Trunk and foot acceleration variability during walking relates to fall history and clinical disability in persons with multiple sclerosis.

BACKGROUND: Persons with multiple sclerosis are often at higher risk for falling, but clinical disability scales and fall risk questionnaires are subjective and don't provide specific feedback about why an individual is unstable. The purpose of this study was to determine how relationships between trunk and foot acceleration variability relate to physiological impairments, clinical disability scales, and mobility questionnaires in persons with multiple sclerosis. METHODS: 15 fallers and 25 non-fallers with multiple sclerosis walked on a treadmill at normal walking speed while trunk and foot accelerations were recorded with wireless accelerometers and variability measures were extracted and used to calculate the gait stability index metrics as a ratio of trunk acceleration variability divided foot acceleration variability. Subjects' sensorimotor delays and lower extremity vibration sensitivity were tested. Subjects also completed clinical disability scales (Guy's Neurological Disability Scale and Patient Reported Expanded Disability Status Scale) and mobility questionnaires (Falls Efficacy Scale, Activities Balance Confidence Scale, 12 Item Multiple Sclerosis Walk Scale). FINDINGS: Multiple gait stability index metrics were significantly correlated with clinical measures of disability and mobility in multiple sclerosis subjects (r = 0.354-0.528), but no correlations were found for sensorimotor delays or lower extremity sensation. Multiple gait stability indices performed at least as well as clinical questionnaires for separating fallers from non-fallers. INTERPRETATION: The gait stability indices can potentially be used outside of a laboratory setting to measure walking characteristics related to fall history and disability level in people with multiple sclerosis.

Altered visual and somatosensory feedback affects gait stability in persons with multiple sclerosis.

Persons with multiple sclerosis (PwMS) often report problems due to sensory loss and have an inability to appropriately reweight sensory information. Both of these issues can affect individual's ability to maintain stability when walking under challenging conditions. The purpose of the current study was to determine how gait stability is adapted when walking under challenging sensory conditions where vision and somatosensation at the feet is manipulated. 25 healthy adults and 40 PwMS (15 fallers, 25 non-fallers) walked on a treadmill at their preferred normal walking speed under 3 conditions: normal walking, altered vision using goggles that shifted visual field laterally, and altered somatosensation using shoes with compliant foam soles. Inertial measurement united recorded acceleration at the lumbar and right ankle, and acceleration variability measures were calculated including root mean square (RMS), range, sample entropy (SaEn), and Lyapunov exponents (LyE). A gait stability index (GSI) was calculated using each of the four variability measures as the ratio of lumbar acceleration variability divided by foot acceleration variability in the frontal and sagittal planes. The sagittal and frontal GSIRMS were larger in the somatosensory condition compared to the normal and visual conditions (p < 0.001). The frontal GSISaEn was greater in the visual condition compared to the somatosensory condition (p = 0.021). The frontal and sagittal GSILyE was greater in the somatosensory condition compared to the normal and visual conditions (p < 0.002). The current study showed that HC, MS non-fallers and MS fallers largely adapted to altered sensory feedback during walking in a similar manner. However, MS faller subjects may be more reliant on visual feedback compared to MS non-fallers and HC subjects.

Coordination of trunk and foot acceleration during gait is affected by walking velocity and fall history in elderly adults.

BACKGROUND: Falling is a significant concern for many elderly adults but identifying individuals at risk of falling is difficult, and it is not clear how elderly adults adapt to challenging walking. AIMS: The aim of the current study was to determine the effects of walking at non-preferred speeds on the coordination between foot and trunk acceleration variability in healthy elderly adults with and without fall history compared to healthy young adults. METHODS: Subjects walked on a treadmill at 80%-120% of their preferred walking speed while trunk and foot accelerations were recorded with wireless inertial sensors. Variability of accelerations was measured by root mean square, range, sample entropy, and Lyapunov exponent. The gait stability index was calculated using each variability metric in the frontal and sagittal plane by taking the ratio of trunk acceleration variability divided by foot acceleration variability. RESULTS: Healthy young adults demonstrated larger trunk accelerations relative to foot accelerations at faster walking speeds compared to elderly adults, but both young and elderly adults show similar adaption to their acceleration regularity. Between group differences showed that elderly adult fallers coordinate acceleration variability between the trunk and feet differently compared to elderly non-fallers and young adults. DISCUSSION: The current results indicate that during gait, elderly fallers demonstrate more constrained, less adaptable trunk movement relative to their foot movement and this pattern is different compared to elderly non-fallers and healthy young. CONCLUSIONS: Coordination between trunk and foot acceleration variability plays an important role in maintaining stability during gait.

Reliability and validity of a motion-based reaction time assessment using a mobile device.

