bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of hoof angle variations on dorsal lamellar load in the equine hoof
Authors: RAMSEY G. D. , HUNTER P. J. , NASH M. P.
Published: March 2011

Reasons for performing study:In the treatment of laminitis it is believed that reducing tension in the deep digital flexor tendon by raising the palmar angle of the hoof can reduce the load on the dorsal lamellae, allowing them to heal or prevent further damage.

Objective:To determine the effect of alterations in hoof angle on the load in the dorsal laminar junction.

Methods:Biomechanical finite element models of equine hooves were created with palmar angles of the distal phalanx varying from 0–15°. Tissue material relations accounting for anisotropy and the effect of moisture were used. Loading conditions simulating the stages in the stance where the vertical ground reaction force, midstance joint moment and breakover joint moment were maximal, were applied to the models. The loads were adjusted to account for the reduction in joint moment caused by increasing the palmar angle. Models were compared using the stored elastic energy, an indication of load, which was sampled in the dorsal laminar junction.

Results:For all loading cases, increasing the palmar angle increased the stored elastic energy in the dorsal laminar junction. The stored elastic energy near the proximal laminar junction border for a palmar angle of 15° was between 1.3 and 3.8 times that for a palmar angle of 0°. Stored elastic energy at the distal laminar junction border was small in all cases. For the breakover case, stored elastic energy at the proximal border also increased with increasing palmar angle.

Conclusions and potential relevance:The models in this study predict that raising the palmar angle increases the load on the dorsal laminar junction. Therefore, hoof care interventions that raise the palmar angle in order to reduce the dorsal lamellae load may not achieve this outcome.

See also correspondence by Redden

See also correspondence by Curtis
The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice
Authors: Tang Wei , Lu Yi , Tian Qing-Yun , Zhang Yan , Guo Feng-Jin , Liu Guang-Yi , Syed Nabeel Muzaffar , Lai Yongjie , Lin Edward Alan , Kong Li , Su Jeffrey , Yin Fangfang , Ding Ai-Hao , Zanin-Zhorov Alexandra , Dustin Michael L. , Tao Jian , Craft Joseph , Yin Zhinan , Feng Jian Q. , Abramson Steven B. , Yu Xiu-Ping , Liu Chuan-ju
Published: March 2011

A growth factor protects against arthritis in mice by blocking tumor necrosis factor–dependent signaling.
Enhanced Turbulence and Energy Dissipation at Ocean Fronts
Authors: D’Asaro Eric , Lee Craig , Rainville Luc , Harcourt Ramsey , Thomas Leif
Published: March 2011

Energy in surface ocean currents can dissipate into deep water via enhanced turbulence at the boundaries between water masses.
Low-Power Switching of Phase-Change Materials with Carbon Nanotube Electrodes
Authors: Xiong Feng , Liao Albert D. , Estrada David , Pop Eric
Published: March 2011

The crystallinity and resistivity of a compound semiconductor was changed with current pulses delivered by nanoelectrodes.
Structure of an Agonist-Bound Human A
2A
Adenosine Receptor
Authors: Xu Fei , Wu Huixian , Katritch Vsevolod , Han Gye Won , Jacobson Kenneth A. , Gao Zhan-Guo , Cherezov Vadim , Stevens Raymond C.
Published: March 2011

Changes associated with conformationally selective agonist binding shed light on G protein–coupled receptor activation.
Fetal wellbeing may be compromised during strenuous exercise among pregnant elite athletes
Authors: Salvesen Kjell Å , Hem Erlend , Sundgot-Borgen Jorunn
Published: March 2011

Objectives

To study fetal wellbeing and uteroplacental blood flow during strenuous treadmill running in the second trimester.

Methods

Six pregnant Olympic-level athletes in endurance events aged 28–37 years and training 15–22 h per week before the pregnancy were tested once at 23–29 weeks of pregnancy. The women ran three to five submaximal workloads on a treadmill with approximately 60–90% of maximal oxygen consumption. The maternal–fetal circulation was assessed with Doppler ultrasound of the uterine and umbilical arteries before, during and after exercise.

Results

Mean uterine artery volume blood flow was reduced to 60–80% after warming up and stayed at 40–75% of the initial value during exercise. Fetal heart rate (FHR) was within the normal range (110–160 bpm) as long as the woman exercised below 90% of maximal maternal heart rate (MHR). Fetal bradycardia and high umbilical artery pulsatility index (PI) occurred when the woman exercised more than 90% of maximal MHR and the mean uterine artery volume blood flow was less than 50% of the initial value. FHR and umbilical artery PI normalised quickly after stopping the exercise.

Conclusions

Exercise at intensity above 90% of maximal MHR in pregnant elite athletes may compromise fetal wellbeing.
Fit for the fight? Illnesses in the Norwegian team in the Vancouver Olympic Games
Authors: Hanstad Dag Vidar , Rønsen Ola , Andersen Svein S , Steffen Kathrin , Engebretsen Lars
Published: March 2011

Background

The development of strategies to prevent illnesses before and during Olympic Games provides a basis for improved health and Olympic results.

Objective

(1) To document the efficacy of a prevention programme on illness in a national Olympic team before and during the 2010 Vancouver Olympic Winter Games (OWG), (2) to compare the illness incidence in the Norwegian team with Norwegian incidence data during the Turin 2006 OWG and (3) to compare the illness incidence in the Norwegian team with illness rates of other nations in the Vancouver OWG.

