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1.  Characteristics of human knee muscle coordination during isometric contractions in a standing posture: The effect of limb task 
Different functional roles for the hands have been demonstrated, however leg control is not as well understood. The purpose of the present study was to evaluate bilateral knee neuromuscular control to determine if the limb receiving greater attention would have more well-tuned control compared to an unattended limb. Surface electrodes were placed on seven muscles of each limb, before standing on two force platforms. Visual feedback was given of the forces and moments of the “focus limb,” but not the “unattended limb.” Static isometric forces were matched with their focus limb, requiring their unattended limb to push in the opposite direction, using a combination of forward-backward-medial-lateral shear forces while muscle activity was collected bilaterally. There was a significant main effect for limb task (p = 0.02), with the medial hamstrings being more specific (p = 0.001) while performing the unattended limb and the lateral hamstring being more well-tuned (p = 0.007) while performing the focus limb task. The focus limb's medial and lateral gastrocnemius were principally active in the forwards direction, but only the unattended limb's lateral gastrocnemius was active in the backwards direction. Findings suggest unique neuromuscular control strategies are used for the legs depending on limb task.
PMCID: PMC4315617  PMID: 23790392
Neuromechanics; Specificity; Synergy; Bidirectional; Intermuscular coordination
2.  Differences in Neuromuscular Control and Quadriceps Morphology Between Potential Copers and Noncopers Following Anterior Cruciate Ligament Injury 
Study Design
Prospective cross-sectional study.
To compare knee muscle morphology and voluntary neuromuscular control in individuals who sustained an anterior cruciate ligament (ACL) injury and were identified as being capable of avoiding surgery (potential copers) and those who were recommended for surgery (noncopers), within 6 months of injury.
Quadriceps atrophy and poor neuromuscular control have been found in noncopers. However, the reasons why some noncopers may be able to avoid surgery remain elusive.
Twenty participants (10 ACL-deficient noncopers and 10 ACL-deficient potential copers) were included in this study. Axial spin-echo, T1-weighted magnetic resonance imaging data of the lower extremities were captured. The volume and maximum cross-sectional area (CSA) of each muscle of the quadriceps and hamstrings were calculated following digital reconstruction. In addition, voluntary neuromuscular control was evaluated using an established target-matching task that required participants to produce static isometric loads across the knee joint. Electromyography was acquired from 5 muscles as participants performed the target-matching task. Circular statistics were used to calculate a specificity index to describe how well focused each muscle was activated toward its primary direction of muscle action. The ACL-deficient limb was then compared to the uninvolved limb of the noncopers and potential copers.
The vasti (vastus medialis and vastus intermedius) of the involved limb of the noncopers were significantly smaller (P<.031) in comparison to those of their uninvolved limb. The potential copers' vastus lateralis maximum CSA (P = .047), total quadriceps muscle volume (P = .020) and maximum CSA (P = .015), and quadriceps-hamstring ratio volume (P = .021) and maximum CSA (P = .007) demonstrated quadriceps atrophy. However, only the ACL-deficient limb of the older (mean ± SD age, 27.4 ± 11.4 versus 19.9 ± 3.3 years; P = .032) and lower-activity-level (3.3 ± 0.5 versus 3.6 ± 0.5; P = .098) noncoper group demonstrated reduced rectus femoris (P = .057) and lateral hamstring (P = .064) neuromuscular control in comparison to their uninvolved limb.
These findings suggest that quadriceps and hamstring muscle function, rather than muscle size, may be an important factor in the varied response early after ACL injury.
PMCID: PMC4314094  PMID: 24261930
ACL; knee; MRI
3.  Longitudinal changes in insulin sensitivity and beta cell function between women with and without a history of gestational diabetes mellitus 
Diabetologia  2013;56(12):2753-2760.
The aim of the study was to compare longitudinal changes in insulin sensitivity (SI) and beta cell function between women with and without a history of gestational diabetes mellitus (GDM).
The prospective follow-up cohort included 235 parous non-diabetic Mexican-American women, 93 with and 142 without a history of GDM. The participants underwent dual-energy x-ray absorptiometry, OGTTs and IVGTTs at baseline and at a median of 4.1 years follow-up. The baseline values and rates of change of metabolic measures were compared between groups.
