Postural Control Deficits After Repetitive Soccer Heading.

OBJECTIVE: To determine the acute effects of repetitive soccer heading on postural control. DESIGN: Prospective study; participants were divided into 2 groups: a soccer heading group and a control group. SETTING: Biomechanics laboratory. PARTICIPANTS: One hundred sixty participants, including youth (age = 13.0 ± 0.8 years), high school (age = 17.2 ± 1.0 years), and collegiate (age = 20.2 ± 1.3 years) male and female soccer players, participated in this study. INTERVENTIONS: Participants in the soccer heading group performed 12 soccer headers (initial velocity = 11.2 m/s). Postural control testing was performed both before (PRE) and immediately after (POST) the purposeful soccer headers. Control participants performed postural control testing PRE and POST a 15-minute wait period. During postural control testing, participants were asked to stand on the MobileMat (Tekscan Inc, Boston, Massachusetts) for two 2-minute intervals with their hands on their hips and their feet together with one eyes-open and one eyes-closed trial. MAIN OUTCOME MEASURES: Using the center-of-pressure data, 95% area, sway velocity, and ApEn were calculated. Multilevel linear models were used to analyze the effects of age, sex, group, condition, and concussion history simultaneously. RESULTS: Participants in the soccer heading group had significantly higher sway velocity POST than participants in the control group after controlling for age, sex, concussion history, condition, and PRE (t = -3.002; P = 0.003; 95% confidence interval, -0.482 to -0.100). There were no significant differences from PRE to POST for 95% area, M/L ApEn, and A/P ApEn. CONCLUSIONS: Repetitive soccer heading does not affect most postural control measures, even among youth athletes. However, sway velocity increased after heading relative to control participants independent of age, sex, and concussion history.

Neuroplastic changes in anterior cruciate ligament reconstruction patients from neuromechanical decoupling.

The purpose of this study was to identify how the brain simultaneously perceives proprioceptive input during joint loading in anterior cruciate ligament reconstruction (ACLR) patients, when compared to healthy controls. Seventeen ACLR patients (ACLR) and seventeen controls (CONT) were tested for the somatosensory cortical activation using electroencephalography (EEG) while measuring knee laxity using a knee arthrometer. The relationship between cortical activation and joint laxity within group was also examined. The ACLR patients had increased cortical activation (36.4% ± 11.5%) in the somatosensory cortex during early loading (ERD1) to the injured limb compared to the CONT's matched limb (25.3% ± 13.2%, P = 0.013) as well as compared to the noninjured limb (25.1% ± 14.2%, P = 0.001). Higher somatosensory cortical activity during midloading (ERD2) to the ACLR knee positively correlated with knee laxity (mm) during early loading (LAX1, r = 0.530), midloading (LAX2, r = 0.506), total anterior loading (LAXA, r = 0.543), and total antero-posterior loading (LAXT, r = 0.501), while the noninjured limb revealed negative correlations between ERD1 and LAXA (r = -0.534) as well as between ERD2 and LAX2 (r = -0.565). ACLR patients demonstrate greater brain activation during joint loading in the injured knees when compared to healthy controls' matched knees as well as contralateral healthy knees, while the CONT group shows similar brain activation patterns during joint loading between limbs. These different neural activation strategies may indicate neuromechanical decoupling following an ACL reconstruction and evidence of altered sensorimotor perception and control of the knee (neuroplasticity), which may be critical to address after surgery for optimal neuromuscular control and patients' outcomes.

Analysis of Shoulder Complex Function After Posterior Spinal Fusion in Adolescents With Idiopathic Scoliosis.