Methods

Information on prevention measures of illnesses in the Norwegian Olympic team was based on interviews with the Chief Medical Officer (CMO) and the Chief Nutrition and Sport Psychology Officers, and on a review of CMO reports before and after the 2010 OWG. The prevalence data on illness were obtained from the daily reports on injuries and illness to the International Olympic Committee.

Results

The illness rate was 5.1% (five of 99 athletes) compared with 17.3% (13 out of 75 athletes) in Turin (p=0.008). A total of four athletes missed one competition during the Vancouver Games owing to illness, compared with eight in Turin. The average illness rate for all nations in the Vancouver OWG was 7.2%.

Conclusions

Although no definite cause-and-effect link between the implementation of preventive measures and the prevalence of illness in the 2010 OWG could be established, the reduced illness rate compared with the 2006 OWG, and the low prevalence of illnesses compared with other nations in the Vancouver OWG suggest that the preparations were effective.
Implementing an exercise-training programme to prevent lower-limb injuries: considerations for the development of a randomised controlled trial intervention delivery plan
Authors: Finch Caroline F , White Peta , Twomey Dara , Ullah Shahid
Published: March 2011

Objective

To identify important considerations for the delivery of an exercise training intervention in a randomised controlled trial to maximise subsequent participation in that randomised controlled trial and intervention uptake.

Design

A cross-sectional survey, with a theoretical basis derived from the Health Belief Model (HBM) and the Reach, Efficacy/Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework.

Participants

374 male senior Australian Football players, aged 17–38 years.

Main outcome measurements

Beliefs about lower-limb injury causation/prevention, and the relative value of exercise training for performance and injury prevention. The data are interpreted within HBM constructs and implications for subsequent intervention implementation considered within the RE-AIM framework. Ordinal logistic regression compared belief scores across player characteristics.

Results

74.4% of players agreed that doing specific exercises during training would reduce their risk of lower-limb injury and would be willing to undertake them. However, 64.1% agreed that training should focus more on improving game performance than injury prevention. Younger players (both in terms of age and playing experience) generally had more positive views. Players were most supportive of kicking (98.9%) and ball-handling (97.0%) skills for performance and warm-up runs and cool-downs (both 91.5%) for injury prevention. Fewer than three-quarters of all players believed that balance (69.2%), landing (71.3%) or cutting/stepping (72.8) training had injury-prevention benefits.

Conclusions

Delivery of future exercise training programmes for injury prevention aimed at these players should be implemented as part of routine football activities and integrated with those as standard practice, as a means of associating them with training benefits for this sport.
Shockwave treatment for medial tibial stress syndrome in athletes; a prospective controlled study
Authors: Moen M H , Rayer S , Schipper M , Schmikli S , Weir A , Tol J L , Backx F J G
Published: March 2011

Objective

The purpose of this study was to describe the results of two treatment regimens for medial tibial stress syndrome (MTSS); a graded running programme and the same running programme with additional shockwave therapy (extracorporeal shockwave therapy; ESWT).

Design

A prospective observational controlled trial.

Setting

Two different sports medicine departments.

Participants

42 athletes with MTSS were included.

Intervention

Patients from one hospital were treated with a graded running programme, while patients from the other hospital were treated with the same graded running programme and focused ESWT (five sessions in 9 weeks).

Main Outcome Measures

Time to full recovery (the endpoint was being able to run 18 min consecutively without pain at a fixed intensity).

Results

The time to full recovery was significantly faster in the ESWT group compared with the patients who only performed a graded running programme, respectively 59.7±25.8 and 91.6±43.0 days (p=0.008).

Conclusions

This prospective observational study showed that MTSS patients may benefit from ESWT in addition to a graded running programme. ESWT as an additional treatment warrants further investigation in a prospective controlled trial with the addition of randomisation and double blinding.
Comparison of 2008 national and state-level self-reported and observed seatbelt use estimates
Authors: Ibrahimova Aybaniz , Shults Ruth A , Beck Laurie F
Published: March 2011

The objective of the study was to compare national and state-level estimates of self-reported and observed seatbelt use for 2008. Self-reported seatbelt use from the 2008 Behavioral Risk Factor Surveillance System was compared with 2008 observed seatbelt use published by the National Highway Traffic Safety Administration. The ratio of self-reported belt use to observed use was calculated for each state, and the correlation between the two seatbelt measures was examined using the Pearson correlation coefficient. The median state ratio of self-reported to observed belt use was 0.97. Self-reported use was lower than observed use in 38 states. A moderate association was revealed between the self-reported and observed use (r=0.71, p<0.01). The findings suggest that, as seatbelt use has increased over time, measures of self-reported and observed use have converged, and any upward bias in self-reported use due to social desirability has substantially declined.
Alcohol in fatal crashes involving Mexican and Canadian drivers in the USA
Authors: Baker Susan P , Brady Joanne E , Rebok George W , Li Guohua
Published: March 2011

Objective

To determine the prevalence of alcohol involvement and impairment in fatal crashes in the USA involving Mexican and Canadian drivers.

Methods

Drivers in fatal crashes in the USA were identified during 1998 to 2008 from the Fatality Analysis Reporting System, and the prevalence of alcohol involvement and impairment (defined as blood alcohol concentrations ≥0.01 g/dl and ≥0.08 g/dl, respectively) was compared among drivers licensed in Mexico (n=687), Canada (n=598), and the USA (n=561 908).