At baseline, women with prior GDM (mean age 36.3 years) had similar values of SI but higher percentages of body fat and trunk fat (p≤0.02), a lower acute insulin response and poorer beta cell compensation (disposition index [DI]) (p<0.0001) than women without GDM (mean age 37.9 years). During the follow-up, women with GDM had a faster decline in SI (p=0.02) and DI (p=0.02) than their counterparts without GDM, with no significant differences in changes of weight or fat (p>0.50). Adjustment for baseline age, adiposity, calorie intake, physical activity, age at first pregnancy, additional pregnancies and changes in adiposity during follow-up increased the between-group differences in the rates of change of SI and DI (p≤0.003).
Mexican-American women with recent GDM had a faster deterioration in insulin sensitivity and beta cell compensation than their parous counterparts without GDM. The differences were not explained by differences in adiposity, suggesting more deleterious effects of existing fat and/or reduced beta cell robustness in women with GDM.
PMCID: PMC4139094  PMID: 24030069
Beta cell function; Gestational diabetes mellitus; Longitudinal change; Insulin sensitivity
4.  Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk 
Diabetes Care  2013;36(11):3607-3612.
Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance.
We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.
In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ∆G0–120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ∆I0–120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [∆I0–120/∆G0–120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.
In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).
PMCID: PMC3816921  PMID: 24062330
5.  Prevention of Diabetes With Pioglitazone in ACT NOW 
Diabetes  2013;62(11):3920-3926.
We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.
PMCID: PMC3806596  PMID: 23863810
6.  Compensatory muscle activation caused by tendon lengthening post Achilles tendon rupture 
The purpose of this study was to establish a relationship between the lengthening of the Achilles tendon post rupture and surgical repair to muscle activation patterns during walking in order to serve as a reference for post-surgical assessment.
The Achilles tendon lengths were collected from 4 patients with an Achilles tendon rupture 6 and 12 month post-surgery along with 5 healthy controls via ultrasound. EMG was collected from the triceps surae muscles and tibialis anterior during over-ground walking.
Achilles lengths at 6 and 12 months post-surgery were significantly longer (p < 0.05) on the involved side compared to the uninvolved side but there were no side to side differences in the healthy controls. The integrated EMG (iEMG) of the involved side was significantly higher than the uninvolved side in the lateral gastrocnemius at 6 months and for the medial gastrocnemius at 12 months in the patients with Achilles tendon rupture; no side to side difference was found in the healthy controls. The triceps surae muscles’ activations were fair to moderately correlated to the Achilles lengths (0.38 < r < 0.52).
The increased Achilles tendon length and iEMG from the triceps surae muscles indicate that loss of function is primarily caused by anatomical changes in the tendon and the appearance of muscle weakness is due to a lack of force transmission capability. This study indicates that when aiming for full return of function and strength an important treatment goal appears to be to minimize tendon elongation.
Level of evidence
Prognostic prospective case series. Level IV.
PMCID: PMC3778146  PMID: 23609529
EMG; gait; neural inhibition; surgery; ankle
7.  Insulin Sensitivity and Insulin Clearance are Heritable and Have Strong Genetic Correlation in Mexican Americans 
Obesity (Silver Spring, Md.)  2014;22(4):1157-1164.
We describe the GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI).
Design and Methods
GUARDIAN is comprised of seven cohorts, consisting of 4336 Mexican-American individuals in 1346 pedigrees. Insulin sensitivity (SI), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3925 individuals) using variance components.
Across studies, age and gender-adjusted heritability of insulin sensitivity (SI, M, M/I) ranged from 0.23–0.48 and of MCRI from 0.35–0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and −0.57 to −0.59 for AIRg and MCRI (all P<0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P<0.0001); and −0.16 to −0.36 for AIRg and MCRI (P <0.0001−0.06).
These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.
PMCID: PMC3968231  PMID: 24124113
insulin sensitivity; insulin clearance; heritability; genetic correlation; environmental correlation
8.  Minimum detectable change for knee joint contact force estimates using an EMG-driven model 
Gait & posture  2013;38(4):1051-1053.
