Long-term Functional Loss Research Articles

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice

BackgroundExtracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA.Materials and methodsTo determine whether Dspp+/– mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/–, and Dspp homozygous (Dspp−/−) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/– mice over time, condyles of Dspp+/– and WT mice were analyzed radiologically, histologically, and immunohistochemically.ResultsMicro-CT and histomorphometric analyses revealed that Dspp+/– and Dspp−/− mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp−/− mice which exhibited tooth loss, Dspp+/– mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/– mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/– mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage.ConclusionsDspp+/– mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

Computational Studies Using COMSOL Multiphysics on Dielectrophoretic Characterization and Separation of Mesenchymal Stem Cells Undergoing Tenogenic Differentiation

Stem cells have unique self-renewal and differentiation capacities, which are advantageous for regenerative medicine and tissue engineering applications. Stem cells can recreate cells needed to repair injured tissues and organs in the body, for example, by regenerating connective tissues, which provide support, protection, and a structural framework for various organs and other tissues. However, a significant limitation is the susceptibility of tendons to injury with long-term loss of function. Mesenchymal Stem Cell (MSC) therapies are promising for healing tendon injuries and tears but controlling stem cell differentiation and generating homogeneous tenogenic stem cell populations remains challenging. Therefore, separating differentiating and non-differentiating MSCs to collect homogenous cells is critical for further tissue repair after transplantation. To substantiate our hypothesis that differentiating and non-differentiating stem cells have unique dielectric properties, we focused on characterizing-obtaining dielectric signatures for differentiating tenogenic and non-tenogenic MSCs on the third day of differentiation using dielectrophoresis (DEP) focused on crossover frequencies [1, 2]. The estimated values for membrane capacitance, conductivity, and permittivity after 3-day treatment of undifferentiated cells differentiating into tenogenic MSCs are 2.46±0.1 pF, 0.82±0.01 S/m, and 1.97±0.05, respectively, and cytoplasm conductivity 0.82±0.02 S/m. The treated stem cells undergo differentiation, but the untreated cells don’t. The results showed a significant difference between the 3-day treatment and no-treatment group. The estimated properties from the dielectrophoretic characterization studies are crucial in designing a DEP-based enrichment microdevice to collect homogeneous differentiated stem cell populations for tendon repair. Using particle tracing, creeping flow (transport of diluted species model), and electric current physics in COMSOL Multiphysics simulation software, we designed a microdevice that achieves 100% separation of untreated and treated mesenchymal stem cells undergoing differentiation towards tendon. Applying dielectrophoresis to the microdevice architecture demonstrated high selectivity and yield, processing one million treated and untreated stem cells in 6.4 and 27.8 hours, respectively.

Genetic Features of Young and Aged Animals After Peripheral Nerve Injury: Implications for Diminished Regeneration Capacity

The spontaneous regeneration capacity of peripheral nerves is fundamentally reduced with advancing age, leading to severe and long-term functional loss. The cellular and molecular basis underlying incomplete and delayed recovery of aging peripheral nerves is still murky. Here, we collected sciatic nerves of aged rats at 1d, 4d, and 7d after nerve injury, systematically analyzed the transcriptional changes of injured sciatic nerves, and examined the differences of injury responses between aged rats and young rats. RNA sequencing revealed that sciatic nerves of aged and young rats exhibit distinctive expression patterns after nerve injury. Acute and vigorous immune responses, including motivated B cell receptor signaling pathway, occurred in injured sciatic nerves of both aged and young rats. Different from young rats, aged rats have more CD8+ T cells and B cells in normal state and the elevation of M2 macrophages seemed to be more robust in sciatic nerves, especially at later time points after nerve injury. Young rats, on the other hand, showed strong and early up-regulation of cell cycle-related genes. These identified unique transcriptional signatures of aged and young rats help the understanding of aged-associated injury responses in the wound microenvironments and provide essential basis for the treatment of regeneration deficits in aged population.

Association of HbA1c with functional outcome by ischemic stroke subtypes and age.