Results

The prevalence of alcohol involvement was 27% for US drivers, 27% for Mexican drivers, and 11% for Canadian drivers. Alcohol impairment was found in 23% of US drivers, 23% of Mexican drivers, and 8% of Canadian drivers. With adjustment for driver demographic characteristics and survival status and for crash circumstances, the prevalence of alcohol involvement was significantly lower for Canadian drivers (adjusted prevalence ratio (PR) 0.63, 95% CI 0.49 to 0.80) than for US drivers, and was similar between Mexican and US drivers (adjusted PR 0.91, 95% CI 0.81 to 1.02).

Conclusions

Alcohol involvement in fatal motor vehicle crashes in the USA is similarly prevalent in US and Mexican drivers, but is substantially less common in Canadian drivers.
National five-year examination of inequalities and trends in emergency hospital admission for violence across England
Authors: Bellis Mark A , Hughes Karen , Wood Sara , Wyke Sacha , Perkins Clare
Published: March 2011

Objectives

To examine relationships between violence, age (0–74 years), and deprivation, and to explore in which communities, age groups, and gender the potential for transmission of violent tendencies between individuals is greatest.

Methods

Five year (2004/2005 to 2008/2009) ecological study of emergency admissions resulting from violence (n=170 074) into all English hospitals using trend and logistic regression analyses.

Results

Hospital admissions for violence peak as individuals achieve legal adulthood (18 years). Risks of admission increase exponentially with increasing quintile of deprivation of residence, with odds overall being 5.5 times higher in the poorest quintile compared with the richest. The greatest absolute difference in violence admissions by deprivation quintile is seen in males aged 18 (218/100 000, richest; 698/100 000, poorest). However, the highest deprivation rate ratios (quintile 5:1) are seen at ages 0–10 years in both sexes and at all ages after 40 years in males (40–58 years, females). In males aged 17–19 years, violence accounts for 20% of the entire gap between wealthiest and poorest quintiles in all cause emergency hospital admissions.

Conclusions

Analyses identify four lifetime periods for violence: up to 10 years (prepubescent), 11–20 years (adolescence), 21–45 years (younger adults), and over 45 years (older adults). While violence is most common in adolescence, its concentration in poorer areas during prepubescence and in younger adulthood (parenting age) suggests that poorer children are exposed to much more aggressive communities. This is likely to contribute to the disproportionate escalation in violence they experience during adolescence. Effective interventions to prevent such escalations are available and need to be implemented particularly in poor communities.
Work-related non-crash heavy vehicle driver fatalities in Australia, 2000–9
Authors: Jones Christopher B , Ibrahim Joseph E , Ozanne-Smith Joan
Published: March 2011

The objective of this study was to describe the nature and mechanisms of a case series of Australian work-related non-crash heavy vehicle driver fatalities. The study used existing population-based mortality data on non-crash work-related heavy vehicle (gross vehicle mass >4.5 t) driver fatalities reported to Australian coroners between 2000 and 2009. There were 47 fatalities with a mean age of 46.5 years. Available toxicology detected that six of 16 drivers consumed illegal drugs or alcohol. The most frequent task was attending to cargo (n=22, 47%); 31 (66%) fatalities occurred when the driver was working alone. Brake issues (n=21, 45%) were the most frequent contributing factor, and crushing the most common mechanism (n=33, 70%), particularly between the vehicle and another object (n=22, 47%). Fatalities occurred in most jurisdictions averaging 4.7 per year overall. A large number of truck drivers die performing non-driving tasks. Crushing following vehicle rolling accounts for almost 50% of fatalities. Considering this pathway may provide prevention opportunities.
How is informed consent related to emotions and empathy? An exploratory neuroethical investigation
Authors: Supady Alexander , Voelkel Antonie , Witzel Joachim , Gubka Udo , Northoff Georg
Published: March 2011

Context

Informed consent is crucial in daily clinical practice and research in medicine and psychiatry. A recent neuroethical investigation explored the psychological factors that are crucial in determining whether or not subjects give consent. While cognitive functions have been shown to play a central role, the impact of empathy and emotions on subjects' decisions in informed consent remains unclear.

Objective

To evaluate the impact of empathy and emotions on subjects' decision in informed consent in an exploratory study.

Design

Decisional capacity and informed consent to a subsequent imaging study were evaluated with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). Empathy and emotion recognition were measured with the Multifaceted Empathy Test (MET) and the Florida Affect Battery (FAB).

Setting

Psychiatric subjects were recruited from a general psychiatric hospital and a forensic state hospital.

Patients

A mixed group of 98 healthy men and forensic and non-forensic psychiatric subjects were investigated.

Results

Both empathy (MET) and emotion recognition (FAB) correlated with MacCAT-CR scores. Higher cognitive empathy and good emotion recognition (compared with low empathy and emotion recognition) were associated with increased decisional capacity and higher rates of refusal to give informed consent.

Conclusions

This study shows an empirical relationship between decision-making and informed consent, on the one hand, and emotions and empathy on the other. While this study is exploratory and preliminary, the findings of a relationship between informed consent, emotions and empathy raise important neuroethical questions with regard to an emotional-social concept of informed consent and potential clinical implications for testing informed consent.
TECHNOLOGY AND FINANCIAL INNOVATION
Authors: BETZ FREDERICK , KHALIL TAREK M.
Published: March 2011

This case study examines the global financial debacle of 2007–2008 to see the roles in which technology played in new financial schemes. It uses theory about social-technical systems and applications of technology to analyze the case. It identifies theoretical issues in which MOT can relate to classical economic theory.
SUPPLY CHAIN COLLABORATIVE FORECASTING METHODS BASED ON FACTORS
Authors: SHU TONG , CHEN SHOU , WANG SHOUYANG , CHAO XIULI
Published: March 2011

