Hypoxia-responsive circular RNA circAAGAB reduces breast cancer malignancy by activating p38 MAPK and sponging miR-378 h.

BACKGROUND: Breast cancer is a prevalent disease in women, with high prevalence worldwide. The hypoxic microenvironment of solid tumors develops during the progress of carcinogenesis and leads to greater malignancy and treatment resistance. Recently, accumulating evidence indicates that non-coding RNAs, such as circular RNAs (circRNAs), play a pivotal role in altering cellular functions. However, the underlying mechanisms of circRNAs in breast cancer are still unclear. Therefore, the purpose of this study was to investigate the role of a tumor-suppressive circRNA, circAAGAB, in breast cancer by assuming down-regulation of circAAGAB under hypoxia and the properties of a tumor suppressor. METHODS: Firstly, circAAGAB was identified from expression profiling by next generation sequencing. Next, the stability of circAAGAB increased by interacting with the RNA binding protein FUS. Moreover, cellular and nuclear fractionation showed that most circAAGAB resided in the cytoplasm and that it up-regulated KIAA1522, NKX3-1, and JADE3 by sponging miR-378 h. Lastly, the functions of circAAGAB were explored by identifying its down-stream genes using Affymetrix microarrays and validated by in vitro assays. RESULTS: The results showed that circAAGAB reduced cell colony formation, cell migration, and signaling through p38 MAPK pathway, as well as increased radiosensitivity. CONCLUSION: These findings suggest that the oxygen-responsive circAAGAB acts as a tumor suppressor in breast cancer, and may contribute to the development of a more specific therapeutic regimen for breast cancer.

Effects of transcranial direct current stimulation on improving performance of delayed- reinforcement attentional set-shifting tasks in attention-deficit/hyperactivity disorder rat model.

Behavioral flexibility (or set-shifting), which is regulated by the prefrontal cortex (PFC), is often impaired in patients with attention-deficit/hyperactivity disorder (ADHD), which is characterized by poor inhibitory control and reinforcement learning. Transcranial direct current stimulation (tDCS) has been proposed as a means of noninvasive brain stimulation and a potential therapeutic tool for modulating behavioral flexibility. Animal studies can pave the way to know if tDCS application can potentially benefit rule- and goal-based activities in ADHD. Spontaneously hypertensive rats (SHRs) and inbred Wistar-Kyoto (WKY) rats were used as an animal model of ADHD and controls, respectively, and their strategy set-shifting abilities, including initial discrimination, set-shifting, and reversal learning tasks under 0-s or 15-s reinforcer delivery delay conditions, were evaluated. The tDCS treatment had a limited effect on the performance of the SHRs and WKY rats in initial discrimination task under 0-s delay condition. Under the 15-s delay condition, the SHRs had longer lever-press reaction times and/or more trial omissions than the WKY rats did when completing set-shifting and reversal-learning tasks. Among the SHRs, tDCS treatment improved the rats' reaction times and/or reduced their trial omissions in the set-shifting and reversal-learning tasks. Although tDCS may improve delayed reinforcement learning set-shifting performance in SHRs, further studies are required to clarify the responsible mechanism.

Regulatory mechanisms and function of hypoxia-induced long noncoding RNA NDRG1-OT1 in breast cancer cells.

Hypoxia is a classic feature of the tumor microenvironment that has profound effects on cancer progression and is tightly associated with poor prognosis. Long noncoding RNAs (lncRNAs), a component of the noncoding genome, have been increasingly investigated due to their diverse roles in tumorigenesis. Previously, a hypoxia-induced lncRNA, NDRG1-OT1, was identified in MCF-7 breast cancer cells using next-generation sequencing. However, the regulatory mechanisms of NDRG1-OT1 remain elusive. Therefore, the purpose of this study was to investigate the regulatory mechanisms and functional roles of NDRG1-OT1 in breast cancer cells. Expression profiling of NDRG1-OT1 revealed that it was upregulated under hypoxia in different breast cancer cells. Overexpression and knockdown of HIF-1α up- and downregulated NDRG1-OT1, respectively. Luciferase reporter assays and chromatin immunoprecipitation assays validated that HIF-1α transcriptionally activated NDRG1-OT1 by binding to its promoter (-1773 to -1769 and -647 to -643 bp). Next, to investigate whether NDRG1-OT1 could function as a miRNA sponge, results of in silico analysis, expression profiling of predicted miRNAs, and RNA immunoprecipitation assays indicated that NDRG1-OT1 could act as a miRNA sponge of miR-875-3p. In vitro and in vivo functional assays showed that NDRG1-OT1 could promote tumor growth and migration. Lastly, a small peptide (66 a.a.) translated from NDRG1-OT1 was identified. In summary, our findings revealed novel regulatory mechanisms of NDRG1-OT1 by HIF-1α and upon miR-875-3p. Also, NDRG1-OT1 promoted the malignancy of breast cancer cells and encoded a small peptide.