To determine whether high HbA1c levels are related to short-and long-term functional outcomes in patients with ischemic stroke (IS) and whether this association differs according to the IS subtype and the patient's age. The data of 7,380 IS patients admitted to 16 hospitals or regional stroke centers in South-Korea, between May 2017 and December 2019, were obtained from the Clinical Research Collaboration for Stroke-Korea-National Institute of Health database and retrospectively analyzed. Among these patients, 4,598 were followed-up for one-year. The HbA1c levels were classified into three groups (<5.7, 5.7 to <6.5%, ≥6.5%). Short-and long-term poor functional outcomes were defined using the modified Rankin Scale score of 2 to 6 at three-months and one-year, respectively. IS subtypes were categorized according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. There was an association between higher HbA1c (≥6.5%) and poor functional outcomes at three-months in all patients (three-months; OR, 1.299, 95% CI 1.098, 1.535, one-year; OR, 1.181, 95% CI 0.952, 1.465). When grouped by age, the associations after both 3 months and 1 year observed in younger adult group (<65 years), but not in group aged 65 years and older (three-months; <65 years OR, 1.467, 95% CI 1.112, 1.936, ≥65 years OR, 1.220, 95% CI 0.987, 1.507, p for interaction = 0.038, one-year; <65 years OR, 1.622, 95% CI 1.101, 2.388, ≥65 years OR, 1.010, 95% CI 0.778, 1.312, p for interaction = 0.018). Among younger adult group, the higher HbA1c level was related to short-and long-term functional loss in patients with the small vessel occlusion subtype (three-months; OR, 2.337, 95%CI 1.334, 4.095, one-year; OR, 3.004, 95% CI 1.301, 6.938). However, in patients with other TOAST subtypes, a high HbA1c level did not increase the risk of poor outcomes, regardless of the age of onset. High HbA1c levels increase the risk of short-and long-term poor functional outcomes after IS onset. However, this association differs according to stroke subtype and age. Thus, pre-stroke hyperglycemia, reflected by HbA1c, may be a significant predictor for a poor prognosis after ischemic stroke, particular in young- and middle-aged adults.

Exploiting synergistic effect of CO/NO gases for soft tissue transplantation using a hydrogel patch

Autologous skin flap transplantation is a common method for repairing complex soft tissue defects caused by cancer, trauma, and congenital malformations. Limited blood supply range and post-transplantation ischemia-reperfusion injury can lead to distal necrosis of the flap and long-term functional loss, which severely restricts the decision-making regarding the optimal surgical plan. To address this issue, we develop a hydrogel patch that releases carbon monoxide and nitric oxide gases on demand, to afford a timely blood supply for skin flap transplantation during surgery. Using an ischemia-reperfusion dorsal skin flap model in rats, we show that the hydrogel patch maintains the immediate opening of blood flow channels in transplanted tissue and effective blood perfusion throughout the perioperative period, activating perfusion of the hemodynamic donor site. We demonstrate that the hydrogel patch promotes distal vascularization and long-term functional reconstruction of transplanted tissues by inhibiting inflammatory damage and accelerating blood vessel formation.

Prevotella bivia Septic Arthritis in an Immunocompetent Adult: A Case Report and Review of Literature.

Septic arthritis is a medical emergency that requires prompt diagnosis to prevent long-term intra-articular complications. Prevotella bivia is an anaerobic gram-negative rod which has been infrequently reported to cause septic arthritis. We present a 49-year-old female that presented with spontaneous left knee pain and swelling without history of insult to the knee. She was initially misdiagnosed with patellar tendinitis and gout but later underwent joint aspiration due to worsening symptoms, which demonstrated 60 800/µL nucleated cells with a polymorphonuclear burden consistent with septic arthritis. Arthroscopy with irrigation and drainage was subsequently performed, and the patient was started on empiric antibiotics while awaiting cultures. Cultures grew Prevotella bivia, and antibiotics were deescalated to ertapenem alone followed by oral metronidazole. Prevotella species as a source of septic arthritis is rare, and its occurrence in a patient without known insult to the knee is even more uncommon. It is essential that it is recognized to treat appropriately and prevent long-term loss of function in the joint.

Dielectrophoretic Characterization of Tenogenically Differentiating Mesenchymal Stem Cells.