This paper proposes that sales and demands information are equally important in the supply chain. It discusses the role of factors in chorological forecasting and puts forth the supply chain collaborative forecasting methods based on factors and presents the relevant empirical studies. In the light of the historical actual sales data, factors of Spring Festival transportation, shutting down for examinations, and repairs and minor repairs are extracted and quantified in different hierarchies and domains. At the same time, they are reverted in the corporate sales forecasting. The empirical studies indicate that factors play an important role in supply chain sales forecasting. Their application can greatly improve the specific and general forecasting accuracy and represents the thought of collaborative forecasting. They can contribute to the supply chain implication and prominent information application; they can contribute to positively employing the potential negative constraints of supply chain enterprises; and they can also contribute to the management of supply chain as the information whole. All these can be considered as an extension of the economic information filter in different hierarchies and modules.
RISK ASSESSMENT AND ACTION SELECTION IN PRELIMINARY DESIGN
Authors: YEH CHUNG , LIU WEN-CHIN , LEE CHIH-LIEH
Published: March 2011

New product development (NPD) has typically had strategic implications for the success and prosperity of an organization. This paper applied refined failure mode and effect analysis and genetic algorithm techniques to develop and establish an integrated risk analysis model for improving preliminary design of NPD. Three core items, technological performance, cost, and schedule risk, were used to improve the process of preliminary design and resource allocation in NPD projects. Risk severity, occurrence, and correlation characteristics are collected for each core item. A real study case was implemented to conclude an improving design decision and process change for NPD project.
HYBRID NANOMATERIALS CONTAINING PAMAM, POLYROTAXANE AND QUANTUM DOT BLOCKS
Authors: ADELI MOHSEN , SARABI REZA SADEGHI , SADEGHI ELHAM
Published: March 2011

Pseudopolyrotaxanes, Ps-PR, consisting of α-cyclodextrin rings, polyethylene glycol axes and end triazine groups were prepared and then were capped by amino-functionalized quantum dots, NH2 -QDs, to achieve polyrotaxanes. The amino-functionalized QDs stoppers of polyrotaxanes were used as core to synthesize polyamidoamine, PAMAM, dendrons divergently and hybrid nanomaterials were obtained. Synthesized hybrid nanomaterials were characterized by different spectroscopy, microscopy and thermal analysis methods. They were freely soluble in water and their aqueous solutions were stable at room temperature over several months. Due to their biocompatible backbone, high functionality and water solubility synthesized hybrid nanomaterials are promising carriers and probes in cancer diagnosis and therapy.
BIOFUNCTIONALIZATION OF PET/SiO2 SURFACES FOR SINGLE MOLECULE EXPERIMENTS AND MEDICAL APPLICATIONS
Authors: KATRANIDIS ALEXANDROS , MELACHROINOS ALEXANDROS , KARAGIANNIDIS PANAGIOTIS G. , LOUSINIAN SYLVIE , PAPADOPOULOS GEORGIOS , LOGOTHETIDIS STERGIOS , CHOLI-PAPADOPOULOU THEODORA
Published: March 2011

PET/ SiO2 layers were chemically modified to maintain immobilization of functional single molecules. GFP molecules provide an ideal system due to their stability and intrinsic fluorescence. GFP in vivo biotinylated within its NH2 -terminal region and attached on the substrate via the biotin–streptavidin bond was further investigated with confocal microscopy, atomic force microscopy (AFM) and spectroscopic ellipsometry (SE). AFM revealed monolayered donut-like structures representing assemblies of biotin–streptavidin–biotin–GFP immobilized onto PET/ SiO2 surfaces via mPEG. In particular, regions with an approximate height of 12 nm, which approaches the molecular dimensions of the above complex given by molecular modeling, could be detected. The dimensions of the donut-like structures suggest a close-to-each-other positioning of the GFP molecules — which, however, retain their functionality, as evidenced by confocal microscopy.
Effect of CO2 on the ventilatory sensitivity to rising body temperature during exercise
Authors: Hayashi Keiji , Honda Yasushi , Miyakawa Natsuki , Fujii Naoto , Ichinose Masashi , Koga Shunsaku , Kondo Narihiko , Nishiyasu Takeshi
Published: March 2011

We examined the degree to which ventilatory sensitivity to rising body temperature (the slope of the regression line relating ventilation and body temperature) is altered by restoration of arterial Pco2 to the eucapnic level during prolonged exercise in the heat. Thirteen subjects exercised for ∼60 min on a cycle ergometer at 50% of peak O2 uptake with and without inhalation of CO2-enriched air. Subjects began breathing CO2-enriched air at the point that end-tidal Pco2 started to decline. Esophageal temperature (Tes), minute ventilation (V̇e), tidal volume (VT), respiratory frequency ( fR), respiratory gases, middle cerebral artery blood velocity, and arterial blood pressure were recorded continuously. When V̇e, VT, fR, and ventilatory equivalents for O2 uptake (V̇e/V̇o2) and CO2 output (V̇e/V̇co2) were plotted against changes in Tes from the start of the CO2-enriched air inhalation (ΔTes), the slopes of the regression lines relating V̇e, VT, V̇e/V̇o2, and V̇e/V̇co2 to ΔTes (ventilatory sensitivity to rising body temperature) were significantly greater when subjects breathed CO2-enriched air than when they breathed room air (V̇e: 19.8 ± 10.3 vs. 8.9 ± 6.7 l·min−1·°C−1, VT: 18 ± 120 vs. −81 ± 92 ml/°C; V̇e/V̇o2: 7.4 ± 5.5 vs. 2.6 ± 2.3 units/°C, and V̇e/V̇co2: 7.6 ± 6.6 vs. 3.4 ± 2.8 units/°C). The increase in V̇e was accompanied by increases in VT and fR. These results suggest that restoration of arterial Pco2 to nearly eucapnic levels increases ventilatory sensitivity to rising body temperature by around threefold.
Pulmonary trunk, ductus arteriosus, and pulmonary arterial phasic blood flow interactions during systole and diastole in the fetus
Authors: Smolich Joseph J. , Mynard Jonathan P. , Penny Daniel J.
Published: March 2011