Adequate test–retest reliability of model estimates is a necessary precursor to examining treatment effects or longitudinal changes in individuals.
The purpose of this study was to establish thresholds for minimal detectable change (MDC) for joint contact forces obtained using a patient specific EMG-driven musculoskeletal model of the knee.
A sample of young, active individuals was selected for this study, and subjects were tested on 2 separate days. Three-dimensional motion analysis with electromyography (EMG) was used to obtain data from each subject during gait for model input. An EMG-driven modeling approach was used to estimate joint contact forces at each session.
MDC’s for contact force variables ranged from 0.30 to 0.66 BW. The lowest MDC was for peak medial compartment force (0.30 BW) and the highest was for peak tibiofemoral contact force (0.66 BW). Test–retest reliability coefficients were also reported for comparison with previous work.
Using the present model, changes in joint contact forces between baseline and subsequent measurements that are greater than these MDCs are greater than typical day-to-day variation and can be identified as real change.
PMCID: PMC3795951  PMID: 23601782
Contact force; Electromyography; Musculoskeletal model; Minimal detectable change; Reliability
9.  Differences in Plantar Flexor Fascicle Length and Pennation Angle between Healthy and Poststroke Individuals and Implications for Poststroke Plantar Flexor Force Contributions 
Stroke Research and Treatment  2014;2014:919486.
Poststroke plantar flexor muscle weakness has been attributed to muscle atrophy and impaired activation, which cannot collectively explain the limitations in force-generating capability of the entire muscle group. It is of interest whether changes in poststroke plantar flexor muscle fascicle length and pennation angle influence the individual force-generating capability and whether plantar flexor weakness is due to uniform changes in individual muscle force contributions. Fascicle lengths and pennation angles for the soleus, medial, and lateral gastrocnemius were measured using ultrasound and compared between ten hemiparetic poststroke subjects and ten healthy controls. Physiological cross-sectional areas and force contributions to poststroke plantar flexor torque were estimated for each muscle. No statistical differences were observed for any muscle fascicle lengths or for the lateral gastrocnemius and soleus pennation angles between paretic, nonparetic, and healthy limbs. There was a significant decrease (P < 0.05) in the paretic medial gastrocnemius pennation angle compared to both nonparetic and healthy limbs. Physiological cross-sectional areas and force contributions were smaller on the paretic side. Additionally, bilateral muscle contributions to plantar flexor torque remained the same. While the architecture of each individual plantar flexor muscle is affected differently after stroke, the relative contribution of each muscle remains the same.
PMCID: PMC4134812  PMID: 25147753
10.  Poststroke Muscle Architectural Parameters of the Tibialis Anterior and the Potential Implications for Rehabilitation of Foot Drop 
Stroke Research and Treatment  2014;2014:948475.
Poststroke dorsiflexor weakness and paretic limb foot drop increase the risk of stumbling and falling and decrease overall functional mobility. It is of interest whether dorsiflexor muscle weakness is primarily neurological in origin or whether morphological differences also contribute to the impairment. Ten poststroke hemiparetic individuals were imaged bilaterally using noninvasive medical imaging techniques. Magnetic resonance imaging was used to identify changes in tibialis anterior muscle volume and muscle belly length. Ultrasonography was used to measure fascicle length and pennation angle in a neutral position. We found no clinically meaningful bilateral differences in any architectural parameter across all subjects, which indicates that these subjects have the muscular capacity to dorsiflex their foot. Therefore, poststroke dorsiflexor weakness is primarily neural in origin and likely due to muscle activation failure or increased spasticity of the plantar flexors. The current finding suggests that electrical stimulation methods or additional neuromuscular retraining may be more beneficial than targeting muscle strength (i.e., increasing muscle mass).
PMCID: PMC4124652  PMID: 25133011
11.  Randomized controlled trial to evaluate the effects of combined progressive exercise on metabolic syndrome in breast cancer survivors: rationale, design, and methods 
BMC Cancer  2014;14:238.