BACKGROUND: Nonsurgically treated patients with AIS demonstrate altered scapular kinematics and decreased patient-reported shoulder function compared with typically developing adolescents. It is unknown whether surgical correction of the spine deformity has beneficial or detrimental effects on scapulothoracic joint function, as previous assessments of shoulder function following surgery have only focused on humerothoracic motion. The objective of this study was to perform a comprehensive analysis of scapular kinematics before and after PSF and compare postoperative scapular kinematics in AIS to those of a typically developing cohort. METHODS: Typically developing adolescents (n=33) and patients with AIS (n=20) with a planned PSF surgery were recruited. Motion capture was used to analyze scapular kinematics at rest and in full abduction. AIS subjects were evaluated before surgery and at a 6-month follow-up. Individual changes following surgery were assessed, and postoperative scapular kinematics were compared with the typically developing subjects. RESULTS: Patients with AIS patients in this study demonstrated significant losses of scapulothoracic range of motion for the convex side shoulder and gains of scapulothoracic range of motion for the concave side shoulder following PSF. When compared with typically developing adolescents, the resting scapular position of the postoperative AIS group seemed normalized, but the AIS group still exhibited altered scapular motion, particularly along the upward rotation and tilt axes. CONCLUSIONS: Patients with AIS demonstrated significant changes at the scapulothoracic joint following PSF. Compared with typically developing adolescents, scapular resting position normalized, but the AIS group still demonstrated altered scapular kinematics, including patterns associated with shoulder pathology. The results of this study will inform the course of short-term postoperative rehabilitation by addressing the upper extremity implications of PSF for individuals with AIS. LEVEL OF EVIDENCE: Level III.

The influence of acute elevations in plasma osmolality and serum sodium on sympathetic outflow and blood pressure responses to exercise.

Elevated plasma osmolality (pOsm) has been shown to increase resting sympathetic nerve activity in animals and humans. The present study tested the hypothesis that increases in pOsm and serum sodium (sNa+) concentration would exaggerate muscle sympathetic nerve activity (MSNA) and blood pressure (BP) responses to handgrip (HG) exercise and postexercise ischemia (PEI). BP and MSNA were measured during HG followed by PEI before and after a 23-min hypertonic saline infusion (HSI-3% NaCl). Eighteen participants (age 23 ± 1 yr; BMI 24 ± 1 kg/m2) completed the protocol; pOsm and sNa+ increased from pre- to post-HSI (285 ± 1 to 291 ± 1 mosmol/kg H2O; 138.2 ± 0.3 to 141.3 ± 0.4 mM; P < 0.05 for both). Resting mean BP (90 ± 2 vs. 92 ± 1 mmHg) and MSNA (11 ± 2 vs. 15 ± 2 bursts/min) were increased pre- to post-HSI ( P < 0.05 for both). Mean BP responses to HG (106 ± 2 vs. 111 ± 2 mmHg, P < 0.05) and PEI (102 ± 2 vs. 107 ± 2 mmHg, P < 0.05) were higher post-HSI. Similarly, MSNA during HG (20 ± 2 vs. 29 ± 2 bursts/min, P < 0.05) and PEI (19 ± 2 vs. 24 ± 3 bursts/min, P < 0.05) were greater post-HSI. In addition, the change in MSNA was greater post-HSI during HG (Δ9 ± 2 vs. Δ13 ± 3 bursts/min, P < 0.05). A second set of participants ( n = 13, age 23 ± 1 yr; BMI 24 ± 1 kg/m2) completed a time control (TC) protocol consisting of quiet rest instead of an infusion. The TC condition yielded no change in resting sNa+, pOsm, mean BP, or MSNA (all P > 0.05); responses to HG and PEI were not different pre- to post-quiet rest ( P > 0.05). In summary, acutely increasing pOsm and sNa+ exaggerates BP and MSNA responses during HG exercise and PEI. NEW & NOTEWORTHY Elevated plasma osmolality has been shown to increase resting sympathetic activity and blood pressure. This study provides evidence that acute elevations in plasma osmolality and serum sodium exaggerated muscle sympathetic nerve activity and blood pressure responses during exercise pressor reflex activation in healthy young adults.

Shoulder Complex Mechanics in Adolescent Idiopathic Scoliosis and Their Relation to Patient-perceived Function.

BACKGROUND: Proper contribution of the scapulothoracic joint is necessary for adequate shoulder complex function. Associations between trunk shape and abnormal scapular kinematics and subsequent shoulder dysfunction have been established; however, the extent of shoulder dysfunction in adolescent idiopathic scoliosis (AIS) is still poorly understood. The purpose of this study was to perform a comprehensive analysis of scapular kinematics during multiplanar arm motion in patients with AIS and compare kinematics and patient-reported function with that of a typically developing cohort. METHODS: Typically developing adolescents (n=33) and patients with AIS (n=26) with no history of spine or shoulder surgery were recruited for this study. A 3-dimensional optoelectronic motion capture system was used to analyze scapular kinematics in 4 positions: rest, full abduction, forward reach, and hand to spine. Subjects in each group also completed the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire as a measure of patient-reported function. RESULTS: The convex shoulders of the patients with AIS exhibited deficits in scapular upward rotation and posterior tilt in all positions and reduced protraction range of motion during reaching. The AIS group also reported worse patient-perceived shoulder function than the typically developing group; however, this dysfunction was not related to specific scapular kinematic patterns. CONCLUSIONS: Patients with AIS show alterations in scapular kinematics that are associated with shoulder pathology. Despite displaying an unaffected ability to place the hand in space, the underlying joint mechanics place these adolescents at risk for future pathology. Accordingly, consideration of scapulothoracic and glenohumeral joint function is warranted in the treatment of AIS. LEVEL OF EVIDENCE: Level III-cross-sectional comparison.