Although the distribution of average fetal pulmonary trunk (PT) blood flow favors the ductus arteriosus (DA) over the lungs, the phasic aspects of this distribution during systole and diastole are not well understood. Accordingly, flow profile and wave intensity (WI) analyses were performed at baseline and during brief flow increases accompanying an extrasystole (ES) in 10 anesthetized late-gestation fetal sheep instrumented with PT, DA, and left pulmonary artery (PA) micromanometer catheters and transit-time flow probes. At baseline, 83% of mean PT flow crossed the DA and 17% entered the lungs. However, early systolic flow associated with a forward-running compression wave (FCWis) was higher in the PA and predominant DA flow only emerged in midsystole when a large PA backward-running compression wave (BCWms), which reduced PA flow, was transmitted into the DA as a forward-running compression wave (FCWms) that increased flow. Subsequent protodiastolic forward DA flow occurring during pulmonary valve closure was associated with substantial retrograde PA flow, but insignificant PT flow. Conversely, forward DA flow in the remainder of diastole occurred with forward PT but near-zero PA flow. These flow and WI patterns, in conjunction with the results of mathematical modeling, suggest that 1) fetal PT flow preferentially passes into the PA during early systole due to a lower PA-than-DA characteristic impedance, while DA flow predominates in mid- and late systole due to flow effects arising from the PA BCWms, and 2) forward DA flow is mainly sustained by reversal of PA flow in protodiastole but discharge of a more central reservoir in diastole.
Conditioning of the Achilles tendon via ankle exercise improves correlations between sonographic measures of tendon thickness and body anthropometry
Authors: Wearing Scott C. , Grigg Nicole L. , Hooper Sue L. , Smeathers James E.
Published: March 2011

Although conditioning is routinely used in mechanical tests of tendon in vitro, previous in vivo research evaluating the influence of body anthropometry on Achilles tendon thickness has not considered its potential effects on tendon structure. This study evaluated the relationship between Achilles tendon thickness and body anthropometry in healthy adults both before and after resistive ankle plantarflexion exercise. A convenience sample of 30 healthy male adults underwent sonographic examination of the Achilles tendon in addition to standard anthropometric measures of stature and body weight. A 10–5 MHz linear array transducer was used to acquire longitudinal sonograms of the Achilles tendon, 20 mm proximal to the tendon insertion. Participants then completed a series (90–100 repetitions) of conditioning exercises against an effective resistance between 100% and 150% body weight. Longitudinal sonograms were repeated immediately on completion of the exercise intervention, and anteroposterior Achilles tendon thickness was determined. Achilles tendon thickness was significantly reduced immediately following conditioning exercise ( t = 9.71, P < 0.001), resulting in an average transverse strain of −18.8%. In contrast to preexercise measures, Achilles tendon thickness was significantly correlated with body weight ( r = 0.72, P < 0.001) and to a lesser extent height ( r = 0.45, P = 0.01) and body mass index ( r = 0.63, P < 0.001) after exercise. Conditioning of the Achilles tendon via resistive ankle exercises induces alterations in tendon structure that substantially improve correlations between Achilles tendon thickness and body anthropometry. It is recommended that conditioning exercises, which standardize the load history of tendon, are employed before measurements of sonographic tendon thickness in vivo.
Differential expression of metabolic genes essential for glucose and lipid metabolism in skeletal muscle from spinal cord injured subjects
Authors: Long Yun Chau , Kostovski Emil , Boon Hanneke , Hjeltnes Nils , Krook Anna , Widegren Ulrika
Published: March 2011

Skeletal muscle plays an important role in the regulation of energy homeostasis; therefore, the ability of skeletal muscle to adapt and alter metabolic gene expression in response to changes in physiological demands is critical for energy balance. Individuals with cervical spinal cord lesions are characterized by tetraplegia, impaired thermoregulation, and altered skeletal muscle morphology. We characterized skeletal muscle metabolic gene expression patterns, as well as protein content, in these individuals to assess the impact of spinal cord injury on critical determinants of skeletal muscle metabolism. Our results demonstrate that mRNA levels and protein expression of skeletal muscle genes essential for glucose storage are reduced, whereas expression of glycolytic genes is reciprocally increased in individuals with spinal cord injury. Furthermore, expression of genes essential for lipid oxidation is coordinately reduced in spinal cord injured subjects, consistent with a marked reduction of mitochondrial proteins. Thus spinal cord injury resulted in a profound and tightly coordinated change in skeletal muscle metabolic gene expression program that is associated with the aberrant metabolic features of the tissue.
Coactivation of renal sympathetic neurons and somatic motor neurons by chemical stimulation of the midbrain ventral tegmental area
Authors: Nakamoto Tomoko , Matsukawa Kanji , Liang Nan , Wakasugi Rie , Wilson L. Britt , Horiuchi Jouji
Published: March 2011