Extracellular domain of semaphorin 5A serves a tumor­suppressing role by activating interferon signaling pathways in lung adenocarcinoma cells.

Semaphorin 5A (SEMA5A), which was originally identified as an axon guidance molecule in the nervous system, has been subsequently identified as a prognostic biomarker for lung cancer in nonsmoking women. SEMA5A acts as a tumor suppressor by inhibiting the proliferation and migration of lung cancer cells. However, the regulatory mechanism of SEMA5A is not clear. Therefore, the purpose of the present study was to explore the roles of different domains of SEMA5A in its tumor­suppressive effects in lung adenocarcinoma cell lines. First, it was revealed that overexpression of full length SEMA5A or its extracellular domain significantly inhibited the proliferation and migration of both A549 and H1299 cells using MTT, colony formation and gap closure assays. Next, microarray analyses were performed to identify genes regulated by different domains of SEMA5A. Among the differentially expressed genes, the most significant function of these genes that were enriched was the 'Interferon Signaling' pathway according to Ingenuity Pathway Analysis. The activation of the 'Interferon Signaling' pathway was validated by reverse transcription­quantitative PCR and western blotting. In summary, the present study demonstrated that the extracellular domain of SEMA5A could upregulate genes in interferon signaling pathways, resulting in suppressive effects in lung adenocarcinoma cells.

Effects of ankle continuous passive motion on soleus hypertonia in individuals with cerebral palsy: A case series.

BACKGROUND: Continuous passive motion device (CPM) provides repetitive movement over extended periods of time for those who have low functional ability. The purpose of this research was to evaluate the effects of a four-week program of continuous passive motion of the ankle joint on the changes in soleus hypertonia in individuals with cerebral palsy who suffered from life-long hypertonia. METHODS: A single group, repeated-measures study was conducted. Eight individuals (7 males and 1 female with a mean age of 21.8 ± 8.5 years) with spastic cerebral palsy underwent bilateral ankle CPM for 1 h a day, 5 days a week, for 4 weeks. The outcome measures included the Modified Ashworth Scale (MAS) score, passive range of motion (PROM) of the ankle, the ratio of maximum H reflex to maximum soleus M-response (H/M ratio), and post-activation depression (PAD). All outcomes were measured before and after the intervention. A paired t-test was used to examine treatment effects pre-versus post-intervention. RESULTS: Paired t-tests showed that the CPM program significantly decreased the MAS score (p = 0.006), decreased the maximum H/M ratio (p=0.001), improved PAD (p = 0.003, p = 0.040, and p = 0.032 at 0.2 Hz, 1 Hz, and 2 Hz, respectively), and increased the passive ankle range of motion (p = 0.049). CONCLUSION: Ankle CPM not only reduced soleus hypertonia but also improved the PROM in individuals with cerebral palsy. The results of this study show ankle CPM to be an effective intervention for individuals with cerebral palsy.

Test-Retest Reliability of Home-Based Fitness Assessments Using a Mobile App (R Plus Health) in Healthy Adults: Prospective Quantitative Study.