Tendons are collagenous musculoskeletal tissues that connect muscles to bones and transfer the forces necessary for movement. Tendons are susceptible to injury and heal poorly, with long-term loss of function. Mesenchymal stem cell (MSC)-based therapies are a promising approach for treating tendon injuries but are challenged by the difficulties of controlling stem cell fate and of generating homogenous populations of stem cells optimized for tenogenesis (differentiation toward tendon). To address this issue, we aim to explore methods that can be used to identify and ultimately separate tenogenically differentiated MSCs from non-tenogenically differentiated MSCs. In this study, baseline and tenogenically differentiating murine MSCs were characterized for dielectric properties (conductivity and permittivity) of their outer membrane and cytoplasm using a dielectrophoretic (DEP) crossover technique. Experimental results showed that unique dielectric properties distinguished tenogenically differentiating MSCs from controls after three days of tenogenic induction. A single shell model was used to quantify the dielectric properties and determine membrane and cytoplasm conductivity and permittivity. Together, cell responses at the crossover frequency, cell morphology, and shell models showed that changes potentially indicative of early tenogenesis could be detected in the dielectric properties of MSCs as early as three days into differentiation. Differences in dielectric properties with tenogenesis indicate that the DEP-based label-free separation of tenogenically differentiating cells is possible and avoids the complications of current label-dependent flow cytometry-based separation techniques. Overall, this work illustrates the potential of DEP to generate homogeneous populations of differentiated stem cells for applications in tissue engineering and regenerative medicine.

How best to palliate and treat emergency conditions in geriatric patients with colorectal cancer

Almost one third of colorectal cancer (CRC) cases are diagnosed in an emergency setting, mostly among geriatric patients. Clinical scenarios are often complex and decision making delicate. Besides the obvious need to consider the patient's and/or family and care givers' desires, the surgeon should be able to make the best educated guess on future outcomes in three areas: oncological prognosis, morbidity and mortality risk, and long-term functional loss. Using simple and brief tools for frailty screening reasonable treatment goals with curative or palliative intent can be planned.The most frequent clinical scenarios of CRC in emergency are bowel obstruction and perforation. We propose treatment algorithms based on assessment of the patient's overall reserve and discuss the indications, techniques and impact of a stoma in the geriatric patient. Bridge to surgery strategies may be best adapted to help the frail geriatric patient overcome the acute disease and maybe return to previous state of function. Post-operative morbidity and mortality rates are high in emergency surgery for CRC, but if the geriatric patient survives the post-operative period, oncological prognosis seems to be similar to younger patients. Because the occurrence of complications is the strongest predictor of functional decline and death, post-operative care plays a major role to optimize outcomes.Future studies should further investigate emergency surgery of CRC in the older adults focusing in particular on functional outcomes in order to help physicians counsel patients and families for a tailored treatment.

Mapping the global distribution of Buruli ulcer: a systematic review with evidence consensus

SummaryBackgroundBuruli ulcer can cause disfigurement and long-term loss of function. It is underdiagnosed and under-reported, and its current distribution is unclear. We aimed to synthesise and evaluate data on Buruli ulcer prevalence and distribution.MethodsWe did a systematic review of Buruli ulcer prevalence and used an evidence consensus framework to describe and evaluate evidence for Buruli ulcer distribution worldwide. We searched PubMed and Web of Science databases from inception to Aug 6, 2018, for records of Buruli ulcer and Mycobacterium ulcerans detection, with no limits on study type, publication date, participant population, or location. English, French, and Spanish language publications were included. We included population-based surveys presenting Buruli ulcer prevalence estimates, or data that allowed prevalence to be estimated, in the systematic review. We extracted geographical data on the occurrence of Buruli ulcer cases and M ulcerans detection from studies of any type for the evidence consensus framework; articles that did not report original data were excluded. For the main analysis, we extracted prevalence estimates from included surveys and calculated 95% CIs using Byar’s method. We included occurrence records, reports to WHO and the Global Infectious Diseases and Epidemiology Network, and surveillance data from Buruli ulcer control programmes in the evidence consensus framework to grade the strength of evidence for Buruli ulcer endemicity. This study is registered with PROSPERO, number CRD42018116260.Findings2763 titles met the search criteria. We extracted prevalence estimates from ten studies and occurrence data from 208 studies and five unpublished surveillance datasets. Prevalence estimates within study areas ranged from 3·2 (95% CI 3·1–3·3) cases per 10000 population in Côte d’Ivoire to 26·9 (23·5–30·7) cases per 10000 population in Benin. There was evidence of Buruli ulcer in 32 countries and consensus on presence in 12.InterpretationThe global distribution of Buruli ulcer is uncertain and potentially wider than currently recognised. Our findings represent the strongest available evidence on Buruli ulcer distribution so far and have many potential applications, from directing surveillance activities to informing burden estimates.FundingAIM Initiative.