We examined whether neurons in the midbrain ventral tegmental area (VTA) play a role in generating central command responsible for autonomic control of the cardiovascular system in anesthetized rats and unanesthetized, decerebrated rats with muscle paralysis. Small volumes (60 nl) of an N-methyl-d-aspartate receptor agonist (l-homocysteic acid) and a GABAergic receptor antagonist (bicuculline) were injected into the VTA and substantia nigra (SN). In anesthetized rats, l-homocysteic acid into the VTA induced short-lasting increases in renal sympathetic nerve activity (RSNA; 66 ± 21%), mean arterial pressure (MAP; 5 ± 2 mmHg), and heart rate (HR; 7 ± 2 beats/min), whereas bicuculline into the VTA produced long-lasting increases in RSNA (130 ± 45%), MAP (26 ± 2 mmHg), and HR (66 ± 6 beats/min). Bicuculline into the VTA increased blood flow and vascular conductance of the hindlimb triceps surae muscle, suggesting skeletal muscle vasodilatation. However, neither drug injected into the SN affected all variables. Renal sympathetic nerve and cardiovascular responses to chemical stimulation of the VTA were not essentially affected by decerebration at the premammillary-precollicular level, indicating that the ascending projection to the forebrain from the VTA was not responsible for evoking the sympathetic and cardiovascular responses. Furthermore, bicuculline into the VTA in decerebrate rats produced long-lasting rhythmic bursts of RSNA and tibial motor nerve discharge, which occurred in good synchrony. It is likely that the activation of neurons in the VTA is capable of eliciting synchronized stimulation of the renal sympathetic and tibial motor nerves without any muscular feedback signal.
Intensive resistance exercise induces lymphocyte apoptosis via cortisol and glucocorticoid receptor-dependent pathways
Authors: Krüger K. , Agnischock S. , Lechtermann A. , Tiwari S. , Mishra M. , Pilat C. , Wagner A. , Tweddell C. , Gramlich I. , Mooren F. C.
Published: March 2011

Intensive endurance exercise is known to induce lymphocyte apoptosis, which might affect immune function. Less is known about the effects of resistance exercise on apoptosis and its underlying mechanisms. In this study, subjects performed an intensive resistance test (IRT) and a moderate resistance test, and lymphocyte apoptosis, apoptosis-related parameters, and underlying mechanisms were investigated. IRT induced a significant increase of lymphocyte apoptosis 3 h after exercise, which was accompanied by a significant decrease of mitochondrial membrane potential, a reduction of Bcl-2, and an upregulation of the CD95 receptor. Blood lactate, IL-6, C-reactive protein, and cortisol increased significantly 3 h after IRT. A significant correlation was observed between the increase of apoptosis and cortisol levels 3 h after IRT. Incubation of freshly isolated lymphocytes in IRT serum indicated an important role of serum correlates for apoptosis induction. Selective incubation of lymphocytes in concentrations of selected serum parameters corresponding to levels found post in IRT serum demonstrated a major role for cortisol in apoptosis induction. This result was confirmed by attenutation of apoptosis after addition of mifepristone before incubation in IRT serum. In summary, resistance exercise induced lymphocyte apoptosis in an intensity-dependent way. Furthermore, cortisol signaling via glucocorticoid receptors might be an important mechanism for lymphocyte apoptosis after resistance exercise.
Effects of acetazolamide and dexamethasone on cerebral hemodynamics in hypoxia
Authors: Subudhi Andrew W. , Dimmen Andrew C. , Julian Colleen G. , Wilson Megan J. , Panerai Ronney B. , Roach Robert C.
Published: March 2011

Previous attempts to detect global cerebral hemodynamic differences between those who develop headache, nausea, and fatigue following rapid exposure to hypoxia [acute mountain sickness (AMS)] and those who remain healthy have been inconclusive. In this study, we investigated the effects of two drugs known to reduce symptoms of AMS to determine if a common cerebral hemodynamic mechanism could explain the prophylactic effect within individuals. With the use of randomized, placebo-controlled, double-blind, crossover design, 20 healthy volunteers were given oral acetazolamide (250 mg), dexamethasone (4 mg), or placebo every 8 h for 24 h prior to and during a 10-h exposure to a simulated altitude of 4,875 m in a hypobaric chamber, which included 2 h of exercise at 50% of altitude-specific V̇o2max. Cerebral hemodynamic parameters derived from ultrasound assessments of dynamic cerebral autoregulation and vasomotor reactivity were recorded 15 h prior to and after 9 h of hypoxia. AMS symptoms were scored using the Lake Louise Questionnaire (LLQ). It was found that both drugs prevented AMS in those who became ill on placebo (∼70% decrease in LLQ), yet a common cerebral hemodynamic mechanism was not identified. Compared with placebo, acetazolamide reduced middle cerebral artery blood flow velocity (11%) and improved dynamic cerebral autoregulation after 9 h of hypoxia, but these effects appeared independent of AMS. Dexamethasone had no measureable cerebral hemodynamic effects in hypoxia. In conclusion, global cerebral hemodynamic changes resulting from hypoxia may not explain the development of AMS.
MicroRNA-301 Mediates Proliferation and Invasion in Human Breast Cancer
Authors: Shi Wei , Gerster Kate , Alajez Nehad M. , Tsang Jasmine , Waldron Levi , Pintilie Melania , Hui Angela B. , Sykes Jenna , P'ng Christine , Miller Naomi , McCready David , Fyles Anthony , Liu Fei-Fei
Published: March 2011