Information processing speed is often altered following a concussion. Few portable assessments exist to evaluate simple reaction time (SRT) in hospitals and clinics. We evaluated the use of a SRT application for mobile device measurement. 27 healthy adults (age = 30.7 ± 11.5 years) completed SRT tests using a mobile device with Sway, an application for SRT testing. Participants completed computerized SRT tests using the Computerized Test of Information Processing (CTIP). Test-retest reliability was assessed using intraclass correlation coefficients (ICC) between Sway trials. Pearson correlations and Bland-Altman analyses were used to assess criterion validity between Sway and CTIP means. ICC comparisons between Sway tests were all statistically significant. ICCs ranged from 0.84-0.90, with p-values <.001. A one-way analysis of variance (ANOVA) revealed no significant differences between trials (F3,104 = 1.35, p = .26. Pearson correlation between Sway and CTIP outcomes yielded a significant correlation (r = 0.59, p = .001). The mean difference between measurement methods was 43.7 ms, with limits of agreement between -140.8-53.4 ms. High ICC indicates Sway is a reliable method to assess SRT. A strong correlation and clinically acceptable agreement between Sway and the computer-based test indicates that Sway is suited for rapid administration of SRT testing in healthy individuals. Future research using Sway to assess altered information processing in a population of individuals after concussion is warranted.

Correction to: Buthionine sulfoximine sensitizes antihormone-resistant human breast cancer cells to estrogen-induced apoptosis.

After the publication of this work [1] an error was noticed in Fig. 3a and Fig. 5a.

The relationship between trunk and foot acceleration variability during walking shows minor changes in persons with multiple sclerosis.

BACKGROUND: Identifying how relationships between variability of upper and lower body segments during walking are altered in persons with multiple sclerosis may uncover specific strategies for maintaining overall stability. The purpose of this study was to examine relationships between trunk and foot acceleration variability during walking in healthy controls and in persons with multiple sclerosis. METHODS: Linear and nonlinear variability measures were calculated for 40 healthy controls and 40 persons with multiple sclerosis from the acceleration time series recorded by inertial sensors attached to the trunk and foot while subjects walked on a treadmill at self-selected preferred pace. FINDINGS: No main effect of group was found for any variability measures. Main effect of location was found for all variability measures, with larger magnitudes of variability at the foot compared to the trunk, and more predictable variability patterns at the foot compared to the trunk. Differences in strength of correlations between trunk and foot accelerations were found between persons with multiple sclerosis and healthy controls in the frontal and sagittal plane. Sample entropy of accelerations at the feet and at the trunk correlated significantly higher in healthy controls than in persons with multiple sclerosis. INTERPRETATION: Relationships between variability of trunk and foot accelerations, which may provide a valuable comprehensive description of whole body stability during gait, showed minor changes in persons with MS compared to healthy controls.

Instrumented balance and walking assessments in persons with multiple sclerosis show strong test-retest reliability.

BACKGROUND: There is a need for objective movement assessment for clinical research trials aimed at improving gait and balance in persons with multiple sclerosis (PwMS). Wireless inertial sensors can accurately measure numerous walking and balance parameters but these measures require evaluation of reliability in PwMS. The current study determined the test-retest reliability of wireless inertial sensor measures obtained during an instrumented standing balance test and an instrumented Timed Up and Go test in PwMS. METHODS: Fifteen PwMS and 15 healthy control subjects (HC) performed an instrumented standing balance and instrumented Timed Up and Go (TUG) test on two separate days. Ten instrumented standing balance measures and 18 instrumented TUG measures were computed from the wireless sensor data. Intraclass correlation coefficients (ICC) were calculated to determine test-retest reliability of all instrumented standing balance and instrumented TUG measures. Correlations were evaluated between the instrumented standing balance and instrumented TUG measures and self-reported walking and balance performance, fall history, and clinical disability. RESULTS: For both groups, ICCs for instrumented standing balance measures were best for spatio-temporal measures, while frequency measures were less reliable. All instrumented TUG measures exhibited good to excellent (ICCs > 0.60) test-retest reliability in PwMS and in HC. There were no correlations between self-report walking and balance scores and instrumented TUG or instrumented standing balance metrics, but there were correlations between instrumented TUG and instrumented standing balance metrics and fall history and clinical disability status. CONCLUSIONS: Measures from the instrumented standing balance and instrumented TUG tests exhibit good to excellent reliability, demonstrating their potential as objective assessments for clinical trials. A subset of the most reliable measures is recommended for measuring walking and balance in clinical settings.

Relationship between trunk and foot accelerations during walking in healthy adults.