BACKGROUND: Poor physical fitness has a negative impact on overall health status. An increasing number of health-related mobile apps have emerged to reduce the burden of medical care and the inconvenience of long-distance travel. However, few studies have been conducted on home-based fitness tests using apps. Insufficient monitoring of physiological signals during fitness assessments have been noted. Therefore, we developed R Plus Health, a digital health app that incorporates all the components of a fitness assessment with concomitant physiological signal monitoring. OBJECTIVE: The aim of this study is to investigate the test-retest reliability of home-based fitness assessments using the R Plus Health app in healthy adults. METHODS: A total of 31 healthy young adults self-executed 2 fitness assessments using the R Plus Health app, with a 2- to 3-day interval between assessments. The fitness assessments included cardiorespiratory endurance, strength, flexibility, mobility, and balance tests. The intraclass correlation coefficient was computed as a measure of the relative reliability of the fitness assessments and determined their consistency. The SE of measurement, smallest real difference at a 90% CI, and Bland-Altman analyses were used to assess agreement, sensitivity to real change, and systematic bias detection, respectively. RESULTS: The relative reliability of the fitness assessments using R Plus Health was moderate to good (intraclass correlation coefficient 0.8-0.99 for raw scores, 0.69-0.99 for converted scores). The SE of measurement and smallest real difference at a 90% CI were 1.44-6.91 and 3.36-16.11, respectively, in all fitness assessments. The 95% CI of the mean difference indicated no significant systematic error between the assessments for the strength and balance tests. The Bland-Altman analyses revealed no significant systematic bias between the assessments for all tests, with a few outliers. The Bland-Altman plots illustrated narrow limits of agreement for upper extremity strength, abdominal strength, and right leg stance tests, indicating good agreement between the 2 assessments. CONCLUSIONS: Home-based fitness assessments using the R Plus Health app were reliable and feasible in young, healthy adults. The results of the fitness assessments can offer a comprehensive understanding of general health status and help prescribe safe and suitable exercise training regimens. In future work, the app will be tested in different populations (eg, patients with chronic diseases or users with poor fitness), and the results will be compared with clinical test results. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000030905; http://www.chictr.org.cn/showproj.aspx?proj=50229.

Regulatory Mechanisms and Functional Roles of Hypoxia-Induced Long Non-Coding RNA MTORT1 in Breast Cancer Cells.

Long non-coding RNAs (lncRNAs) have been found to participate in multiple genetic pathways in cancer. Also, mitochondria-associated lncRNAs have been discovered to modulate mitochondrial function and metabolism. Previously, we identified oxygen-responsive lncRNAs in MCF-7 breast cancer cells under different oxygen concentrations. Among them, a novel mitochondria-encoded lncRNA, mitochondrial oxygen-responsive transcript 1 (MTORT1), was chosen for further investigation. Nuclear, cytoplasmic, and mitochondrial fractionation assays were performed to evaluate the endogenous expression levels of MTORT1 in breast cancer cells. In vitro proliferation and migration assays were conducted to investigate the functions of MTORT1 in breast cancer cells by knockdown of MTORT1. RNA immunoprecipitation and luciferase reporter assays were used to examine the physical binding between MTORT1 and microRNAs. Our results showed that MTORT1 had low endogenous expression levels in breast cancer cells and was mainly located in the mitochondria. Knockdown of MTORT1 enhanced cell proliferation and migration, implying a tumor suppressor role of this novel mitochondrial lncRNA. MTORT1 served as sponge of miR-26a-5p to up-regulate its target genes, CREB1 and STK4. Our findings shed some light on the characterization, function, and regulatory mechanism of the novel hypoxia-induced mitochondrial lncRNA MTORT1, which functions as a microRNA sponge and may inhibit breast cancer progression. These data suggest that MTORT1 may be a candidate for therapeutic targeting of breast cancer progression.

Hypoxia-Induced MALAT1 Promotes the Proliferation and Migration of Breast Cancer Cells by Sponging MiR-3064-5p.