Several microRNAs have been implicated in human breast cancer but none to date have been validated or utilized consistently in clinical management. MicroRNA-301 (miR-301) overexpression has been implicated as a negative prognostic indicator in lymph node negative (LNN) invasive ductal breast cancer, but its potential functional impact has not been determined. Here we report that in breast cancer cells, miR-301 attenuation decreased cell proliferation, clonogenicity, migration, invasion, tamoxifen resistance, tumor growth, and microvessel density, establishing an important oncogenic role for this gene. Algorithm-based and experimental strategies identified FOXF2, BBC3, PTEN, and COL2A1 as candidate miR-301 targets, all of which were verified as direct targets through luciferase reporter assays. We noted that miR-301 is located in an intron of the SKA2 gene which is responsible for kinetochore assembly, and both genes were found to be coexpressed in primary breast cancer samples. In summary, our findings define miR-301 as a crucial oncogene in human breast cancer that acts through multiple pathways and mechanisms to promote nodal or distant relapses. Cancer Res; 71(8); 2926–37. ©2011 AACR.
Human CD271-Positive Melanoma Stem Cells Associated with Metastasis Establish Tumor Heterogeneity and Long-term Growth
Authors: Civenni Gianluca , Walter Anne , Kobert Nikita , Mihic-Probst Daniela , Zipser Marie , Belloni Benedetta , Seifert Burkhardt , Moch Holger , Dummer Reinhard , van den Broek Maries , Sommer Lukas
Published: March 2011

Human melanoma is composed of distinct cell types reminiscent of neural crest derivatives and contains multipotent cells that express the neural crest stem cell markers CD271(p75NTR) and Sox10. When isolated from solid tumors by using a method that leaves intact cell surface epitopes, CD271-positive, but not CD271-negative, cells formed tumors on transplantation into nude or nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. These tumors fully mirrored the heterogeneity of the parental melanoma and could be passaged more than 5 times. In contrast, in more immunocompromised NOD/SCID/IL2rγnull mice, or in natural killer cell–depleted nude or NOD/SCID mice, both CD271-positive and CD271-negative tumor cell fractions established tumors. However, tumors resulting from either fraction did not phenocopy the parental tumors, and tumors derived from the CD271-negative cell fraction could not be passaged multiple times. Together, our findings identify CD271-positive cells as melanoma stem cells. Our observation that a relatively high frequency of CD271/Sox10-positive cells correlates with higher metastatic potential and worse prognosis further supports that CD271-positive cells within human melanoma represent genuine cancer stem cells. Cancer Res; 71(8); 3098–109. ©2011 AACR.
Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A
Authors: Chen Kuen-Feng , Yu Hui-Chuan , Liu Chun-Yu , Chen Hui-Ju , Chen Yi-Ching , Hou Duen-Ren , Chen Pei-Jer , Cheng Ann-Lii
Published: March 2011

Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration- and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008–induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008–induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A. Mol Cancer Ther; 10(5); 892–901. ©2011 AACR.
Targeted Delivery of an Antibody–Mutant Human Endostatin Fusion Protein Results in Enhanced Antitumor Efficacy
Authors: Shin Seung-Uon , Cho Hyun-Mi , Merchan Jaime , Zhang Jin , Kovacs Krisztina , Jing Yawu , Ramakrishnan Sundaram , Rosenblatt Joseph D.
Published: March 2011

The antiangiogenic protein endostatin showed considerable preclinical antitumor activity, but limited efficacy in phase I/II trials. Prior studies using an anti-HER2 antibody–murine endostatin fusion showed enhanced antitumor activity compared to anti-HER2 antibody or endostatin given alone, or in combination. We have generated two anti-HER2 human endostatin fusion proteins by fusing either wild-type or a mutant human endostatin (huEndo-P125A) to the 3′ end of a humanized anti-HER2 IgG3 antibody. Antitumor efficacy was examined in murine and human breast tumor models. HuEndo-P125A antibody fusion protein (αHER2-huEndo-P125A) inhibited VEGF and bFGF induced endothelial cell proliferation, and tube formation in vitro, more efficiently than endostatin alone, wild-type endostatin fusion protein (αHER2-huEndo), or parental anti-HER2 antibody (αHER2 IgG3). Wild-type and mutant human endostatin was rapidly cleared from serum in mice (T½2 = 2.0–2.1 hours), whereas αHER2-huEndo fusion proteins had a significantly prolonged half-life (T½2 = 40.7–57.5 hours). Treatment of SK-BR-3 breast cancer xenografts with anti-HER2 IgG3-huEndo-P125A fusion resulted in greater inhibition of tumor growth and improved survival, compared to treatment with either αHER2 IgG3 (P = 0.025), human endostatin (P = 0.034), or anti-HER2 IgG3-huEndo (P = 0.016). αHER2-huEndo-P125A specifically inhibited tumors expressing HER2 in mice simultaneously implanted with murine mammary tumor EMT6 cells and with EMT6 engineered to express HER2 antigen (EMT6-HER2). Targeting of endostatin using antibody fusion proteins could improve antitumor activity of either anti-HER2 antibody and/or endostatin and provides a versatile approach that could be applied to other tumor targets with alternative antibody specificities. Mol Cancer Ther; 10(4); 603–14. ©2011 AACR.
CCN1, a Candidate Target for Zoledronic Acid Treatment in Breast Cancer
Authors: Espinoza Ingrid , Liu Hong , Busby Robert , Lupu Ruth
Published: March 2011