Hair Follicle Stem Cell Faith Is Dependent on Chromatin Remodeling Capacity Following Low-Dose Radiation.

The main function of the skin, to protect against the environment, is supported by the activity of different stem cell populations. The main focus of this study was elucidating the coping mechanisms of stem cells against the stimulation of constant exposure to genotoxic stresses, both endogenous and exogenous, to ensure long-term function. Investigation of various mouse strains, differing in their DNA repair capacity, enables us to clarify fractionated low-dose irradiation (LDR)-induced consequences for different stem cell populations of the murine hair follicle (HF) in their physiological stem cell niche. Using microscopic techniques combined with flow cytometry, we could show that LDR induces accumulation of persisting; pKu70-independent 53BP1-foci ("chromatin-alterations") in heterochromatic regions of the HF stem cells (HFSCs). These remaining chromatin-alterations result in varying stem cell consequences. CD34-positive HFSCs react by ataxia telangiectasia mutated-dependent, premature senescence, which correlates with global chromatin compaction, whereby apoptosis is prevented by the activity of DNA-dependent protein kinase catalytic subunit. However, distinctively highly damaged HFSCs seem to be sorted out of the niche by differentiation, transferring their chromatin-alterations to more proliferative G protein-coupled receptor 5-positive stem cells. Consequentially, the loss of basal HFSCs is compensated by increased proliferation within the stem cell pool. Despite the initial success of these mechanisms in stem cell population maintenance, the combined effect of the chromatin-alterations and the modification in stem cell pool composition may lead to downstream long-term functional loss of tissue or organs. Stem Cells 2018;36:574-588.

Telomere Length Assessment for Prediction of Organ Transplantation Outcome. Future or Failure: A Review of the Literature

Telomeres are located at each end of eukaryotic chromosomes. Their functional role is genomic stability maintenance. The protective role of telomeres depends on various factors, including number of nucleotides repeats, telomere-binding proteins, and telomerase activity. Organ transplantation is the preferred replacement therapy in the case of chronic kidney disease and the only possibility of sustaining recipients’ life in the case of advanced liver failure. While the prevalence of acute rejection is constantly decreasing, prevention of transplanted organ long-term function loss is still challenging. It has been demonstrated that post-transplant stressors accelerate aging of the allografts manifested through telomere shortening.The aim of this paper was to evaluate the importance of telomere length assessment for prediction of organ transplantation outcome. Literature review included the 10 most important studies regarding linkage between allograft function and telomere erosion, including 2 of our own reports.Telomere length assessment is useful to predict organ transplantation outcome. The importance of telomere length as a prediction marker depends on the analyzed material. To obtain reliable results, both graft cells (donor material) and lymphocytes (recipient material) should be examined. In the case of kidney transplantation, assessment of telomere length in the early post-transplant period allows prediction of the long-term function of the transplanted organ. To increase the accuracy of transplantation outcome prediction, telomere length assessment should be combined with evaluation of other aging biomarkers, like CDKN2A (p16). Large-scale clinical studies regarding telomere length measurement, including genome wide association analysis introducing relevant genetic factors, are needed for the future.

Long-Term Loss of Function in Rat Skeletal Muscle After a Single Botox Injection

Long-Term Loss of Function in Rat Skeletal Muscle After a Single Botox Injection

Predicting Persistent Back Symptoms by Psychosocial Risk Factors: Validity Criteria for the ÖMPSQ and the HKF-R 10 in Germany.