Metabolic syndrome (MetS) is increasingly present in breast cancer survivors, possibly worsened by cancer-related treatments, such as chemotherapy. MetS greatly increases risk of cardiovascular disease and diabetes, co-morbidities that could impair the survivorship experience, and possibly lead to cancer recurrence. Exercise has been shown to positively influence quality of life (QOL), physical function, muscular strength and endurance, reduce fatigue, and improve emotional well-being; however, the impact on MetS components (visceral adiposity, hyperglycemia, low serum high-density lipoprotein cholesterol, hypertriglyceridemia, and hypertension) remains largely unknown. In this trial, we aim to assess the effects of combined (aerobic and resistance) exercise on components of MetS, as well as on physical fitness and QOL, in breast cancer survivors soon after completing cancer-related treatments.
This study is a prospective randomized controlled trial (RCT) investigating the effects of a 16-week supervised progressive aerobic and resistance exercise training intervention on MetS in 100 breast cancer survivors. Main inclusion criteria are histologically-confirmed breast cancer stage I-III, completion of chemotherapy and/or radiation within 6 months prior to initiation of the study, sedentary, and free from musculoskeletal disorders. The primary endpoint is MetS; secondary endpoints include: muscle strength, shoulder function, cardiorespiratory fitness, body composition, bone mineral density, and QOL. Participants randomized to the Exercise group participate in 3 supervised weekly exercise sessions for 16 weeks. Participants randomized to the Control group are offered the same intervention after the 16-week period of observation.
This is the one of few RCTs examining the effects of exercise on MetS in breast cancer survivors. Results will contribute a better understanding of metabolic disease-related effects of resistance and aerobic exercise training and inform intervention programs that will optimally improve physiological and psychosocial health during cancer survivorship, and that are ultimately aimed at improving prognosis.
Trial registration
NCT01140282; Registration: June 10, 2010
PMCID: PMC3985576  PMID: 24708832
Exercise; Breast cancer; Metabolic syndrome
12.  Altered Loading in the Injured Knee after ACL Rupture 
Articular loading is an important factor in the joint degenerative process for individuals with anterior cruciate ligament (ACL) rupture. Evaluation of loading for a population that exhibits neuromuscular compensation for injury requires an approach which can incorporate individual muscle activation strategies in its estimation of muscle forces. The purpose of this study was to evaluate knee joint contact forces for patients with ACL deficiency using an EMG-driven modeling approach to estimate muscle forces. Thirty (30) athletes with acute, unilateral ACL rupture underwent gait analysis after resolving range of motion, effusion, pain and obvious gait impairments. Electromyography was recorded bilaterally from 14 lower extremity muscles and input to a musculoskeletal model for estimation of muscle forces and joint contact forces. Gait mechanics were consistent with previous reports for individuals with ACL-deficiency. Our major finding was that joint loading was altered in the injured limb after acute ACL injury; patients walked with decreased contact force on their injured knee compared to their uninjured knee. Both medial and lateral compartment forces were reduced without a significant change in the distribution of tibiofemoral load between compartments. This is the first study to estimate medial and lateral compartment contact forces in patients with acute ACL rupture using an approach which is sensitive to individual muscle activation patterns. Further work is needed to determine whether this early decreased loading of the injured limb is involved in the development of osteoarthritis in these patients.
PMCID: PMC3553294  PMID: 23097309
13.  Self-Reported Physical Activity Is Associated With β-Cell Function in Mexican American Adults 
Diabetes Care  2013;36(3):638-644.
To examine the association between self-reported physical activity (PA) and diabetes-related quantitative traits.
The observational cohort was 1,152 Mexican American adults with dual-energy X-ray absorptiometry, oral and intravenous glucose tolerance tests, and self-reported dietary and PA questionnaires. PA was categorized into three mutually exclusive groups according to the U.S. Department of Health and Human Services PA guidelines for Americans: low (vigorous <75 min/week and moderate <150 min/week), moderate (vigorous ≥75 min/week or moderate ≥150 min/week), and high (vigorous ≥75 min/week and moderate ≥150 min/week). Trends in PA groups were tested for association with metabolic traits in a cross-sectional analysis.