CCN1, also known as CYR61, is a survival and proangiogenic factor overexpressed in about 30% of invasive breast carcinomas, and particularly in triple-negative breast carcinomas (TNBC). CCN1 expression in breast cancer promotes tumorigenicity, metastasis, antihormone, and chemoresistance. TNBCs often develop bone metastasis, thus the vast majority of patients receive bisphosphonate treatment as a companion to chemotherapy. Zoledronic acid (ZOL), a bisphosphonate currently in use, inhibits bone resorption, prevents development of new osteolytic lesions induced by tumor metastasis, and has a direct antitumor activity in breast cancer cells and tumors. We have shown that ZOL inhibits anchorage independent growth as well as branching and morphogenesis in CCN1 overexpressing cells. However, the mechanism is not yet well understood. In this study, we investigate the effect of ZOL in breast cancer cells with high and undetectable CCN1 expression levels. We show that CCN1-expressing cells are more sensitive to ZOL, that ZOL induces downregulation of the CCN1 promoter activity and CCN1 protein expression in a dose-dependent manner, and that ZOL is associated with a decrease in phosphorylated Akt and translocation of FOXO3a, a negative regulator of CCN1 expression, to the nucleus. Deletion of the FOXO3a binding site in the CCN1 promoter prevents ZOL inhibition of the CCN1 promoter activity showing that FOXO3a transcriptional activation is necessary for ZOL to induce CCN1 inhibition. This study provides evidence that ZOL targets the proangiogenic factor (CCN1) through FOXO3a and reveals a new mechanism of ZOL action in breast cancer cells. Mol Cancer Ther; 10(5); 732–41. ©2011 AACR.
Modulation of Protein Phosphatase 2A Activity Alters Androgen-Independent Growth of Prostate Cancer Cells: Therapeutic Implications
Authors: Bhardwaj Arun , Singh Seema , Srivastava Sanjeev K. , Honkanen Richard E. , Reed Eddie , Singh Ajay P.
Published: March 2011

Earlier we identified PPP2CA, which encodes for the α-isoform of protein phosphatase 2A (PP2A) catalytic subunit, as one of the downregulated genes in androgen-independent prostate cancer. PP2A is a serine/threonine phosphatase and a potent tumor suppressor involved in broad cellular functions; however, its role in prostate cancer has not yet been determined. Here, we have investigated the effect of PP2A activity modulation on the androgen-independent growth of prostate cancer cells. Our data show that the PPP2CA expression and PP2A activity is downregulated in androgen-independent (C4-2) prostate cancer cells as compared with androgen-dependent (LNCaP) cells. Downregulation of PP2A activity by pharmacologic inhibition or short interfering RNA-mediated PPP2CA silencing sustains the growth of LNCaP cells under an androgen-deprived condition by relieving the androgen deprivation–induced cell-cycle arrest and preventing apoptosis. Immunoblot analyses reveal enhanced phosphorylation of Akt, extracellular signal–regulated kinase (ERK), BAD, increased expression of cyclins (A1/D1), and decreased expression of cyclin inhibitor (p27) on PP2A downregulation. Furthermore, our data show that androgen receptor (AR) signaling is partially maintained in PP2A-inhibited cells through increased AR expression and ligand-independent phosphorylation. Pharmacologic inhibition of Akt, ERK, and AR suggest a role of these signaling pathways in facilitating the androgen-independent growth of LNCaP cells. These observations are supported by the effect of ceramide, a PP2A activator, on androgen-independent C4-2 cells. Ceramide inhibited the growth of C4-2 cells on androgen deprivation, an effect that could be abrogated by PP2A downregulation. Altogether, our findings suggest that modulation of PP2A activity may represent an alternative therapeutic approach for the treatment of advanced androgen-independent prostate cancer. Mol Cancer Ther; 10(5); 720–31. ©2011 AACR.
Retinal Pigment Epithelium Cell Alignment on Nanostructured Collagen Matrices
Authors: Ulbrich Stefan , Friedrichs Jens , Valtink Monika , Murovski Simo , Franz Clemens M. , Müller Daniel J. , Funk Richard H.W. , Engelmann Katrin
Published: March 2011

We investigated attachment and migration of human retinal pigment epithelial cells (primary, SV40-transfected and ARPE-19) on nanoscopically defined, two-dimensional matrices composed of parallel-aligned collagen type I fibrils. These matrices were used non-cross-linked (native) or after riboflavin/UV-A cross-linking to study cell attachment and migration by time-lapse video microscopy. Expression of collagen type I and IV, MMP-2 and of the collagen-binding integrin subunit α2 were examined by immunofluorescence and Western blotting. SV40-RPE cells quickly attached to the nanostructured collagen matrices and aligned along the collagen fibrils. However, they disrupted both native and cross-linked collagen matrices within 5 h. Primary RPE cells aligned more slowly without destroying either native or cross-linked substrates. Compared to primary RPE cells, ARPE-19 cells showed reduced alignment but partially disrupted the matrices within 20 h after seeding. Expression of the collagen type I-binding integrin subunit α2 was highest in SV40-RPE cells, lower in primary RPE cells and almost undetectable in ARPE-19 cells. Thus, integrin α2 expression levels directly correlated with the degree of cell alignment in all examined RPE cell types. Specific integrin subunit α2-mediated matrix binding was verified by preincubation with an α2-function-blocking antibody, which impaired cell adhesion and alignment to varying degrees in primary and SV40-RPE cells. Since native matrices supported extended and directed primary RPE cell growth, optimizing the matrix production procedure may in the future yield nanostructured collagen matrices serving as transferable cell sheet carriers.