Hypoxia, a common process during tumor growth, can lead to tumor aggressiveness and is tightly associated with poor prognosis. Long noncoding RNAs (lncRNAs) are long ribonucleotides (>200 bases) with limited ability to translate proteins, and are known to affect many aspects of cellular function. One of their regulatory mechanisms is to function as a sponge for microRNA (miRNA) to modulate its biological functions. Previously, MALAT1 was identified as a hypoxia-induced lncRNA. However, the regulatory mechanism and functions of MALAT1 in breast cancer are still unclear. Therefore, we explored whether MALAT1 can regulate the functions of breast cancer cells through miRNAs. Our results showed the expression levels of MALAT1 were significantly up-regulated under hypoxia and regulated by HIF-1α and HIF-2α. Next, in contrast to previous reports, nuclear and cytoplasmic fractionation assays and fluorescence in situ hybridization indicated that MALAT1 was mainly located in the cytoplasm. Therefore, the labeling of MALAT1 as a nuclear marker should be done with the caveat. Furthermore, expression levels of miRNAs and RNA immunoprecipitation using antibody against AGO2 showed that MALAT1 functioned as a sponge of miRNA miR-3064-5p. Lastly, functional assays revealed that MALAT1 could promote cellular migration and proliferation of breast cancer cells. Our findings provide evidence that hypoxia-responsive long non-coding MALAT1 could be transcriptionally activated by HIF-1α and HIF-2α, act as a miRNA sponge of miR-3064-5p, and promote tumor growth and migration in breast cancer cells. These data suggest that MALAT1 may be a candidate for therapeutic targeting of breast cancer progression.

Motor Cortical Activity during Observing a Video of Real Hand Movements versus Computer Graphic Hand Movements: An MEG Study.

Both action observation (AO) and virtual reality (VR) provide visual stimuli to trigger brain activations during the observation of actions. However, the mechanism of observing video movements performed by a person's real hand versus that performed by a computer graphic hand remains uncertain. We aimed to investigate the differences in observing the video of real versus computer graphic hand movements on primary motor cortex (M1) activation by magnetoencephalography. Twenty healthy adults completed 3 experimental conditions: the resting state, the video of real hand movements (VRH), and the video of computer graphic hand movements (CGH) conditions with the intermittent electrical stimuli simultaneously applied to the median nerve by an electrical stimulator. The beta oscillatory activity (~20 Hz) in the M1 was collected, lower values indicating greater activations. To compare the beta oscillatory activities among the 3 conditions, the Friedman test with Bonferroni correction (p-value < 0.017 indicating statistical significance) were used. The beta oscillatory activities of the VRH and CGH conditions were significantly lower than that of the resting state condition. No significant difference in the beta oscillatory activity was found between the VRH and CGH conditions. Observing hand movements in a video performed by a real hand and those by a computer graphic hand evoked comparable M1 activations in healthy adults. This study provides some neuroimaging support for the use of AO and VR in rehabilitation, but no differential activations were found.

Low-Intensity Electrical Stimulation to Improve the Neurological Aspect of Weakness in Individuals with Chronic Anterior Cruciate Ligament Lesion.

PURPOSE: This study is aimed at investigating the effect of low-intensity electrical stimulation on the voluntary activation level (VA) and the cortical facilitation/inhibition of quadriceps in people with chronic anterior cruciate ligament lesion. METHODS: Twenty former athletes with unilateral ACL deficiencies (ACL group) and 20 healthy subjects (healthy control group) participated in the study. The quadriceps VA level, motor-evoked potential (MEP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) elicited by transcranial magnetic stimulation were tested before and after 30 minutes of low-intensity electrical stimulation (ES). RESULTS: Before ES, the quadriceps VA in the ACL lesion legs of the ACL group was lower compared to the legs of the healthy control group (P < 0.05). The MEP sizes in the ACL lesion legs and the healthy control were not significantly different. The ACL lesion legs showed lower SICI and higher ICF compared to the healthy control group (P < 0.05). After ES, the quadriceps VA level increased and the SICI-ICF was modulated only in the ACL lesion legs (P < 0.05) but not in the healthy controls. CONCLUSIONS: Low-intensity ES can normalize the modulation of intracortical inhibition and facilitation, thereby ameliorating the activation failure in individuals with ACL lesion.

Validity and reliability of the Traditional Chinese version of the Multidimensional Fatigue Inventory in general population.

