 vs 10.5 ± 8.4 µmol/kgFFM/min, P < .0001) and plasma fatty acid oxidation rates (0.0 ± 1.8 vs 5.1 ± 3.9 µmol/kgFFM/min, P < .0001) from rest to exercise were severely blunted in BTHS compared to controls. Conclusion: An inability to upregulate fat metabolism during moderate intensity exercise appears to be partially compensated by elevations in glucose metabolism. Derangements in fat and glucose metabolism are characteristic of the pathophysiology of BTHS. A severely blunted ability to upregulate fat metabolism during a modest level of physical activity is a defining pathophysiologic characteristic in children, adolescents, and young adults with BTHS.

Effect of a Shoulder Movement Intervention on Joint Mobility, Pain, and Disability in People With Diabetes: A Randomized Controlled Trial.

Background: People with diabetes are at high risk for shoulder pain, limited joint mobility, and adhesive capsulitis. Objective: The objective of this study was to evaluate the effects of a shoulder movement intervention (ShoMo) compared to a wellness intervention on the primary outcomes of active shoulder flexion and reported Shoulder Pain and Disability Index (SPADI) measured after intervention and 9 months later. Design: The design was a prospective, randomized, controlled clinical trial. Setting: The setting was a research center at an academic medical center. Participants: Fifty-two participants with type 2 diabetes and shoulder pain or limited motion were randomized to a group receiving ShoMo (N = 27; mean age = 59.3; SD = 7.0) or a group receiving wellness activities (N = 25; mean age = 57.9; SD = 7.7). Intervention: The ShoMo group received instruction in a progressive, active shoulder movement program. The wellness group received instruction in diabetes management. Measurements: Measurements were made at baseline, after 3 months of intervention, and at 6, 9, and 12 months after baseline. Results: After intervention, the ShoMo group had a 7.2-degree increase in active shoulder flexion compared with the wellness group (95% CI = 0.9-13.5°), but there was no difference at subsequent follow-ups. The ShoMo group showed a 12.7-point improvement in the SPADI score compared to the wellness group after intervention (95% CI = 1.1-24.3), which remained better than the wellness group 9 months later. Limitations: The number of participants and duration of follow-up were inadequate to determine if intervention can help to prevent future severe shoulder problems. Conclusions: A progressive shoulder movement program can have meaningful effects on active motion and symptoms in people with type 2 diabetes and mild-to-moderate shoulder symptoms, with symptom improvement lasting at least 9 months.

Peak oxygen uptake (VO2peak) across childhood, adolescence and young adulthood in Barth syndrome: Data from cross-sectional and longitudinal studies.

Barth syndrome (BTHS) is an ultra-rare, X-linked recessive disorder characterized by cardio-skeletal myopathy, exercise intolerance, and growth delay. Oxygen uptake during peak exercise (VO2peak) has been shown to be severely limited in individuals with BTHS however; the trajectory of VO2peak from childhood to young adulthood is unknown. The objective of this study was to describe VO2peak from childhood through young adulthood in BTHS. METHODS AND MATERIALS: VO2peak over time was presented through cross-sectional (n = 33 participants) and a longitudinal analyses (n = 12 participants). Retrospective data were obtained through maximal exercise testing on a cycle ergometer from individuals with BTHS who were or are currently enrolled in a research study during July 2006-September 2017. Participants included in the cross-sectional analysis were divided into 3 groups for analysis: 1) children (n = 13), 2) adolescents (n = 8), and 3) young adults (n = 12). Participants in the longitudinal analysis had at least two exercise tests over a span of 2-9 years. RESULTS: VO2peak relative to body weight (ml/kgBW/min), fat-free mass (FFM) and by percent of predicted VO2peak obtained were not significantly different between children, adolescents and young adults. VO2peak did not longitudinally change over a mean time of ~5 years in late adolescent and young adult participants with repeated tests. A model including both cardiac and skeletal muscle variables best predicted VO2peak. CONCLUSIONS: In conclusion, VO2peak relative to body weight and fat-free mass demonstrates short- and long-term stability from childhood to young adulthood in BTHS with some variability among individuals.

Reduced Muscle Strength in Barth Syndrome May Be Improved by Resistance Exercise Training: A Pilot Study.