The participants’ mean age was 35 years (range, 18–66 years), mean BMI was 29.6 kg/m2, and 73% were female. Among them, 501 (43%), 448 (39%), and 203 (18%) were classified as having low, moderate, and high PA, respectively. After adjustment for age, a higher PA was significantly associated with lower 2-h glucose, fasting insulin, and 2-h insulin and greater β-cell function (P = 0.001, 0.0003, 0.0001, and 0.004, respectively). The association did not differ significantly by sex. Results were similar after further adjustment for age, sex, BMI, or percent body fat.
An increasing level of PA is associated with a better glucose and insulin profile and enhanced β-cell function that is not explained by differences in BMI or percent body fat. Our results suggest that PA can be beneficial to β-cell function and glucose regulation independent of obesity.
PMCID: PMC3579363  PMID: 23223346
14.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
15.  Subject-specific measures of Achilles tendon moment arm using ultrasound and video-based motion capture 
Physiological Reports  2013;1(6):e00139.
The Achilles tendon (AT) moment arm is an important biomechanical parameter most commonly estimated using one of two methods: (A) center of rotation and (B) tendon excursion. Conflicting findings regarding magnitude and whether it changes with contraction intensity have been reported when using these methods. In this study, we present an alternate method of measuring the AT moment arm by combining ultrasound and video-based motion capture. Moment arms for 10 healthy male subjects were measured at five different joint angles in 10° increments ranging from 20° of dorsiflexion (DF) to 20° of plantar flexion (PF). Moment arms were measured at rest and also during maximum voluntary contraction (MVC). For both conditions, the AT moment arm increased in magnitude as the ankle moved from DF to PF. In 20° of DF, the moment arm at rest averaged 34.6 ± 1.8 mm and increased to a maximum value of 36.9 ± 1.9 mm when plantar flexed to 10°. Moment arms during MVC ranged from 35.7 ± 1.8 mm to 38.1 ± 2.6 mm. The moment arms we obtained were much more consistent with literature values derived using ultrasound and tendon excursion compared to center of rotation or in vitro methods. This is noteworthy as the hybrid method is easy to implement and as it is less costly and timing consuming than other methods, including tendon excursion, it is well suited for large-scale studies involving many subjects.
PMCID: PMC3871454  PMID: 24400141
Ankle joint; center of rotation; displacement; lever arm; tendon excursion
16.  Gait and Neuromuscular Asymmetries after Acute ACL Rupture 
The decreased internal knee extensor moment is a significant gait asymmetry among patients with anterior cruciate ligament (ACL) deficiency, yet the muscular strategy driving this altered moment for the injured limb is unclear.
To determine whether patients with ACL deficiency and characteristic knee instability would demonstrate normal extensor and increased flexor muscle force to generate a decreased internal extensor moment (i.e. employ a hamstring facilitation strategy).
Gait analysis was performed on 31 athletes with acute ACL rupture who exhibited characteristic knee instability after injury. Peak internal knee extensor moment was calculated using inverse dynamics and muscle forces were estimated using an EMG-driven modeling approach. Comparisons were made between the injured and contralateral limbs.
As expected, patients demonstrated decreased peak knee flexion (p=0.028) and internal knee extensor moment (p=0.0004) for their injured limb, but exhibited neither an isolated decrease in extensor force (quadriceps avoidance), nor an isolated increase in flexor force (hamstring facilitation) at peak knee moment. Instead, they exhibited decreased muscle force from both flexor (p=0.0001) and extensor (p=0.0103) groups. This strategy of decreased muscle force may be explained in part by muscle weakness which frequently accompanies ACL injury, or by apprehension, low confidence and fear of further injury.
This is the first study to estimate muscle forces in the ACL-deficient knee using an EMG-driven approach. These results affirm the existence of neuromuscular asymmetries in the individuals with ACL deficiency and characteristic knee instability.
PMCID: PMC3399054  PMID: 22330021
Knee Moment; Muscle Force; Quadriceps Avoidance; Hamstring Facilitation; Instability
American journal of hypertension  2012;25(7):812-817.
Hypertension represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP).
Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type and LSD-1 heterozygote knockout (LSD-1+/−) mice. Clinical relevance was tested by multivariate associations between single nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American).
LSD1 expression was modified by dietary salt in wild-type mice with lower levels associated with liberal salt intake. LSD-1+/− mice expressed lower LSD-1 protein levels than wild-type mice in kidney tissue. Similar to LSD-1+/− mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP in response to change from low to liberal salt diet (rs671357, p=0.01; rs587168, p=0.005). This association was replicated in the Hispanic (rs587168, p=0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1+/− mice, decreased alpha-EnaC expression in LSD-1+/− mice, and impaired renovascular responsiveness to salt loading in minor allele carriers.
The results of this translational research study support a role for LSD1 in the pathogenesis of salt-sensitive hypertension.
PMCID: PMC3721725  PMID: 22534796
Hypertension; Salt-sensitivity; LSD1; Genetics; Epigenetic
The semitendinosus‐gracilis tendon autograft is often used to reconstruct the anterior cruciate ligament. Tendon regeneration appears to occur for most individuals in the short term, but little is known about the long‐term effects of graft harvest. The purpose of this study was to describe the effect of semitendinosis‐gracilis tendon graft harvest on muscle and tendon morphology at least five years following reconstruction in a case series.
Magnetic resonance images were taken of the knees of three subjects at least five years following anterior cruciate ligament reconstruction. These subjects represented the different regeneration patterns at the time of return‐to‐sport. Muscle and tendon morphology were analyzed by calculating the volume, peak cross‐sectional area, and length of the knee flexors. Muscle and tendon morphological changes were analyzed individually, and then in combination as defined as a knee flexor group.
Muscle and tendon regeneration continued in those tendons that had begun regeneration at the time of return‐to‐sports in two subjects. There was significant additional muscle degeneration in those muscles whose tendons had not regenerated at the time of return‐to‐sports, in the remaining subject. Compensatory hypertrophy of the remaining knee flexors restored the knee flexor group to near preoperative peak cross‐sectional area and volume across the each of the three case subjects.
Knee flexor morphology at the time of return‐to‐sports foreshadowed the long‐term outcome in the three studied subjects. Preservation of the tendon sheath in situ may play a role in tendon regeneration. When tendon regeneration did not occur, fatty infiltration of the muscle may be a worst‐case outcome. Semitendinosus‐gracilis muscle synergists demonstrated hypertrophy, perhaps in an effort to compensate for knee flexor group morphology deficits that existed after Semitendinosus gracilis tendon graft harvest.
Clinical Relevance:
Semitendinosus and gracilis tendon harvest technique may play a role in regeneration. Additionally, knee flexor morphology at the time of return‐to‐sports may foreshadow the long‐term outcome.
Level of Evidence:
prospective (longitudinal) cohort ‐ level II
PMCID: PMC3679632  PMID: 23772342
Anterior cruciate ligament; magnetic resonance imaging; tendon regrowth
19.  Mechanisms Undlerlying Quadriceps Weakness in Knee Osteoarthritis 
To identify determinants of quadriceps weakness among persons with end-stage knee osteoarthritis (OA).
One-hundred twenty-three individuals (mean age 64.9 ± 8.5 yr) with Kellgren/Lawrence grade IV knee OA participated. Quadriceps strength (MVIC) and volitional muscle activation (CAR) were measured using a burst superimposition test. Muscle composition (lean muscle cross-sectional area (LMCSA) and fat CSA (FCSA)) were quantified using magnetic resonance imaging. Specific strength (MVIC/LMCSA) was computed. Interlimb differences were analyzed using paired-sample t-tests. Regression analysis was applied to identify determinants of MVIC. An alpha level of 0.05 was adopted.
The OA limb was significantly weaker, had lower CAR, and had smaller LMCSA than the contralateral limb. CAR explained 17% of the variance in the contralateral limb's MVIC compared with 40% in the OA limb. LMCSA explained 41% of the variance in the contralateral limb's MVIC compared with 27% in the OA limb.