BACKGROUND: Fatigue is a common symptom in the general population and has a substantial effect on individuals' quality of life. The Multidimensional Fatigue Inventory (MFI) has been widely used to quantify the impact of fatigue, but no Traditional Chinese translation has yet been validated. The goal of this study was to translate the MFI from English into Traditional Chinese ('the MFI-TC') and subsequently to examine its validity and reliability. METHODS: The study recruited a convenience sample of 123 people from various age groups in Taiwan. The MFI was examined using a two-step process: (1) translation and back-translation of the instrument; and (2) examination of construct validity, convergent validity, internal consistency, test-retest reliability, and measurement error. The validity and reliability of the MFI-TC were assessed by factor analysis, Spearman rho correlation coefficient, Cronbach's alpha coefficient, intraclass correlation coefficient (ICC), minimal detectable change (MDC), and Bland-Altman analysis. All participants completed the Short-Form-36 Health Survey Taiwan Form (SF-36-T) and the Chinese version of the Pittsburgh Sleep Quality Index (PSQI) concurrently to test the convergent validity of the MFI-TC. Test-retest reliability was assessed by readministration of the MFI-TC after a 1-week interval. RESULTS: Factor analysis confirmed the four dimensions of fatigue: general/physical fatigue, reduced activity, reduced motivation, and mental fatigue. A four-factor model was extracted, combining general fatigue and physical fatigue as one factor. The results demonstrated moderate convergent validity when correlating fatigue (MFI-TC) with quality of life (SF-36-T) and sleep disturbances (PSQI) (Spearman's rho = 0.68 and 0.47, respectively). Cronbach's alpha for the MFI-TC total scale and subscales ranged from 0.73 (mental fatigue subscale) to 0.92 (MFI-TC total scale). ICCs ranged from 0.85 (reduced motivation) to 0.94 (MFI-TC total scale), and the MDC ranged from 2.33 points (mental fatigue) to 9.5 points (MFI-TC total scale). The Bland-Altman analyses showed no significant systematic bias between the repeated assessments. CONCLUSIONS: The results support the use of the Traditional Chinese version of the MFI as a comprehensive instrument for measuring specific aspects of fatigue. Clinicians and researchers should consider interpreting general fatigue and physical fatigue as one subscale when measuring fatigue in Traditional Chinese-speaking populations.

Effect of EMG-triggered neuromuscular electrical stimulation with bilateral arm training on hemiplegic shoulder pain and arm function after stroke: a randomized controlled trial.

BACKGROUND: Hemiplegic shoulder pain is a frequent complication after stroke, leading to limited use of the affected arm. Neuromuscular electrical stimulation (NMES) and transcutaneous electrical nerve stimulation (TENS) are two widely used interventions to reduce pain, but the comparative efficacy of these two modalities remains uncertain. The purpose of this research was to compare the immediate and retained effects of EMG-triggered NMES and TENS, both in combination with bilateral arm training, on hemiplegic shoulder pain and arm function of stroke patients. METHODS: A single-blind, randomized controlled trial was conducted at two medical centers. Thirty-eight patients (25 males and 13 females, 60.75 ± 10.84 years old, post stroke duration 32.68 ± 53.07 months) who had experienced a stroke more than 3 months ago at the time of recruitment and hemiplegic shoulder pain were randomized to EMG-triggered NMES or TENS. Both groups received electrical stimulation followed by bilateral arm training 3 times a week for 4 weeks. The primary outcome measures included a vertical Numerical Rating Scale supplemented with a Faces Rating Scale, and the short form of the Brief Pain Inventory. The secondary outcome measures were the upper-limb subscale of the Fugl-Meyer Assessment, and pain-free passive shoulder range of motion. All outcomes were measured pretreatment, post-treatment, and at 1-month after post-treatment. Two-way mixed repeated measures ANOVAs were used to examine treatment effects. RESULTS: Compared to TENS with bilateral arm training, the EMG-triggered NMES with bilateral arm training was associated with lower pain intensity during active and passive shoulder movement (P =0.007, P =0.008), lower worst pain intensity (P = 0.003), and greater pain-free passive shoulder abduction (P =0.001) and internal rotation (P =0.004) at follow-up. Both groups improved in pain at rest (P =0.02), pain interference with daily activities, the Fugl-Meyer Assessment, and pain-free passive shoulder flexion and external rotation post-treatment (P < 0.001) and maintained the improvement at follow-up (P < 0.001), except for resting pain (P =0.08). CONCLUSIONS: EMG-triggered NMES with bilateral arm training exhibited greater immediate and retained effects than TENS with bilateral arm training with respect to pain and shoulder impairment for chronic and subacute stroke patients with hemiplegic shoulder pain. TRIAL REGISTRATION: NCT01913509 .