Objective10% of all individuals in Germany develop persistent symptoms due to nonspecific back pain (NSBP) causing up to 90% of direct and indirect expenses for health care systems. Evidence indicates a strong relationship between chronic nonspecific back pain and psychosocial risk factors. The Örebro Musculoskeletal Pain Screening Questionnaire (ÖMPSQ) and the German Heidelberger Kurzfragebogen Rückenschmerz (HKF-R 10) are deemed valid in prediction of persistent pain, functional loss or amount of sick leave. This study provides and discusses validity criteria for these questionnaires using ROC-curve analyses. Quality measurements included sensitivity and specificity, likelihood-ratio related test-efficiencies and clinical utility in regard to predictive values.Methods265 patients recruited from primary and secondary care units completed both questionnaires during the same timeframe. From the total, 133 patients returned a 6-month follow-up questionnaire to assess the validity criteria for outcomes of pain, function and sick leave.ResultsBased on heterogeneous cut-offs for the ÖMPSQ, sensitivity and specificity were moderate for outcome of pain (72%/75%). Very high sensitivity was observed for function (97%/57%) and high specificity for sick leave (63%/85%). The latter also applied to the HKF-R 10 (pain 50%/84%). Proportions between sensitivity and specificity were unbalanced except for the ÖMPSQ outcome of pain. Likelihood-ratios and positive predictive values ranged from low to moderate.ConclusionAlthough the ÖMPSQ may be considered useful in identification of long-term functional loss or pain, over- and underestimation of patients at risk of chronic noncspecific back pain led to limited test-efficiencies and clinical utility for both questionnaires. Further studies are required to quantify the predictive validity of both questionnaires in Germany.

Rehabilitation after Traumatic Brain Injuries - The Challenge of the Elderly

Traumatic brain injury (TBI) is a worldwide public health problem, with high mortality rates and long-term loss of function for the survivors. The incidence of TBI is related to environmental, socio-cultural and individual factors that vary over time. International epidemiological studies have reported changes during the last decades with decreasing incidence, hospitalization, and mortality from severe TBI except for the elderly. The TBI survivors in general display functional impairments and physical, cognitive and emotional disabilities causing restriction in activities and participation. Dependency in daily activities is associated to poor quality of life and recognized to be very costly for the society. Vegetative state and reduced consciousness are feared consequences after TBI, and yet incidence and course of these conditions are largely unknown. In the elderly, the consequences of biological ageing and comorbidity may put them at risk of greater injury-related disability and complications. However, the knowledge is generally lacking regarding functional recovery of elderly with TBI and their long term needs. There is a long tradition for public organization and resource allocation for trauma care and following rehabilitation in Norway, rendering representative cohort suited to address the impact of age on outcome as well as the health care offered.

Rehabilitation after Brain Injuries in Elderly People

Traumatic brain injury (TBI) is a worldwide public health problem, with high mortality rates and long-term loss of function for the survivors. The incidence of TBI is related to environmental, sociocultural and individual factors that vary over time. International epidemiological studies have reported changes during the last decades with decreasing incidence, hospitalization, and mortality from severe TBI except for the elderly. The TBI survivors in general display functional impairments and physical, cognitive and emotional disabilities causing restriction in activities and participation. Dependency in daily activities is associated to poor quality of life and recognized to be very costly for the society. Vegetative state and reduced consciousness are feared consequences after TBI, and yet incidence and course of these conditions are largely unknown. In the elderly, the consequences of biological ageing and comorbidity may put them at risk of greater injury-related disability and complications. However, the knowledge is generally lacking regarding functional recovery of elderly with TBI and their long term needs. There is a long tradition for public organization and resource allocation for trauma care and following rehabilitation in Norway, rendering representative cohort suited to address the impact of age on outcome as well as the health care offered.

P4-12-08: Five Year Preliminary Outcomes of a Prospective Surveillance Model To Reduce Upper Extremity Morbidity Related to Breast Cancer Treatment.