Sex and age differences in head acceleration during purposeful soccer heading.

Differences in head-neck segment mass, purposeful heading technique, and cervical strength and stiffness may contribute to differences in head accelerations across sex and age. The purpose of this study was to compare head acceleration across sex and age (youth [12-14 years old], high school and collegiate) during purposeful soccer heading. One-hundred soccer players (42 male, 58 female, 17.1 ± 3.5 years, 168.5 ± 20.3 cm, 61.5 ± 13.7 kg) completed 12 controlled soccer headers at an initial ball velocity of 11.2 m/s. Linear and rotational accelerations were measured using a triaxial accelerometer and gyroscope and were transformed to the head centre-of-mass. A MANOVA revealed a significant multivariate main effect for sex (Pillai's Trace = .165, F(2,91) = 11.868, p < .001), but not for age (Pillai's Trace = .033, F(4,182) = 0.646, p = .630). Peak linear and rotational accelerations were higher in females (40.9 ± 13.3 g; 3279 ± 1065 rad/s2) than males (27.6 ± 8.5 g, 2219 ± 823 rad/s2). These data suggest that under controlled soccer heading conditions, females may be exposed to higher head accelerations than males.

Effect of Footwear on Dynamic Stability during Single-leg Jump Landings.

Barefoot and minimal footwear running has led to greater interest in the biomechanical effects of different types of footwear. The effect of running footwear on dynamic stability is not well understood. The purpose of this study was to compare dynamic stability and impact loading across 3 footwear conditions; barefoot, minimal footwear and standard running shoes. 25 injury free runners (21 male, 4 female) completed 5 single-leg jump landings in each footwear condition. Dynamic stability was assessed using the dynamic postural stability index and its directional components (mediolateral, anteroposterior, vertical). Peak vertical ground reaction force and vertical loadrates were also compared across footwear conditions. Dynamic stability was dependent on footwear type for all stability indices (ANOVA, p<0.05). Post-hoc tests showed dynamic stability was greater when barefoot than in running shoes for each stability index (p<0.02) and greater than minimal footwear for the anteroposterior stability index (p<0.01). Peak vertical force and average loadrates were both dependent on footwear (p≤0.05). Dynamic stability, peak vertical force, and average loadrates during single-leg jump landings appear to be affected by footwear type. The results suggest greater dynamic stability and lower impact loading when landing barefoot or in minimal footwear.

Effect of elastic taping on postural control deficits in subjects with healthy ankles, copers, and individuals with functional ankle instability.

BACKGROUND: Ankle sprains are the most common injury among physically active people, with common sequelae including repeated episodes of giving way, termed functional ankle instability. Copers are a cohort in ankle research comprised of those who have sprained their ankle but have not suffered any further dysfunction. The use of an elastic tape, Kinesio Tape, in sports medicine practice has recently gained popularity and may help improve postural control deficits related to functional ankle instability. The purpose of this study was to examine the immediate and prolonged effects of Kinesio Taping on postural control in healthy, coper, and unstable ankles as measured through single-limb balance on a force plate. METHODS: Sixty physically active, college-aged participants (72.5 ± 9.7 cm, 74.2 ± 16.2 kg, 21.5 ± 2.6 years) were stratified into healthy, coper, or unstable groups using the Cumberland Ankle Instability Tool (CAIT) combined with their history of ankle injury. Dependent variables included time-to-boundary (TTB) measures and traditional center of pressure (COP) measures in both the mediolateral (frontal) and anteroposterior (sagittal) planes. Testing was performed prior to tape application, immediately after application of the tape, 24 hours following tape application, and immediately after tape removal. RESULTS: Significant differences between groups were observed for COP standard deviation and range in the sagittal plane. Significant differences between tape conditions for TTB absolute minima and standard deviation were also noted. Post hoc testing revealed large to medium effect sizes for the group differences and very small effect sizes for the differences between conditions. CONCLUSIONS: Our study did not reveal decisively relevant changes following application of Kinesio Tape to the ankle. However, we did observe sagittal plane postural control deficits in subjects with ankle instability measured through summary COP variables over 20-second trials. CLINICAL RELEVANCE: Ankle instability is a concern for many clinicians. Kinesio Taping, although a popular form of clinical intervention, remains understudied. Evidence from this study does not support the use of Kinesio Taping for improving postural control deficits in those with ankle instability.