Understanding upper body and lower body segment relationships may be an important step in assessing stability during gait. This study explored the relationship between acceleration patterns at the trunk and at the foot during treadmill walking at self-selected pace in healthy adults. Forty healthy subjects walked on a treadmill for 3 minutes at self-selected speed. Root mean square (RMS) and approximate entropy (ApEn) were derived from the acceleration time series at the trunk and at the foot in the frontal and sagittal plane. RMS of accelerations at the trunk were strongly correlated with RMS values at the foot in the sagittal plane (r=0.883, p<0.01) and in the frontal plane (r=0.811, p<0.01). ApEn values at the trunk were moderately correlated with ApEn values at the foot in the sagittal plane (r=0.603, p<0.01) only. These results show that acceleration variability at the foot is related to acceleration variability at the trunk, specifically that increased variability at the foot is tied to increased variability at the trunk in healthy adults. Portable inertial sensors can potentially be used in any environment including a laboratory, clinic, or at home to measure lower and upper body segment motion, and assessing relationships between upper and lower body motion may provide a more comprehensive evaluation of overall stability.

The evolution of nonsteroidal antiestrogens to become selective estrogen receptor modulators.

The discovery of the first nonsteroidal antiestrogen ethamoxytriphetol (MER25) in 1958, opened the door to a wide range of clinical applications. However, the finding that ethamoxytriphetol was a "morning after" pill in laboratory animals, energized the pharmaceutical industry to discover more potent derivatives. In the wake of the enormous impact of the introduction of the oral contraceptive worldwide, contraceptive research was a central focus in the early 1960's. Numerous compounds were discovered e.g., clomiphene, nafoxidine, and tamoxifen, but the fact that clinical studies showed no contraceptive actions, but, in fact, induced ovulation, dampened enthusiasm for clinical development. Only clomiphene moved forward to pioneer an application to induce ovulation in subfertile women. The fact that all the compounds were antiestrogenic made an application in patients to treat estrogen responsive breast cancer, an obvious choice. However, toxicities and poor projected commercial returns severely retarded clinical development for two decades. In the 1970's a paradigm shift in the laboratory to advocate long term adjuvant tamoxifen treatment for early (non-metastatic) breast cancer changed medical care and dramatically increased survivorship. Tamoxifen pioneered that paradigm shift but it became the medicine of choice in a second paradigm shift for preventing breast cancer during the 1980's and 1990's. This was not surprising as it was the only medicine available and there was laboratory and clinical evidence for the eventual success of this application. Tamoxifen is the first medicine to be approved by the Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at high risk. But it was the re-evaluation of the toxicology of tamoxifen in the 1980's and the finding that there was both carcinogenic potential and a significant, but small, risk of endometrial cancer in postmenopausal women that led to a third paradigm shift to identify applications for selective estrogen receptor (ER) modulation. This idea was to establish a new group of medicines now called selective ER modulators (SERMs). Today there are 5 SERMs FDA approved (one other in Europe) for applications ranging from the reduction of breast cancer risk and osteoporosis to the reduction of menopausal hot flashes and improvements in dyspareunia and vaginal lubrication. This article charts the origins of the current path for progress in women's health with SERMs.

Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations.

Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long been a therapeutic choice for all stages of estrogen receptor (ER)-positive breast cancer. The clinical application of long-term adjuvant antihormone therapy for the breast cancer has significantly improved breast cancer survival. However, acquired resistance to SERM remains a significant challenge in breast cancer treatment. The evolution of acquired resistance to SERMs treatment was primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic years of adjuvant treatment in patients. Acquired resistance to tamoxifen is unique because the growth of resistant tumors is dependent on SERMs. It appears that acquired resistance to SERM is initially able to utilize either E2 or a SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic studies reveal that SERMs continuously suppress nuclear ER-target genes even during resistance, whereas they function as agonists to activate multiple membrane-associated molecules to promote cell growth. Laboratory observations in vivo further show that three phases of acquired SERM-resistance exists, depending on the length of SERMs exposure. Tumors with Phase I resistance are stimulated by both SERMs and estrogen. Tumors with Phase II resistance are stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The laboratory models suggest a new treatment strategy, in which limited-duration, low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. This discovery provides an invaluable insight into the evolution of drug resistance to SERMs, and this knowledge is now being used to justify clinical trials of estrogen therapy following long-term antihormone therapy. All of these results suggest that cell populations that have acquired resistance are in constant evolution depending upon selection pressure. The limited availability of growth stimuli in any new environment enhances population plasticity in the trial and error search for survival.

Exploiting the apoptotic actions of oestrogen to reverse antihormonal drug resistance in oestrogen receptor positive breast cancer patients.