Abstract Background Early detection and management of physical impairments after breast cancer treatment contribute to successful functional outcomes and improved quality of life throughout disease treatment and survivorship. Assessment of upper extremity (UE) morbidity including; shoulder dysfunction, scarring, pain, fatigue and lymphedema should be conducted through a prospective surveillance model of care to promote early identification of impairments and provide intervention while functional limitations are minimal, thereby preventing long term loss of function. This report highlights 5-year findings related to physical function in patients participating in a prospective surveillance model of care. Methods: A prospective, observational study enrolled women with breast cancer at the point of disease diagnosis (n=196) and measured UE morbidity, impairments and functional disability over a 5 year period. Patient demographics, cancer characteristics, measures of UE strength, range of motion (ROM) and limb volume were taken pre-operatively and repeated at 1, 3, 6, 9, 12 and 60 months post-operatively. Subjective assessment of physical activity, health status and quality of life were assessed by questionnaire at 12 and 60 months. 166 subjects completed visits at 1 year and 95 completed visits at 5 years. All subjects received education regarding exercise, risk reduction and advice on return to activity. If physical impairments were detected during the study, immediate physical therapy intervention was initiated to alleviate the impairment. Results: The incidence of objective UE impairments at five years after treatment was 9% with loss of shoulder ROM, 25% with subclinical lymphedema (defined as a ≥ 3% change in limb volume from baseline), 5.6% with advanced lymphedema (Stage I or II) and 27.8% with clinically significant fatigue (defined as ≥ 3 on a visual analog scale). Subjectively 8.4% reported feeling moderately or severely disabled with their affected arm, 11.1% reported moderate to severe difficulty carrying heavy objects, 4.2% reported moderate to severe limitations with heavy household chores. Discussion: This is the first prospective cohort study in the United States to specifically monitor physical and functional outcomes to 5-years post breast cancer treatment. The prospective surveillance model of care, conducted by the physical therapist, enabled early detection and treatment of breast cancer treatment-related impairments resulting in improved long-term function. Long-term incidence of UE morbidity after breast cancer treatment has been documented in the literature as high as 40–60% with lymphedema and up to 60% with fatigue. This study clearly demonstrates the potential for substantial reduction in UE dysfunction related to breast cancer treatment when using an early identification and intervention model. Morbidity such as pain, reduced range of motion, decreased strength and sub-clinical lymphedema were detected early and managed through the prospective model. These results strongly suggest that prospective surveillance monitoring for functional impairments is an optimal construct to assure long-term function in women after breast cancer treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-08.

Performance-based physical function in long-term survivors of Hodgkin lymphoma.

9532 Background: Survivors of pediatric Hodgkin lymphoma (HL) are at increased risk for late effects including loss of physical function, which may interfere with an active lifestyle. The aims of these analyses were to describe the prevalence of physical performance limitations, and to determine associations between treatment exposures and long-term functional loss. Methods: Clinical assessment including measures of ankle flexibility and strength, quadriceps strength, and walking endurance were completed in HL survivors 10+ years from diagnosis. Those with ankle motion < 5 degrees of dorsiflexion (required for foot clearance during walking), and isokinetic strength or distances on the six minute walk in the lowest 10th percentiles of age/sex predicted norms were classified as having severe limitations. The prevalence of severe loss was calculated for each measure. Associations between HL treatment and functional loss were evaluated in regression models. Results: Among the first 196 eligible HL participants randomly recruited to participate in a large cohort study, 188 (median age 40 (26-61) years; median time since diagnosis 26 (11-45) years) completed the performance measures. Severe limitations were present in ankle motion for 29.0%, ankle strength for 22.3%, quadriceps strength for 21.8%, and endurance for 31.9% of survivors. Among those with severe limitations, 53.3% had limitations on 2+ performance measures. Those treated with vinca alkaloids had mean ankle dorsiflexion age/sex specific z-scores of -0.35±1.0 vs. 0.19±1.3 (p=0.007) among those not exposed. Mean quadriceps z-scores were -0.45±1.0 among those exposed to vinca alkaloids vs. -0.29±0.97 (p=0.01) among those not exposed. After adjusting for anthracycline and radiation exposure, those treated were 2.4 (95% CI 1.1-5.2) times more likely than those not treated with glucocorticoids to have poor endurance. Conclusions: Severe physical performance limitations are present in 20-30% of long-term HL survivors. Exposure to vinca alkaloids and glucocorticoids are associated with decreased strength and walking ability, respectively. Losses in lower extremity motion and strength, and in sustained walking ability, may provide targets for intervention.