Both reduced CAR and LMCSA contribute to muscle weakness in persons with knee OA. Similar to healthy elders, the best predictor of strength in the contralateral, nondiseased limb was largely determined by LMCSA, whereas CAR was found to be the primary determinant of strength in the OA limb. Deficits in CAR may undermine the effectiveness of volitional strengthening programs in targeting quadriceps weakness in the OA population.
PMCID: PMC3573845  PMID: 18379202
20.  Hybrid models of the neuromusculoskeletal system improve subject-specificity 
Muscle-actuated simulations of pathological gait have the capacity to identify muscle impairments and compensatory strategies, but the lack of subject-specific solutions prevents the prescription of personalized therapies. Conversely, electromyographic-driven models are limited to muscles for which data are available but can capture the true neural drive initiated by an individual subject. In order to improve subject-specificity and enforce physiological constraints on muscle activity, we propose a hybrid strategy for the optimization of subject-specific muscle patterns that involves forward dynamic simulation of whole body movement coupled with electromyographic-driven models of muscle subsets. In this paper we apply the hybrid approach to an example of post-stroke gait and demonstrate its unique ability to account for the unusual muscle activation patterns and muscle properties in patients with neuromuscular impairments.
PMCID: PMC3573850  PMID: 22468463
Neuromuscular; musculoskeletal; model; gait; optimization
21.  A Real-time EMG-driven Musculoskeletal Model of the Ankle 
Multibody system dynamics  2011;28(1-2):169-180.
The real-time estimation of muscle forces could be a very valuable tool for rehabilitation. By seeing how much muscle force is being produced during rehabilitation, therapists know whether they are working within safe limits in their therapies and patients know if they are producing enough force to expect improvement. This is especially true for rehabilitation of Achilles tendon ruptures where, out of fear of overloading and causing a re-rupture, minimal therapy is typically done for eight weeks post-surgery despite animal studies that show that low-level loading is beneficial. To address this need, we have developed a biomechanical model that allows for the real-time estimation of forces in the triceps surae muscle and Achilles tendon. Forces are estimated using a Hill-type muscle model. To account for differences in neuromuscular control of each subject, the model used EMGs as input. To make this clinically useful, joint angles were measured using electrogoniometers. A dynamometer was used to measure joint moments during the model calibration stage, but was not required during real-time studies. The model accounts for the force-length and force-velocity properties of muscles, and other parameters such as tendon slack length and optimal fiber length. Additional parameters, such as pennation angle and moment arm of each muscle in the model, vary as functions of joint angle. In this paper, the model is presented and it application is demonstrated in two subjects: one with a healthy Achilles tendon and a second six months post Achilles tendon rupture and repair.
PMCID: PMC3571695  PMID: 23419878
Muscle Force; Joint Moment; Multibody Dynamics; Rehabilitation; Feedback
22.  Variants in MTNR1B influence fasting glucose levels 
Prokopenko, Inga | Langenberg, Claudia | Florez, Jose C | Saxena, Richa | Soranzo, Nicole | Thorleifsson, Gudmar | Loos, Ruth J F | Manning, Alisa K | Jackson, Anne U | Aulchenko, Yurii | Potter, Simon C | Erdos, Michael R | Sanna, Serena | Hottenga, Jouke-Jan | Wheeler, Eleanor | Kaakinen, Marika | Lyssenko, Valeriya | Chen, Wei-Min | Ahmadi, Kourosh | Beckmann, Jacques S | Bergman, Richard N | Bochud, Murielle | Bonnycastle, Lori L | Buchanan, Thomas A | Cao, Antonio | Cervino, Alessandra | Coin, Lachlan | Collins, Francis S | Crisponi, Laura | de Geus, Eco J C | Dehghan, Abbas | Deloukas, Panos | Doney, Alex S F | Elliott, Paul | Freimer, Nelson | Gateva, Vesela | Herder, Christian | Hofman, Albert | Hughes, Thomas E | Hunt, Sarah | Illig, Thomas | Inouye, Michael | Isomaa, Bo | Johnson, Toby | Kong, Augustine | Krestyaninova, Maria | Kuusisto, Johanna | Laakso, Markku | Lim, Noha | Lindblad, Ulf | Lindgren, Cecilia