The ubiquitous application of selective oestrogen receptor modulators (SERMs) and aromatase inhibitors for the treatment and prevention of breast cancer has created a significant advance in patient care. However, the consequence of prolonged treatment with antihormonal therapy is the development of drug resistance. Nevertheless, the systematic description of models of drug resistance to SERMs and aromatase inhibitors has resulted in the discovery of a vulnerability in tumour homeostasis that can be exploited to improve patient care. Drug resistance to antihormones evolves, so that eventually the cells change to create novel signal transduction pathways for enhanced oestrogen (GPR30+OER) sensitivity, a reduction in progesterone receptor production and an increased metastatic potential. Most importantly, antihormone resistant breast cancer cells adapt with an ability to undergo apoptosis with low concentrations of oestrogen. The oestrogen destroys antihormone resistant cells and reactivates sensitivity to prolonged antihormonal therapy. We have initiated a major collaborative program of genomics and proteomics to use our laboratory models to map the mechanism of subcellular survival and apoptosis in breast cancer. The laboratory program is integrated with a clinical program that seeks to determine the minimum dose of oestrogen necessary to create objective responses in patients who have succeeded and failed two consecutive antihormonal therapies. Once our program is complete, the new knowledge will be available to translate to clinical care for the long-term maintenance of patients on antihormone therapy.

Activated estrogens and antiestrogens: a 30-year journey with David Kupfer.

David Kupfer had a passion for drug metabolism and used his talents to understand the putative metabolic activation of the insecticides o, p'DDT and methoxychlor to estrogens. His research helped to create a scientific foundation for the current interest in endocrine disruption. With the increasing clinical significance of tamoxifen in the late 1980s, and the proposal to test tamoxifen as a breast cancer chemopreventive in healthy women, David initiated laboratory studies on the mechanisms of tamoxifen metabolism. He was the first to note that tamoxifen is metabolically activated to alkylating species. Tamoxifen and insecticides covalently bind to microsomal proteins. His contribution presaged worldwide studies of the induction of rat liver carcinogenesis by tamoxifen.

Stable transfection of an estrogen receptor beta cDNA isoform into MDA-MB-231 breast cancer cells.

We previously reported stable transfection of estrogen receptor alpha (ERalpha) into the ER-negative MDA-MB-231 cells (S30) as a tool to examine the mechanism of action of estrogen and antiestrogens [J. Natl. Cancer Inst. 84 (1992) 580]. To examine the mechanism of ERbeta action directly, we have similarly created ERbeta stable transfectants in MDA-MB-231 cells. MDA-MB-231 cells were stably transfected with ERbeta cDNA and clones were screened by estrogen response element (ERE)-luciferase assay and ERbeta mRNA expression was quantified by real-time RT-PCR. Three stable MDA-MB-231/ERbeta clones were compared with S30 cells with respect to their growth properties, ability to activate ERE- and activating protein-1 (AP-1) luciferase reporter constructs, and the ability to activate the endogenous ER-regulated transforming growth factor alpha (TGFalpha) gene. ERbeta6 and ERbeta27 clones express 300-400-fold and the ERbeta41 clone express 1600-fold higher ERbeta mRNA levels compared with untransfected MDA-MB-231 cells. Unlike S30 cells, 17beta-estradiol (E2) does not inhibit ERbeta41 cell growth. ERE-luciferase activity is induced six-fold by E2 whereas neither 4-hydroxytamoxifen (4-OHT) nor ICI 182, 780 activated an AP-1-luciferase reporter. TGFalpha mRNA is induced in response to E2, but not in response to 4-OHT. MDA-MB-231/ERbeta clones exhibit distinct characteristics from S30 cells including growth properties and the ability to induce TGFalpha gene expression. Furthermore, ERbeta, at least in the context of the MDA-MB-231 cellular milieu, does not enhance AP-1 activity in the presence of antiestrogens. In summary, the availability of both ERalpha and ERbeta stable breast cancer cell lines now allows us to compare and contrast the long-term consequences of individual signal transduction pathways.

Tamoxifen, raloxifene and the prevention of breast cancer.

The recognition of a new group of drugs, now named selective estrogen receptor modulators (SERMs) has revolutionized prospects for the prevention of breast cancer. New agents will continue to be tested against tamoxifen, the first SERM and an established treatment of ER positive breast cancer. Raloxifene a related SERM is used to treat and prevent osteoporosis with the potential beneficial side effect of preventing breast cancer. The Study of Tamoxifen and Raloxifene (STAR) trial will establish whether raloxifene is an improvement over tamoxifen. Most importantly, emerging information about the molecular pharmacology of SERMs will be used to decipher the mechanism of action at specific target sites around a woman's body. This knowledge can be used to design new SERMs and advance the prospects for multifunctional medicine to prevent breast cancer, osteoporosis and coronary heart disease.