Integrating Contemporary Models of Motor Control and Health in Chronic Ankle Instability: A Review of the Literature

Numerous structural and functional alterations have been identified as contributing factors associated with chronic ankle instability (CAI). However, little evidence has connected local instability with self-reported disability or functional loss. The dynamical-systems theory of motor control offers a constraints-led approach for interpreting movement dysfunction based on organismic, task-specific, and environmental factors. These factors interact to organize sensorimotor coordination, creating functional variability to complete movement goals. The International Classification of Functioning, Disability, and Health (ICF) is a model of health, examining function at the level of the body or body parts, the whole person, and the whole person in his or her environment. Combining the fundamental components of both theories offers a model that may recognize the link between instability and function. The purpose of this literature review is to discuss the dynamic systems theory, the ICF model, and how integrating both concepts can be used to address, track, and interpret deficits associated with CAI. Ankles sprains are the most frequently reported injury among physically active individuals.1 Approximately 1 of 3 people who sustain a single ankle sprain experience reoccurring sprains and residual bouts of joint instability known as chronic ankle instability (CAI).2 In addition, ankle sprains are one of the major contributing factors in the development of posttraumatic ankle osteoarthritis.3 High reoccurrence rates and the prevalence of long-term functional loss related to ankle sprains begs the question if current rehabilitation strategies are effective.4 Examining CAI through the integration of the most contemporary theory of motor control and the most contemporary model of health may provide a comprehensive assessment of a person’s overall functional ability and elucidate the link between disability and health in this population. Recent advancement in motor control theory may help interpret how sources of functional loss and disability are manifestations of impaired sensorimotor coordination.5,6 This theory, known as dynamic systems, views movement from a context-specific perspective. The dynamic systems theory aims to explain how we use the freedom of the sensorimotor system to develop strategies to cope with changes in health, task complexity, and the environment.5 Similarly, the International Classification of Functioning, Disability, and Health (ICF) examines the effects of injury and illness on the dynamic nature of function based on quality of life, overall health status, and impairment associated with societal and environmental factors.7 The authors are from the Division of Athletic Training, University of Kentucky, College of Health Sciences, Lexington, Ky. Originally submitted April 6, 2009. Accepted for publication June 4, 2009. The authors have no financial or proprietary interest in the materials presented herein. Address correspondence to Matt Hoch, MS, ATC, Division of Athletic Training & Rehabilitation Sciences Doctoral Program, University of Kentucky, College of Health Sciences, Wethington Building, Room 206B, 900 South Limestone, Lexington, KY 40536-0200; e-mail: mcho222@uky.edu. doi:10.3928/19425864-2010xxxx-xx

Pre operative assessment enables the early detection and treatment of shoulder impairments related to breast cancer treatment.

Abstract Abstract #4091 Background: Early detection and management of impairments and limb dysfunction after breast cancer treatment contribute to more successful functional outcomes. Health care providers should be encouraged to provide a pre-operative screening visit to ascertain the patient's baseline physical function measures. Patients should then be followed prospectively at regular intervals during and after treatment for early identification of impairments and to provide intervention while the functional limitations are minimal, thereby preventing long term loss of function.&amp;#x2028; Materials and Methods: A prospective, observational study (n=196) with interval follow up over one year assessed the effects of an early identification and intervention model of physical therapy care on women after breast cancer treatment. Measurement of upper extremity (UE) function included; active range of motion (ROM), strength, and limb volume as measured by the optoelectronic volumeter (Perometer®), and self-reported physical activity disability. Individuals were seen for an initial visit prior to surgical treatment and followed-up at approximately one month post-operatively and at three month intervals thereafter, up to 18 months. Patients received a general home exercise program pre-operatively and instructed to initiate at 2 weeks post op. If impairments were identified at any of the follow up visits, physical therapy intervention was prescribed.&amp;#x2028; Results: A significant decrease in active shoulder ROM was noted at one month post-op as compared to baseline measurement in 102 patients. This significance resolved at the 12+ month follow up visit. Loss of shoulder ROM correlated with other UE treatment related morbidities including; axillary web syndrome, seroma and pain.&amp;#x2028; Discussion: Incidence of upper extremity morbidity after breast cancer treatment is documented as high as 70%. This study clearly demonstrates the potential for substantial reduction in UE dysfunction related to breast cancer treatment when using an early identification and intervention model. Many morbidities such as pain, reduced range of motion, decreased strength and sub-clinical lymphedema can be detected early and managed with minimal, cost-effective intervention. Additional research is needed to assess ways of maintaining this cost effective model of care in the long-term. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4091.