Fatigue and Muscle Strength Involving Walking Speed in Parkinson's Disease: Insights for Developing Rehabilitation Strategy for PD.

Background. Problems with gait in Parkinson's disease (PD) are a challenge in neurorehabilitation, partly because the mechanisms causing the walking disability are unclear. Weakness and fatigue, which may significantly influence gait, are commonly reported by patients with PD. Hence, the aim of this study was to investigate the association between weakness and fatigue and walking ability in patients with PD. Methods. We recruited 25 patients with idiopathic PD and 25 age-matched healthy adults. The maximum voluntary contraction (MVC), twitch force, and voluntary activation levels were measured before and after a knee fatigue exercise. General fatigue, central fatigue, and peripheral fatigue were quantified by exercise-induced changes in MVC, twitch force, and activation level. In addition, subjective fatigue was measured using the Multidimensional Fatigue Inventory (MFI) and Fatigue Severity Scale (FSS). Results. The patients with PD had lower activation levels, more central fatigue, and more subjective fatigue than the healthy controls. There were no significant differences in twitch force or peripheral fatigue index between the two groups. The reduction in walking speed was related to the loss of peripheral strength and PD itself. Conclusion. Fatigue and weakness of central origin were related to PD, while peripheral strength was important for walking ability. The results suggest that rehabilitation programs for PD should focus on improving both central and peripheral components of force.

Reliability and validity of a vertical numerical rating scale supplemented with a faces rating scale in measuring fatigue after stroke.

BACKGROUND: Poststroke fatigue is a persistent and distressing symptom among stroke survivors. In this study, we investigated the reliability and validity of a vertical numerical rating scale supplemented with a faces rating scale (NRS-FRS) in measuring poststroke fatigue. METHODS: The fatigue intensity of 106 individuals with stroke was measured twice, 1 week apart, using a vertical NRS-FRS to measure test-retest reliability. The intraclass correlation coefficient, a relative reliability index, was calculated to examine the degree of consistency and agreement between the two test occasions. Absolute reliability indices, including the standard error of measurement, minimal detectable change, and Bland-Altman limits of agreement, were used to quantify measurement errors and determine systematic biases of the two test occasions. We also administered the vertical NRS concurrently as a comparator measure for assessing fatigue in 50 consecutive patients with stroke who were recruited later in the study period. The Spearman rank correlation coefficient (ρ) was used to examine the concurrent validity of the NRS-FRS. Discriminant validity was assessed by means of receiver operating characteristic curves, sensitivity, and specificity. RESULTS: The intraclass correlation coefficient was 0.95 for the NRS-FRS. The standard error of measurement and the minimal detectable change at the 95 % confidence interval of the NRS-FRS were 0.50 and 1.39, respectively. The Bland-Altman analyses showed no significant systematic bias between the repeated measurements. A narrow range of the limits of agreement was shown on the Bland-Altman plot, indicating the NRS-FRS had high stability and low variation between the two test occasions. The correlations between the NRS-FRS and NRS were good at test (ρ = 0.85) and retest (ρ = 0.84). Compared with the NRS cutoff value of ≥1, sensitivity with the NRS-FRS at test and retest was 94 and 92 % and specificity was 79 and 90 %, respectively. CONCLUSIONS: This study provides further evidence of the reliability and validity of the NRS-FRS in measuring fatigue intensity in patients with stroke. The NRS-FRS had high sensitivity and specificity. The NRS-FRS may be a reliable and valid measure for clinicians and researchers to assess fatigue and determine whether a real change has occurred in groups and at the individual level of patients with stroke.

Combined heart rate variability and dynamic measures for quantitatively characterizing the cardiac stress status during cycling exercise.