Celecoxib does not alter cardiovascular and renal function during dietary salt loading.

1. Cyclo-oxygenase-2 (COX-2)-derived prostaglandins are important in controlling sodium excretion and renin release. In the present study, we tested the hypothesis that a clinical dose of celecoxib would impair urinary sodium excretion and elevate blood pressure (BP) during dietary salt loading. 2. Twelve normotensive individuals (mean (± SEM) age 35 ± 2 years) completed two separate 17 day dietary perturbations, one taking 200 mg/day celecoxib (CX2) and the other taking placebo (PL), randomized with a 1 month wash out. The controlled 17 day diet consisted of a 3 day run-in diet, 7 days of a low-salt (LS, 20 mmol sodium/day) diet and 7 days of a high-salt diet (HS, 350 mmol sodium/day) diet. The order in which the diets were applied was randomized. Data were collected on the last day of the LS and HS diets. 3. Plasma and urinary prostaglandins were modestly lower during celecoxib (P < 0.05). Urinary sodium excretion was greater (P < 0.01) during the HS diet (253 ± 10 vs 281 ± 27 mmol/24 h for PL vs CX2, respectively) compared with the LS diet (14 ± 3 vs 17 ± 7 mmol/24 h for PL vs CX2, respectively; P(drug) = 0.26). Celecoxib did not alter creatinine clearance (P > 0.50). Twenty-four hour mean arterial BP was similar during PL (87 ± 2 vs 87 ± 2 mmHg for LS and HS, respectively) and CX2 (88 ± 2 vs 87 ± 2 mmHg for LS and HS, respectively; P = 0.85), with no effect of dietary salt (P > 0.80). Plasma renin activity, angiotensin II and aldosterone were all suppressed with dietary salt loading (P < 0.05), with no effect of drug (P > 0.35). 4. In conclusion, blood pressure and renal function were not adversely affected by celecoxib, even during dietary salt loading. These findings support current guidelines suggesting minimal cardiovascular risks associated with short-term, low-dose use of celecoxib in young to middle-aged adults.

Exaggerated sympathetic and pressor responses to handgrip exercise in older hypertensive humans: role of the muscle metaboreflex.

Recent animal studies have reported that exercise pressor reflex (EPR)-mediated increases in blood pressure are exaggerated in hypertensive (HTN) rodents. Whether these findings can be extended to human hypertension remains unclear. Mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and venous metabolites were measured in normotensive (NTN; n = 23; 60 ± 1 yr) and HTN (n = 15; 63 ± 1 yr) subjects at baseline, and during static handgrip at 30 and 40% maximal voluntary contraction (MVC) followed by a period of postexercise ischemia (PEI) to isolate the metabolic component of the EPR. Changes in MAP from baseline were augmented in HTN subjects during both 30 and 40% MVC handgrip (P < 0.05 for both), and these group differences were maintained during PEI (30% PEI trial: Δ15 ± 2 NTN vs. Δ19 ± 2 HTN mmHg; 40% PEI trial: Δ16 ± 1 NTN vs. Δ23 ± 2 HTN mmHg; P < 0.05 for both). Similarly, in HTN subjects, MSNA burst frequency was greater during 30 and 40% MVC handgrip (P < 0.05 for both), and these differences were maintained during PEI [30% PEI trial: 35 ± 2 (NTN) vs. 44 ± 2 (HTN) bursts/min; 40% PEI trial: 36 ± 2 (NTN) vs. 48 ± 2 (HTN) bursts/min; P < 0.05 for both]. No group differences in metabolites were observed. MAP and MSNA responses to a cold pressor test were not different between groups, suggesting no group differences in generalized sympathetic responsiveness. In summary, compared with NTN subjects, HTN adults exhibit exaggerated sympathetic and pressor responses to handgrip exercise that are maintained during PEI, indicating that activation of the metabolic component of the EPR is augmented in older HTN humans.