BACKGROUND: Cardioskeletal myopathy is thought to contribute to exercise intolerance, and reduced quality of life (QOL) in Barth syndrome (BTHS). The objectives of this study were to examine: (1) skeletal muscle strength/performance in adolescents and young adults with BTHS and (2) the safety, feasibility, and initial efficacy of 12 weeks of progressive resistance exercise training (RET) on muscle strength, mass, and performance, bone mineral density, exercise tolerance, cardiac function, and QOL in individuals with BTHS. METHODS: Individuals with BTHS (n = 9, 23 ± 6 years), and age-, sex-, and activity level-matched unaffected Controls (n = 7, 26 ± 5 years) underwent baseline testing to assess muscle performance, exercise capacity, cardiac structure and function, body composition, and health-related QOL. Subsequently, n = 3 participants with BTHS performed 12 weeks of supervised RET (60 min per session, 3 sessions/week). All testing was repeated post-RET. RESULTS: BTHS had lower strength and lean muscle mass compared to Controls (all p < 0.05). BTHS also had diminished lower extremity, upper extremity, thoracic spine, lumbar spine, and pelvic bone mineral density (all p < 0.05) and reduced exercise capacity (p < 0.001) compared to Controls. RET was well-tolerated and attended, was not associated with any adverse events, and significantly increased muscle strength (p < 0.05). CONCLUSIONS: Individuals with BTHS demonstrate reduced muscle strength and mass, bone mineral density, and exercise capacity. RET appears safe and well-tolerated in BTHS and promotes increased muscle strength. Larger studies are needed to confirm these improvements and to fully determine the effects of RET in individuals with BTHS.

A Candidate Imaging Marker for Early Detection of Charcot Neuroarthropathy.

Inflammation-mediated foot osteopenia may play a pivotal role in the etiogenesis, pathogenesis, and therapeutic outcomes in individuals with diabetes mellitus (DM), peripheral neuropathy (PN), and Charcot neuroarthropathy (CN). Our objective was to establish a volumetric quantitative computed tomography-derived foot bone measurement as a candidate prognostic imaging marker to identify individuals with DMPN who were at risk of developing CN. We studied 3 groups: 16 young controls (27 ± 5 years), 20 with DMPN (57 ± 11 years), and 20 with DMPN and CN (55 ± 9 years). Computed tomography image analysis was used to measure metatarsal and tarsal bone mineral density in both feet. The mean of 12 right (7 tarsals and 5 metatarsals) and 12 left foot bone mineral densities, maximum percent difference in bone mineral density between paired bones of the right and the left feet, and the mean difference of the 12 right and the 12 left bone mineral density measurements were used as input variables in different classification analysis methods to determine the best classifier. Classification tree analysis produced no misclassification of the young controls and individuals with DMPN and CN. The tree classifier found 7 of 20 (35%) individuals with DMPN to be classified as CN (1 participant developed CN during follow-up) and 13 (65%) to be classified as healthy. These results indicate that a decision tree employing 3 measurements derived from volumetric quantitative computed tomography foot bone mineral density defines a candidate prognostic imaging marker to identify individuals with diabetes and PN who are at risk of developing CN.

Immobilization-induced osteolysis and recovery in neuropathic foot impairments.

BACKGROUND: Neuropathic foot impairments treated with immobilization and off-loading result in osteolysis. In order to prescribe and optimize rehabilitation programs after immobilization we need to understand the magnitude of pedal osteolysis after immobilization and the time course for recovery. OBJECTIVE: To determine differences in a) foot skin temperature; b) calcaneal bone mineral density (BMD) after immobilization; c) calcaneal BMD after 33-53weeks of recovery; and d) percent of feet classified as osteopenic or osteoporotic after recovery in participants with neuropathic plantar ulcers (NPU) compared to Charcot neuroarthropathy (CNA). METHODS: Fifty-five participants with peripheral neuropathy were studied. Twenty-eight participants had NPU and 27 participants had CNA. Bilateral foot skin temperature was assessed before immobilization and bilateral calcaneal BMD was assessed before immobilization, after immobilization and after recovery using quantitative ultrasonometry. RESULTS: Before immobilization, skin temperature differences in CNA between their index and contralateral foot were markedly higher than NPU feet (3.0 degree C versus 0.7 degree C, respectively, p<0.01); BMD in NPU immobilized feet averaged 486±136mg/cm2, and CNA immobilized feet averaged 456±138mg/cm2, p>0.05). After immobilization, index NPU feet lost 27mg/cm2; CNA feet lost 47mg/cm2 of BMD, p<0.05. After recovery, 61% of NPU index feet and 84% of CNA index feet were classified as osteopenic or osteoporotic. CONCLUSIONS: There was a greater osteolysis after immobilization with an attenuated recovery in CNA feet compared to NPU feet. The attenuated recovery of pedal BMD in CNA feet resulted in a greater percentage of feet classified as osteoporotic and osteopenic.

Relationship of shoulder activity and skin intrinsic fluorescence with low level shoulder pain and disability in people with type 2 diabetes.