In this study, we aimed to seek for different ways of measuring cardiac stress in terms of heart rate variability (HRV) and heart rate (HR) dynamics, and to develop a novel index that can effectively summarize the information reflected by these measures to continuously and quantitatively characterize the cardiac stress status during physical exercise. Standard deviation, spectral measure of HRV as well as a nonlinear detrended fluctuation analysis (DFA) based fractal-like behavior measure of HR dynamics were all evaluated on the RR time series derived from windowed electrocardiogram (ECG) data for the subjects undergoing cycling exercise. We recruited eleven young healthy subjects in our tests. Each subject was asked to maintain a fixed speed under a constant load during the pedaling test. We obtained the running estimates of the standard deviation of the normal-to-normal interval (SDNN), the high-fidelity power spectral density (PSD) of HRV, and the DFA scaling exponent α, respectively. A trend analysis and a multivariate linear regression analysis of these measures were then performed. Numerical experimental results produced by our analyses showed that a decrease in both SDNN and α was seen during the cycling exercise, while there was no significant correlation between the standard lower frequency to higher frequency (LF-to-HF) spectral power ratio of HRV and the exercise intensity. In addition, while the SDNN and α were both negatively correlated with the Borg rating of perceived exertion (RPE) scale value, it seemed that the LF-to-HF power ratio might not have substantial impact on the Borg value, suggesting that the SDNN and α may be further used as features to detect the cardiac stress status during the physical exercise. We further approached this detection problem by applying a linear discriminant analysis (LDA) to both feature candidates for the task of cardiac stress stratification. As a result, a time-varying parameter, referred to as the cardiac stress measure (CSM), is developed for quantitatively on-line measuring and stratifying cardiac stress status.

Effects of whole body vibration on spasticity and lower extremity function in children with cerebral palsy.

AIM: The aim of this study was to evaluate the effect of whole body vibration (WBV) on lower extremity spasticity and ambulatory function in children with cerebral palsy (CP) with a complete crossover design. METHOD: Sixteen participants aged 9.8(2.3) years received a 20-min WBV and a control condition in a counterbalanced order on two separate days. Change scores of each outcome variable were used to show the improvement. RESULTS: Repeated-measures analyses revealed significant differences in condition scores among variables including active range-of-motion (active ROM, increased), relaxation index (RI, increased), Modified Ashworth Scale (MAS, decreased), timed up-and-go (TUG, decreased), and Six Minute Walk Test (6MWT, increased). Significant differences were also found in time change scores for MAS and 6MWT. Correlation results revealed that TUG was significantly correlated with RI (r=-.512, p=.042), and 6MWT (r=-.700, p=.003). INTERPRETATION: This study suggested that WBV intervention can control the spasticity, enhance ambulatory performance and increase active ROM. Along with previous results, data from this study revealed the potential use of WBV in clinical rehabilitation in children with CP. Future investigations should focus on finding the combination of treatment frequency and duration to achieve an ideal result.

MicroRNA-769-3p down-regulates NDRG1 and enhances apoptosis in MCF-7 cells during reoxygenation.

Hypoxia and reoxygenation are common characteristics of solid tumors, which lead to oxidative stress and activation of stress-response genes. Previously, we observed that N-myc downstream-regulated gene 1 (NDRG1) was strongly down-regulated after shifting to reoxygenation, but the regulatory mechanism of NDRG1 remained elusive. Here we focused on the regulation of NDRG1 by microRNAs (miRNAs). Breast cancer MCF-7 cells were cultured under hypoxia for 24 h followed by 24 h of reoxygenation. The miRNA profiles were examined by Nanostring nCounter assays. Forty-three miRNAs had significant changes upon reoxygenation. In silico analysis identified four oxygen-sensitive miRNAs whose seed regions perfectly matched the 3'-UTR of NDRG1. In particular, miR-769-3p was able to inhibit the expression of NDRG1, which caused a significant reduction of NDRG1 protein upon reoxygenation. Furthermore, overexpression of miR-769-3p significantly inhibited cell proliferation and enhanced apoptosis. Our results revealed that miR-769-3p can functionally regulate NDRG1 during changes in oxygen concentration.

ADAM9 up-regulates N-cadherin via miR-218 suppression in lung adenocarcinoma cells.