Discovery of anticancer agents of diverse natural origin.

A collaborative multidisciplinary research project is described in which new natural product anticancer drug leads are obtained from a diverse group of organisms, constituted by tropical plants, aquatic cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which crude extracts of these acquisitions are tested. Progress made in the isolation of lead bioactive secondary metabolites from three tropical plants is discussed.

Evidence of bilinearity in the relationship between rate of neuromuscular excitation and rate of force development.

The purpose was to examine the relationship between the rate of neural excitation (rate of rise in the electromyogram, EMG) and the rate of isometric force development (RFD) to determine whether surface EMG measures can detect nonlinearity that is expected due to underlying motor unit discharge behavior and the summation of progressively larger motor unit potentials throughout recruitment. Due to interest in obtaining a change point, a bilinear model was hypothesized to provide the best fit of the EMG-RFD relationship compared to a linear model, exponential model and log-transformed data. 21 young adult participants performed isometric dorsiflexion contractions to 40% of their maximal voluntary contraction (MVC) force. Contractions were performed in RFD conditions ranging from slow (20 %MVC/s) to fast (peak volitional rate). The Akaike Information Criterion supported nonlinear best fit models in 16 of the 21 participants with the greatest overall support for the bilinear model (n = 13). The bilinear models indicated a mean change point at 204%MVC/s. The present data do not identify the specific motor unit control mechanisms at play and the influence of amplitude cancellation on the electromyogram must be carefully considered.

Negative Emotion and Joint-Stiffness Regulation Strategies After Anterior Cruciate Ligament Injury.

CONTEXT: Fear of reinjury after an anterior cruciate ligament (ACL) reconstruction (ACLR) may be associated with persistent deficits in knee function and subsequent injury. However, the effects of negative emotion on neuromuscular-control strategies after an ACL injury have remained unclear. OBJECTIVE: To identify how negative emotional stimuli affect neural processing in the brain and muscle coordination in patients after anterior cruciate ligament reconstruction compared with healthy control participants. DESIGN: Case-control study. SETTING: Neuromechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty patients after unilateral anterior cruciate ligament reconstruction and 20 healthy recruits. MAIN OUTCOME MEASURE(S): Electrocortical θ (4-8 Hz) activity (event-related synchronization, % increased power relative to a nonactive baseline) at selected electrodes placed at the frontal (F3, Fz, F4) and parietal (P3, Pz, P4) cortices using electroencephalography, neurophysiological cardiac changes (beats/min), and subjective fear perceptions were measured, along with joint stiffness (Nm/°/kg) with and without an acoustic stimulus in response to 3 types of emotionally evocative images (neutral, fearful, and knee-injury pictures). RESULTS: Both groups had greater frontoparietal θ power with fearful pictures (Fz: 35.9% ± 29.4%; Pz: 81.4% ± 66.8%) than neutral pictures (Fz: 24.8% ± 29.7%, P = .002; Pz: 64.2 ± 54.7%, P = .024). The control group had greater heart-rate deceleration with fearful (-4.6 ± 1.4 beats/min) than neutral (-3.6 ± 1.3 beats/min, P < .001) pictures, whereas the ACLR group exhibited decreased heart rates with both the fearful (-4.6 ± 1.3 beats/min) and injury-related (-4.4 ± 1.5 beats/min) pictures compared with neutral pictures (-3.4 ± 1.4 beats/min, P < .001). Furthermore, during the acoustic startle condition, fearful pictures increased joint stiffness (Nm/°/kg) in the ACLR group at the midrange (0°-20°: 0.027 ± 0.02) and long range (0°-40°: 0.050 ± 0.02) compared with the neutral pictures (0°-20°: 0.017 ± 0.01, P = .024; 0°-40°: 0.043 ± 0.02, P = .014). CONCLUSIONS: Negative visual stimuli simultaneously altered neural processing in the frontoparietal cortices and joint-stiffness regulation strategies in response to a sudden perturbation. The adverse effects of fear on neuromuscular control may indicate that psychological interventions should be incorporated in neuromuscular-control exercise programs after ACL injury.

