Activin A downregulates the CD69-MT2A axis via p38MAPK to induce erythroid differentiation that sensitizes BCR-ABL-positive cells to imatinib.

Induction of differentiation sensitizes chronic myeloid leukemia (CML) cells to the BCR-ABL inhibitor imatinib by mechanisms that remain unknown. We previously identified the BCR-ABL downstream effector CD69 which inhibits imatinib-induced CML cell differentiation. Herein, we found that the erythroid differentiation inducers activin A and aclacinomycin A induced expression of erythroid markers (α-globin, ζ-globin, GATA-1, and glycophorin A) and simultaneously reduced CD69 levels in K562 CML cells. Blockade of p38MAPK by SB203580 and shRNA eliminated the inhibitory effect of activin A on the promoter, mRNA, and protein levels and positive cell population of CD69. CD69 overexpression inhibited activin A-induced erythroid marker expression. Pretreatment of K562 cells with activin A to induce differentiation followed by a subtoxic concentration of imatinib caused growth inhibition and apoptosis that was reduced by CD69 overexpression. Activin A also reduced the expression of CD69's potential downstream molecule metallothionein 2A (MT2A) via p38MAPK. MT2A-knockdown reduced CD69 inhibition of activin A-induced erythroid marker expression. Furthermore, MT2A-knockdown reduced CD69 inhibition of activin A-imatinib sequential treatment-mediated growth inhibition and apoptosis in K562 and BCR-ABL-expressing CD34+ cells. These results suggest that CD69 inhibits activin A induction of erythroid differentiation-mediated CML cell sensitivity to imatinib via MT2A. Therefore, activin A induction of erythroid differentiation sensitizes BCR-ABL-positive cells to imatinib by downregulating the erythroid differentiation suppressors CD69 and MT2A.

A novel tubulin polymerization inhibitor, MPT0B206, downregulates Bcr-Abl expression and induces apoptosis in imatinib-sensitive and imatinib-resistant CML cells.

Imatinib, a Bcr-Abl-specific inhibitor, is effective for treating chronic myeloid leukemia (CML), but drug resistance has emerged for this disease. In this study, we synthesized a novel tubulin polymerization inhibitor, MPT0B206 (N-[1-(4-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-formamide), and demonstrated its apoptotic effect and mechanism in imatinib-sensitive K562 and imatinib-resistant K562R CML cells. Western blotting and immunofluorescence microscopy showed that MPT0B206 induced microtubule depolymerization in K562 and K562R cells. MPT0B206 inhibited the growth of these cells in a concentration- and time-dependent manner. It did not affect the viability of normal human umbilical vein endothelial cells. MPT0B206 induced G2/M cell cycle arrest and the appearance of the mitotic marker MPM-2 in K562 and K562R cells, which is associated with the upregulation of cyclin B1 and the dephosphorylation of Cdc2. Treatment of K562 and K562R cells with MPT0B206 induced apoptosis and reduced the protein levels of procaspase-9 and procaspase-3 and increased caspase-3 activity and PARP cleavage. MPT0B206 also reduced the levels of the antiapoptotic proteins Mcl-1 and Bcl-2 and increased the level of the apoptotic protein Bax. Additional experiments showed that MPT0B206 markedly downregulated Bcr-Abl mRNA expression and total and phosphorylated Bcr-Abl protein levels and inhibited the phosphorylation of its downstream proteins STAT5, MAPK, and AKT, and the protein level of c-Myc in K562 and K562R cells. Furthermore, MPT0B206 triggered viability reduction and apoptosis in CML cells carrying T315I-mutated Bcr-Abl. Together, these results suggest that MPT0B206 is a promising alternative for treating imatinib-resistant CML.

Effects of a single session of whole body vibration on ankle plantarflexion spasticity and gait performance in patients with chronic stroke: a randomized controlled trial.