Absence of the Rho GTPase Activating Protein p190-B Enhances Long Term Hematopoietic Stem Cell Engraftment

Hematopoietic stem cell (HSC) engraftment is a multistep process involving HSC homing to bone marrow (BM), self-renewal, proliferation and differentiation to mature blood cells. However, the molecular regulation of HSC engraftment is still poorly defined. Small Rho GTPases are critical regulator of cell migration, proliferation and differentiation in multiple cell types. While their role in HSC functions has begun to be understood, the role of their regulator in vivo has been understudied. P190-B GTPase Activating Protein (GAP), a negative regulator of Rho activity, has been implicated in regulating cell size and adipogenesis-myogenesis cell fate determination during fetal development (Sordella, Dev Cell, 2002; Cell 2003). Here, we investigated the role of p190-B in HSC/P engraftment. Since mice lacking p190-B die before birth, serial competitive repopulation assay was performed using fetal liver (FL) tissues from day E14.5 WT and p190-B−/− embryos. WT and p190-B−/− FL cells exhibited similar levels of engraftment in primary recipients. However, the level of contribution of p190-B−/− cells to peripheral blood and bone marrow was maintained between the primary and secondary recipients and still easily detectable in tertiary recipients, while the level of contribution of FL WT cells dramatically decreased with successive serial transplantion and was barely detectable in tertiary recipients. The contribution to T cell, B cell and myeloid cell reconstitution was similar between the genotypes. A pool of HSC was maintained in serially transplanted p190-B−/− animals, since LinnegScaposKitpos (LSK) cells were still present in the BM of p190-B−/− secondary engrafted mice while this population disappeared in WT controls. Importantly, this enhanced long term engraftment was due to a difference in the functional capacity of p190-B−/− HSC compared to WT HSC since highly enriched p190-B−/− HSC (LSK) demonstrated similar enhanced serial transplantation potential. Because previous studies have suggested that the loss of long term function of HSC during serial transplantation can depend, at least in part, on the upregulation of the cyclin dependent kinase inhibitor p16Ink4a (Ito et al, Nat Med 2006), the expression of p16Ink4a was examined during serial transplantation. While expression of p16Ink4a increased in WT HSC in primary and secondary recipients, p16Ink4a remained low in p190-B−/− HSC, which indicated that p190-B-deficiency represses the upregulation of p16Ink4a in HSC in primary and secondary transplant recipients. This provides a possible mechanism of p190-B-mediated HSC functions. We next examined whether p190-B-deficiency may preserve the repopulating capacity of HSC/P during ex vivo cytokine-induced culture. While freshly isolated LSK cells from WT and p190-B−/− mice exhibited comparable intrinsic clonogenic capacity, the frequency of colony-forming unit after 7 days in culture was 2 fold-higher in p190-B−/− compared with WT cultures, resulting in a net CFU expansion. Furthermore, competitive repopulation assays showed significantly higher repopulating activity in mice that received p190-B−/− cultured cells compared with WT cells equivalent to a 4.4-fold increase in the estimated frequency of repopulating units. Interestingly, p190-deficiency did not alter cell cycling rate or survival both in vivo and in vitro. Therefore, p190-B-deficiency maintains key HSC functions either in vivo or in ex vivo culture without altering cycling rate and survival of these cells. These findings define p190-B as a critical regulator of HSC functions regulating self renewal activity while maintaining a balance between proliferation and differentiation.