M | McCann, Owen T | Mohlke, Karen L | Morris, Andrew D | Naitza, Silvia | Orrù, Marco | Palmer, Colin N A | Pouta, Anneli | Randall, Joshua | Rathmann, Wolfgang | Saramies, Jouko | Scheet, Paul | Scott, Laura J | Scuteri, Angelo | Sharp, Stephen | Sijbrands, Eric | Smit, Jan H | Song, Kijoung | Steinthorsdottir, Valgerdur | Stringham, Heather M | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Uitterlinden, André G | Voight, Benjamin F | Waterworth, Dawn | Wichmann, H-Erich | Willemsen, Gonneke | Witteman, Jacqueline C M | Yuan, Xin | Zhao, Jing Hua | Zeggini, Eleftheria | Schlessinger, David | Sandhu, Manjinder | Boomsma, Dorret I | Uda, Manuela | Spector, Tim D | Penninx, Brenda WJH | Altshuler, David | Vollenweider, Peter | Jarvelin, Marjo Riitta | Lakatta, Edward | Waeber, Gerard | Fox, Caroline S | Peltonen, Leena | Groop, Leif C | Mooser, Vincent | Cupples, L Adrienne | Thorsteinsdottir, Unnur | Boehnke, Michael | Barroso, Inês | Van Duijn, Cornelia | Dupuis, Josée | Watanabe, Richard M | Stefansson, Kari | McCarthy, Mark I | Wareham, Nicholas J | Meigs, James B | Abecasis, Gonçalo R
Nature genetics  2008;41(1):77-81.
To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 = × 10−50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10−15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10−7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10−57) and GCK (rs4607517, P = 1.0 × 10−25) loci.
PMCID: PMC2682768  PMID: 19060907
23.  Paretic Muscle Atrophy and Non-Contractile Tissue Content in Individual Muscles of the Post-Stroke Lower Extremity 
Journal of biomechanics  2011;44(16):2741-2746.
Muscle atrophy is one of many factors contributing to post-stroke hemiparetic weakness. Since muscle force is a function of muscle size, the amount of muscle atrophy an individual muscle undergoes has implications for its overall force-generating capability post-stroke. In this study, post-stroke atrophy was determined bilaterally in fifteen leg muscles with volumes quantified using magnetic resonance imaging (MRI). All muscle volumes were adjusted to exclude non-contractile tissue content, and muscle atrophy was quantified by comparing the volumes between paretic and non-paretic sides. Non-contractile tissue or intramuscular fat was calculated by determining the amount of tissue excluded from the muscle volume measurement. With the exception of the gracilis, all individual paretic muscles examined had smaller volumes in the non-paretic side. The average decrease in volume for these paretic muscles was 23%. The gracilis volume, on the other hand, was approximately 11% larger on the paretic side. The amount of non-contractile tissue was higher in all paretic muscles except the gracilis, where no difference was observed between sides. To compensate for paretic plantar flexor weakness, one idea might be that use of the paretic gracilis actually causes the muscle to increase in size and not develop intramuscular fat. By eliminating non-contractile tissue from our volume calculations, we have presented volume data that more appropriately represents force-generating muscle tissue. Non-uniform muscle atrophy was observed across muscles and may provide important clues when assessing the effect of muscle atrophy on post-stroke gait.
PMCID: PMC3208767  PMID: 21945568
stroke; hemiparesis; magnetic resonance imaging (MRI); muscle volume; non-contractile tissue
24.  A Better Index of Body Adiposity 
Obesity (Silver Spring, Md.)  2011;19(5):1083-1089.
Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5) − 18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the “BetaGene” study, to develop the new index of body adiposity. %Body fat, as measured by the dual-energy X-ray absorptiometry (DXA), was used as a “gold standard” for validation. Hip circumference (R = 0.602) and height (R = −0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the “Triglyceride and Cardiovascular Risk in African-Americans (TARA)” study of African Americans. Correlation between DXA-derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.
PMCID: PMC3275633  PMID: 21372804
25.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants 
Science (New York, N.Y.)  2007;316(5829):1341-1345.
Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.
PMCID: PMC3214617  PMID: 17463248

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