Acute NaCl Loading Reveals a Higher Blood Pressure for a Given Serum Sodium Level in African American Compared to Caucasian Adults.

Purpose: African American individuals are more prone to salt-sensitive hypertension than Caucasian individuals. Small changes in serum sodium (Na+) result in increased blood pressure (BP). However, it remains unclear if there are racial differences in BP responsiveness to increases in serum Na+. Therefore, the purpose of this investigation was to determine if African American adults have altered BP responsiveness to acute changes in serum Na+ compared to Caucasian adults. Methods: We measured beat-by-beat BP, serum Na+, plasma renin activity (PRA), angiotensin II (Ang II), and aldosterone (Aldo) during a 60-min 3% NaCl infusion (hypertonic saline infusion, HSI) in 39 participants (19 African Americans, age: 23 ± 1, 20 Caucasians, age: 25 ± 1). Data reported as African American vs. Caucasian cohort, mean ± SEM. Results: Baseline BP and serum Na+ were similar between groups and increased during HSI in both African American and Caucasian participants (p < 0.01). However, the peak change in serum Na+ was greater in African American participants (Δ5.8 ± 0.34 vs. Δ4.85 ± 0.38 mmol/L, p = 0.03). There was a significant group effect (p = 0.02) and an interaction between race and serum Na+ on systolic BP (p = 0.02). Larger categorical changes in serum Na+ corresponded to changes in systolic BP (p < 0.01) and African American participants demonstrated greater systolic BP responses for a given categorical serum Na+ increase (p < 0.01). Baseline Aldo was lower in African American adults (7.2 ± 0.6 vs. 12.0 ± 1.9 ng/dL, p = 0.03), there was a trend for lower baseline PRA (0.59 ± 0.9 vs. 1.28 ± 0.34 ng/mL/h, p = 0.07), and baseline Ang II was not different (14.2 ± 1.8 vs. 18.5 ± 1.4 pg/mL, p = 0.17). PRA and Aldo decreased during the HSI (p ≤ 0.01), with a greater decline in PRA (Δ-0.31 ± 0.07 vs. Δ-0.85 ± 0.25 ng/mL/h, p < 0.01) and Aldo (Δ-2.5 ± 0.5 vs. Δ-5.0 ± 1.1 ng/dL, p < 0.01) in Caucasian participants. However, the racial difference in PRA (p = 0.57) and Aldo (p = 0.59) reduction were no longer significant following baseline covariate analysis. Conclusion: African American individuals demonstrate augmented serum Na+ to an acute hypertonic saline load and greater systolic BP responsiveness to a given serum Na+. The altered BP response may be attributable to lower basal PRA and Aldo and a subsequently blunted RAAS response during the HSI.

Head and neck size and neck strength predict linear and rotational acceleration during purposeful soccer heading.

There is increasing societal concern about the long-term effects of repeated impacts from soccer heading, but there is little information about ways to reduce head impact severity. The purpose of this study was to identify factors that contribute to head acceleration during soccer heading. One-hundred soccer players completed 12 controlled soccer headers. Peak linear (PLA) and rotational (PRA) accelerations were measured using a triaxial accelerometer and gyroscope. Head acceleration contributing factors were grouped into 3 categories: size (head mass, neck girth), strength (sternocleidomastoid, upper trapezius) and technique [kinematics (trunk, head-to-trunk range-of-motion), sternocleidomastoid and upper trapezius activity]. Multiple regression analyses indicated size variables explained 22.1% of the variance in PLA and 23.3% of the variance in PRA; strength variables explained 13.3% of the variance in PLA and 17.2% of the variance in PRA; technique variables did not significantly predict PLA or PRA. These findings suggest that head and neck size and neck strength predict PLA and PRA. Anthropometric and neck strength measurements should be considered when determining an athlete's readiness to begin soccer heading.

Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels.