OBJECTIVE: To investigate the effects of a single session of whole body vibration training on ankle plantarflexion spasticity and gait performance in chronic stroke patients. DESIGN: Randomized controlled trial. SETTING: Rehabilitation unit in university hospital. PARTICIPANTS: Thirty subjects with chronic stroke were randomized into either a control group (n = 15) or a group receiving a single session of whole body vibration (n = 15). INTERVENTION: The intervention group was actually treated with whole body vibration while the control group was treated with placebo treatment. MAIN MEASURES: The spastic changes were measured clinically and neurophysiologically. Subjective evaluation of ankle spasticity was performed via a visual analogue scale. Gait performances were evaluated by the timed up and go test, 10-meter walk test and cadence. A forceplate was used for measuring foot pressure. RESULTS: The changes between whole body vibration and control groups were significantly different in Modified Ashworth Scale (1.33, 95% confidence interval (CI) = 1.06~1.60). The H (max)/M (max) ratio (0.14, 95% CI = 0.01~0.26) and visual analogue scale (1.87, 95% CI = 1.15~2.58) were significantly decreased. Whole body vibration could significantly improve gait velocity, timed up and go test (6.03, 95% CI = 3.17~8.89) and 10-meter walk test (1.99, 95% CI = 0.11~3.87). The uneven body weight posture on bilateral feet was also improved after vibration. CONCLUSION: These results suggest that a single session of whole body vibration training can reduce ankle plantarflexion spasticity in chronic stroke patients, thereby potentially increasing ambulatory capacity.

CHM-1, a novel microtubule-destabilizing agent exhibits antitumor activity via inducing the expression of SIRT2 in human breast cancer cells.

Breast cancer is a major public health problem throughout the world. In this report, we investigated whether CHM-1, a novel synthetic antimitotic agent could be developed into a potent antitumor agent for treating human breast cancer. CHM-1 induced growth inhibition in MDA-MB-231, MDA-MB-453 and MCF-7 cells in a concentration-dependent manner. Importantly, CHM-1 is less toxic to normal breast (HBL-100) cells. CHM-1 interacted with tubulin, markedly inhibited tubulin polymerization, and disrupted microtubule organization. Proteins from control and CHM-1-treated animal tumor specimens were analyzed by two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Our results indicated that CHM-1 increased the expression of SIRT2 protein, an NAD-dependent tubulin deacetylase. A prodrug strategy was also investigated to address the problem of low aqueous solubility and low bioavailability of the antitumor agent CHM-1. The water-soluble prodrug of CHM-1 (CHM-1-P) was synthesized. After oral and intravenous administration, CHM-1-P induced a dose-dependent inhibition of tumor growth. The aforementioned excellent anti-tumor activity profiles of CHM-1 and its prodrug CHM-1-P, suggests that CHM-1-P deserves to further develop as a clinical trial candidate for treating human breast carcinoma.

Effect of knee sleeve on static and dynamic balance in patients with knee osteoarthritis.

Patients with knee osteoarthritis (OA) find that use of elastic knee sleeves gives them partial pain relief and a greater sense of joint stability. However, the scientific effects of knee OA patients wearing braces are unclear. The purpose of this study was to investigate the effects of knee sleeves on static and dynamic balance in knee OA patients. Fifty patients with knee OA were enrolled in the study and all subjects were randomly divided into two groups. Initially, subjects in group A did not wear a neoprene sleeve while receiving balance tests but then wore them to be re-tested. Subjects in group B did just the reverse procedure. In this investigation, an instrument (KAT 2000; Breg Inc., Vista, CA, USA), which quantified motor control performance of the lower extremities was used and balance scores from the KAT 2000 software were obtained. The results revealed that the scores of patients wearing braces were significantly lower than those of patients without braces (p < 0.05).The finding of this study demonstrated that knee OA patients wearing knee sleeves could experience increased balance ability in both static and dynamic conditions. The improvement might prevent knee OA patients from falling down and increase their sense of security during physical activities.

Effects of functional electrical stimulation on peak torque and body composition in patients with incomplete spinal cord injury.