AIM: People with type 2 diabetes (T2DM) have a high incidence of musculoskeletal disorders thought to be influenced by high non-enzymatic advanced glycated end-products (AGEs). The goals of this study were to determine differences in shoulder activity level and AGEs in people with T2DM compared to matched controls, and to determine factors associated with shoulder pain and disability. METHODS: Eighty-one participants, T2DM (n=52) and controls (n=29), were examined for magnitude and duration of shoulder activity (measured using accelerometers), skin intrinsic florescence (SIF) as a surrogate measure of AGE level, and the Shoulder Pain and Disability Index (SPADI) as a self-report of shoulder pain and disability. RESULTS: Compared with controls, T2DM participants had 23% less shoulder activity (p=0.01), greater SIF level (3.6±1.7 vs 2.7±0.6AU, p=0.01), less shoulder strength (p<0.05), and the duration of their shoulder activity was moderately associated (r=0.40; p<0.01) with reported shoulder pain and disability. Shoulder pain and disability were not related to SIF level. CONCLUSIONS: Persons with T2DM have higher SIF levels and shoulder symptoms and disability indices than controls. Research is needed to determine if a shoulder mobility intervention to increase strength and mobility can help decrease shoulder pain and disability.

Persistent inflammation with pedal osteolysis 1year after Charcot neuropathic osteoarthropathy.

AIMS: To determine local and systemic markers of inflammation and bone mineral density (BMD) in the foot and central sites in participants with diabetes mellitus and peripheral neuropathy (DMPN) with and without acute Charcot neuropathic osteoarthropathy (CN). METHODS: Eighteen participants with DMPN and CN and 19 participants without CN had foot temperature assessments, serum markers of inflammation [C-reactive protein, (CRP) and erythrocyte sedimentation rate, (ESR)] and BMD of the foot, hip and lumbar spine at baseline and 1year follow-up. RESULTS: CN foot temperature difference was higher compared to DMPN controls at baseline (4.2±1.9°F vs. 1.2±0.9°F, P<0.01) and after 1year (2.9±3.2°F vs. 0.9±1.1°F, P<0.01). Serum inflammatory markers in the CN group were greater at baseline and remained elevated 1year later compared to DMPN controls (CRP, P=0.02, ESR, P=0.03). All pedal bones' BMD decreased an average of 3% in the CN foot with no changes in hip or lumbar spine. DMPN controls' foot, hip and lumbar spine BMD remained unchanged. CONCLUSIONS: Local and systemic inflammation persists 1 year after CN with an accompanying pedal osteolysis that may contribute to mid foot deformity which is the hallmark of the chronic Charcot foot.

Impaired cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with Barth syndrome.

Barth syndrome (BTHS) is an X-linked condition characterized by altered cardiolipin metabolism and cardioskeletal myopathy. We sought to compare cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardiac function and exercise capacity. Children/adolescents and young adults with BTHS (n = 20) and children/adolescent and young adult control participants (n = 23, total n = 43) underwent 31P magnetic resonance spectroscopy (31P-MRS) of the lower extremity (calf) and heart for estimation of skeletal muscle and cardiac bioenergetics. Peak exercise testing (VO2peak) and resting echocardiography were also performed on all participants. Cardiac PCr/ATP ratio was significantly lower in children/adolescents (BTHS: 1.5 ± 0.2 vs. CONTROL: 2.0 ± 0.3, P < 0.01) and adults (BTHS: 1.9 ± 0.2 vs. CONTROL: 2.3 ± 0.2, P < 0.01) with BTHS compared to Control groups. Adults (BTHS: 76.4 ± 31.6 vs. CONTROL: 35.0 ± 7.4 sec, P < 0.01) and children/adolescents (BTHS: 71.5 ± 21.3 vs. CONTROL: 31.4 ± 7.4 sec, P < 0.01) with BTHS had significantly longer calf PCr recovery (τPCr) postexercise compared to controls. Maximal calf ATP production through oxidative phosphorylation (Qmax-lin) was significantly lower in children/adolescents (BTHS: 0.5 ± 0.1 vs. CONTROL: 1.1 ± 0.3 mmol/L per sec, P < 0.01) and adults (BTHS: 0.5 ± 0.2 vs. CONTROL: 1.0 ± 0.2 mmol/L sec, P < 0.01) with BTHS compared to controls. Blunted cardiac and skeletal muscle bioenergetics were associated with lower VO2peak but not resting cardiac function. Cardiac and skeletal muscle bioenergetics are impaired and appear to contribute to exercise intolerance in BTHS.

Endurance Exercise Training in Young Adults with Barth Syndrome: A Pilot Study.