Although Erbitux (cetuximab) has proven therapeutic benefit in the clinical setting, the molecular determinants predicting responsiveness to this agent are still not very well understood. Here, we assessed the relationship between basal total and activated (pY1068) epidermal growth factor receptor (EGFR) levels in a tumor and the responsiveness to cetuximab monotherapy or combination-based treatment using human xenograft models. Cetuximab treatment alone (0.25-1 mg/mouse/injection, q3d, i.p.) effectively delayed the growth of GEO and L2987 tumors by a minimum of 10 days corresponding to log cell kill values of >or=1.0. Borderline activity was seen in the A549 and WiDr xenografts. However, cetuximab failed to show any significant antitumor activity in the HT29, HCT116, LOVO, Colo205, LX-1, HCC70, and N87 models. All of the studied tumors had detectable yet variable levels of EGFR. For combination regimens, cetuximab (1 mg/mouse/injection, q3dx5, i.p.) and cisplatin (4.5 mg/kg/injection, q3dx5, i.v.) proved to be significantly more efficacious than individual monotherapies in the cisplatin-refractory yet cetuximab-responsive GEO tumor model (P < 0.001). However, no therapeutic enhancement was observed in the cisplatin and cetuximab weakly responsive A549 xenograft. Similarly, combinations of CPT-11 (48 mg/kg/injection, q3dx5, i.v.) with cetuximab (1 mg/mouse/injection, q3dx5, i.p.) failed to show any improvements over individual monotherapies in the cetuximab resistant/weakly responsive HT29, A549, and WiDr models. We conclude that preclinical activity associated with cetuximab monotherapy does not correlate directly with relative basal levels of total or activated (pY1068) EGFR in a tumor. Moreover, robust single-agent activity by cetuximab may be the best predictor for this agent to potentiate chemotherapy-mediated antitumor activities.

A comparison of two non-invasive methods for measuring scapular orientation in functional positions.

Identification of scapular dyskinesis and evaluation of interventions depend on the ability to properly measure scapulothoracic (ST) motion. The most widely used measurement approach is the acromion marker cluster (AMC), which can yield large errors in extreme humeral elevation and can be inaccurate in children and patient populations. Recently, an individualized regression approach has been proposed as an alternative to the AMC. This technique utilizes the relationship between ST orientation, humerothoracic orientation and acromion process position derived from calibration positions to predict dynamic ST orientations from humerothoracic and acromion process measures during motion. These individualized regressions demonstrated promising results for healthy adults; however, this method had not yet been compared to the more conventional AMC. This study compared ST orientation estimates by the AMC and regression approaches to static ST angles determined by surface markers placed on palpated landmarks in typically developing adolescents performing functional tasks. Both approaches produced errors within the range reported in the literature for skin-based scapular measurement techniques. The performance of the regression approach suffered when applied to positions outside of the range of motion in the set of calibration positions. The AMC significantly underestimated ST internal rotation across all positions and overestimated posterior tilt in some positions. Overall, root mean square errors for the regression approach were smaller than the AMC for every position across all axes of ST motion. Accordingly, we recommend the regression approach as a suitable technique for measuring ST kinematics in functional motion.

Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization.

PURPOSE: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential. METHODS: In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. RESULTS: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclinical antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicological assessment of GI injury in mice. The generation of parent compound from BMS-422461 was qualitatively similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equilibrium was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. CONCLUSIONS: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclinical GI toxicity, make this novel camptothecin analog attractive for clinical development.

A Simple Adaptive Transfer Function for Deriving the Central Blood Pressure Waveform from a Radial Blood Pressure Waveform.

Generalized transfer functions (GTFs) are available to compute the more relevant central blood pressure (BP) waveform from a more easily measured radial BP waveform. However, GTFs are population averages and therefore may not adapt to variations in pulse pressure (PP) amplification (ratio of radial to central PP). A simple adaptive transfer function (ATF) was developed. First, the transfer function is defined in terms of the wave travel time and reflection coefficient parameters of an arterial model. Then, the parameters are estimated from the radial BP waveform by exploiting the observation that central BP waveforms exhibit exponential diastolic decays. The ATF was assessed using the original data that helped popularize the GTF. These data included radial BP waveforms and invasive reference central BP waveforms from cardiac catheterization patients. The data were divided into low, middle, and high PP amplification groups. The ATF estimated central BP with greater accuracy than GTFs in the low PP amplification group (e.g., central systolic BP and PP root-mean-square-errors of 3.3 and 4.2 mm Hg versus 6.2 and 7.1 mm Hg; p ≤ 0.05) while showing similar accuracy in the higher PP amplification groups. The ATF may permit more accurate, non-invasive central BP monitoring in elderly and hypertensive patients.

Discovery of a fluoroindolo[2,3-a]carbazole clinical candidate with broad spectrum antitumor activity in preclinical tumor models superior to the marketed oncology drug, CPT-11.

A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.