Lung cancer is the leading cause of cancer death worldwide, and brain metastasis is a major cause of morbidity and mortality in lung cancer. CDH2 (N-cadherin, a mesenchymal marker of the epithelial-mesenchymal transition) and ADAM9 (a type I transmembrane protein) are related to lung cancer brain metastasis; however, it is unclear how they interact to mediate this metastasis. Because microRNAs regulate many biological functions and disease processes (e.g., cancer) by down-regulating their target genes, microRNA microarrays were used to identify ADAM9-regulated miRNAs that target CDH2 in aggressive lung cancer cells. Luciferase assays and western blot analysis showed that CDH2 is a target gene of miR-218. MiR-218 was generated from pri-mir-218-1, which is located in SLIT2, in non-invasive lung adenocarcinoma cells, whereas its expression was inhibited in aggressive lung adenocarcinoma. The down-regulation of ADAM9 up-regulated SLIT2 and miR-218, thus down-regulating CDH2 expression. This study revealed that ADAM9 activates CDH2 through the release of miR-218 inhibition on CDH2 in lung adenocarcinoma.

Relative and absolute reliability of a vertical numerical pain rating scale supplemented with a faces pain scale after stroke.

BACKGROUND: Pain is a serious adverse complication after stroke. The combination of a vertical numerical pain rating scale (NPRS) and a faces pain scale (FPS) has been advocated to measure pain after stroke. OBJECTIVE: This study was conducted to investigate whether an NPRS supplemented with an FPS (NPRS-FPS) would show good test-retest reliability in people with stroke. The relative and absolute reliability of the NPRS-FPS were examined. DESIGN: A test-retest design was used for this study. METHODS: Fifty people (>3 months after stroke) participating in an outpatient occupational therapy program were recruited through medical centers to rate current pain intensity twice, at a 1-week interval, with the NPRS-FPS (on a scale from 0 to 10). The relative reliability of the NPRS-FPS was analyzed with the intraclass correlation coefficient for determining the degree of consistency and agreement between 2 measures. The standard error of measurement, the smallest real difference, and Bland-Altman limits of agreement were the absolute reliability indexes used to quantify measurement errors and determine systematic biases of repeated measurements. RESULTS: The relative reliability of the NPRS-FPS was substantial (intraclass correlation coefficient=.82). The standard error of measurement and the smallest real difference at the 90% confidence interval of the NPRS-FPS were 0.81 and 1.87, respectively. The Bland-Altman analyses revealed no significant systematic bias between repeated measurements for the NPRS-FPS. The range of the limits of agreement for the NPRS-FPS was narrow (-2.50 to 1.90), indicating a high level of stability and little variation over time. LIMITATIONS: The pain intensity of the participants ranged from no pain to a moderate level of pain. CONCLUSIONS: These findings suggest that the NPRS-FPS is a reliable measure of pain in people with stroke, with good relative and absolute reliability.

Transcription of Tnfaip3 is regulated by NF-κB and p38 via C/EBPß in activated macrophages.

Macrophages play a pivotal role in the immune system through recognition and elimination of microbial pathogens. Toll-like receptors (TLRs) on macrophages interact with microbial substances and initiate signal transduction through intracellular adapters. TLR4, which recognizes the lipopolysaccharides (LPS) on Gram-positive and Gram-negative bacteria, triggers downstream signaling mediators and eventually activates IκB kinase (IKK) complex and mitogen-activated protein kinases (MAPKs) such as p38. Previous reports revealed that, in addition to NF-κB, a core transcription factor of the innate immune response, the induction of some LPS-induced genes in macrophages required another transcription factor whose activity depends on p38. However, these additional transcription factors remain to be identified. In order to identify p38-activated transcription factors that cooperate with NF-κB in response to LPS stimulation, microarrays were used to identify genes regulated by both NF-κB and p38 using wild-type, IKK-depleted, and p38 inhibitor-treated mouse bone marrow-derived macrophages (BMDMs). In silico analysis of transcription factor binding sites was used to predict the potential synergistic transcription factors from the co-expressed genes. Among these genes, NF-κB and C/EBPß, a p38 downstream transcription factor, were predicted to co-regulate genes in LPS-stimulated BMDMs. Based on the subsequent results of a chromatin immunoprecipitation assay and TNFAIP3 expression in C/EBPß-ablated macrophages, we demonstrated that Tnfaip3 is regulated by both NF-κB and p38-dependent C/EBPß. These results identify a novel regulatory mechanism in TLR4-mediated innate immunity.