BACKGROUND: Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by mitochondrial abnormalities, cardio-skeletal myopathy, exercise intolerance, and premature mortality. The effect on endurance exercise training on exercise tolerance, cardio-skeletal function, and quality of life in BTHS is unknown. METHODS: Four young adults (23 ± 5 years, n = 4) with BTHS participated in a 12-week, supervised, individualized endurance exercise training program. Exercise training was performed on a cycle ergometer for 30-45' three times per week at a moderate intensity level. Exercise tolerance was measured by graded exercise testing and peak oxygen consumption, heart function via two-dimensional and M-mode echocardiography, skeletal muscle function by near-infrared spectroscopy, and quality of life through the Minnesota Living with Heart Failure questionnaire. RESULTS: There were no adverse events during exercise testing or training for any participant. Peak oxygen consumption modestly (~5%) improved in three or four participants. Mean quality of life questions regarding dyspnea and side effects from medications significantly improved following exercise training. Mean resting heart function or skeletal muscle oxygen extraction during exercise did not improve after exercise training. CONCLUSION: Endurance exercise training is safe and appears to modestly improve peak exercise tolerance and certain measures of quality of life in young adults with BTHS. However, compared to improvements resulting from endurance exercise training seen in other non-BTHS mitochondrial myopathies and heart failure, these improvements appear blunted. Further research into the most beneficial mode, intensity and frequency of exercise training in BTHS is warranted.

Impact of foot progression angle modification on plantar loading in individuals with diabetes mellitus and peripheral neuropathy.

AIMS: To determine if participants can reduce foot progression angle (FPA), and if FPA reduction decreases regional plantar stresses and forces in individuals with diabetes. METHODS: Design: Three-group cross-sectional design with repeated measures. subjects: twenty-eight participants either with diabetes mellitus (DM), diabetes and peripheral neuropathy with (DMPN+NPU) or without a prior history of ulceration (DMPN-NPU) were studied. Intervention: Participants were first instructed to walk over a 3.6 m walkway at their preferred FPA, and then to walk with their foot aligned parallel with the line of gait progression at their self-selected speed. Dynamic plantar kinetics in six masked regions were collected using an EMED-st-P-2 pedobarograph. Main measures: Primary outcome measures were FPA, peak plantar pressure (PPP), and force-time integral (FTI). A repeated measures ANOVA was conducted to determine group differences in FPA for both walking conditions. Regional differences in PPPs and FTIs between preferred and corrected walking conditions were analyzed using repeated measures ANCOVA. RESULTS: Participants showed a reduction in FPA magnitude on the 'Involved' foot between the preferred and corrected walking conditions (p<0.01). There were no differences in PPPs or FTIs in any mask between walking conditions (p>0.05). CONCLUSION: Results from this investigation offer important evidence that people with diabetes can modify their FPA with a simple intervention of visual and verbal cueing. Future research should examine if gait retraining strategies in regular footwear more effectively offload areas of elevated regional plantar stresses and forces in adults with diabetes mellitus and peripheral neuropathy.

Static and Dynamic Predictors of Foot Progression Angle in Individuals with and without Diabetes Mellitus and Peripheral Neuropathy.

INTRODUCTION: Foot progression angle (FPA) is a predictor of elevated regional plantar stresses and loads, which are indicators of dermal injury risk in individuals with diabetes mellitus and peripheral neuropathy (DMPN). FPA accounts for 15-45% of the variance in plantar stresses and loads in adults with DMPN. However, the biomechanical factors underlying an "out-toeing" gait pattern in this clinical population have not been examined. The primary purpose of this study was to identify static and dynamic predictors of foot progression angle magnitude in adults with and without DMPN. METHODS: Thirty-three adults with and 12 adults without diabetes mellitus participated. Hip rotation, ankle dorsiflexion, and resting calcaneal stance position were measured using a standard goniometer. Kinematic and kinetic data were collected during walking. RESULTS AND DISCUSSION: Static predictor variables did not significantly predict foot progression angle magnitude using multiple regression analysis. Of the dynamic predictor variables, thigh and shank lateral rotation accounted for 37% of foot progression angle variance (p<.01). CONCLUSIONS: Our results show that dynamic measures of external rotation of proximal segments (thigh, shank) during gait are strong predictors of foot progression angle. Static measures of limited joint mobility and joint position do not predict foot progression angle. These findings suggest that targeting the thigh and shank rotation using verbal or tactile cueing may be a potential strategy when trying to alter walking movement patterns towards decreasing external (lateral) FPA to minimize risk of elevated regional plantar stresses in adults with DMPN at risk for ulceration.