The aim of this study was to investigate the change in body composition, leg girths, and muscle strength of patients with incomplete spinal cord injury (SCI) after functional electrical stimulation cycling exercises (FESCE). Eighteen subjects with incomplete SCI were recruited. Each patient received FESCE three times per week for 8 weeks. Body composition, thigh and calf girths of bilateral legs, muscle strength of bilateral knee flexors and extensors were measured before and after 4 and 8 weeks of FESCE. A significant increase in bilateral thigh girth after 4 weeks of FESCE and significant increase in muscular peak torque of knee flexion and extension were found after 8 weeks of training. Besides, lean body mass increased significantly after complete treatment. FESCE can increase the thigh girth and muscular peak torque of patients with incomplete spinal cord injury.

Effect on spasticity after performance of dynamic-repeated-passive ankle joint motion exercise in chronic stroke patients.

Spasticity associated with abnormal muscle tone is a common motor disorder following stroke, and the spastic ankle may affect ambulatory function. The purpose of this study was to investigate the short-term effect of dynamic-repeated-passive ankle movements with weight loading on ambulatory function and spastic hypertonia of chronic stroke patients. In this study, 12 chronic stroke patients with ankle spasticity and inefficient ambulatory ability were enrolled. Stretching of the plantar-flexors of the ankle in the standing position for 15 minutes was performed passively by a constant-speed and electrically powered device. The following evaluations were done before and immediately after the dynamic-repeated-passive ankle movements. Spastic hypertonia was assessed by the Modified Ashworth Scale (MAS; range, 0-4), Achilles tendon reflexes test (DTR; range, 0-4), and ankle clonus (range, 0-5). Improvement in ambulatory ability was determined by the timed up-and-go test (TUG), the 10-minute walking test, and cadence (steps/minute). In addition, subjective experience of the influence of ankle spasticity on ambulation was scored by visual analog scale (VAS). Subjective satisfaction with the therapeutic effect of spasticity reduction was evaluated by a five-point questionnaire (1 = very poor, 2 = poor, 3 = acceptable, 4 = good, 5 = very good). By comparison of the results before and after intervention, these 12 chronic stroke patients presented significant reduction in MAS and VAS for ankle spasticity, the time for TUG and 10-minute walking speed (p < 0.01). The cadence also increased significantly (p < 0.05). In addition, subjective satisfaction with the short-term therapeutic effect was mainly good (ranging from acceptable to very good). In conclusion, 15 minutes of dynamic-repeated-passive ankle joint motion exercise with weight loading in the standing position by this simple constant-speed machine is effective in reducing ankle spasticity and improving ambulatory ability.

Relationship between carpal tunnel syndrome and wrist angle in computer workers.

Carpal tunnel syndrome (CTS) is the most widely known entrapment neuropathy. The aim of this study was to assess the incidence of CTS in a group of computer workers by typical symptoms, median nerve conduction studies, and their combinations. The posture of extended wrists while typing on a computer keyboard seems to be a predisposing factor for CTS. However, the correlation between wrist extension angle and the incidence of CTS is not well known. Forty-five subjects (mean age, 38.8 +/- 7.8 years) who used a computer for more than 6 hours daily in a medical center in southern Taiwan were studied. All completed questionnaires to ascertain their age, employment duration, dominant hand, and the severity of symptoms. Physical examinations (Tinel's sign and Phalen's test) were performed by a physician. The maximal wrist extension angle when typing on a computer keyboard was also measured by the same physician. Nerve conduction studies were performed on each subject to determine the severity of CTS. Results showed that the incidence of CTS in the computer workers was 16.7% (15 of 90 hands). Twelve subjects showed electrodiagnostic evidence of CTS: it involved the dominant hand in seven, the non-dominant hand in two, and bilateral hands in three. The severity of clinical symptoms was compatible with the findings of the nerve conduction studies. Among the major predisposing factors, we found significant correlation between CTS development and the wrist extension angle while typing on a computer keyboard. Computer workers who kept their wrists extended by more than 20 degrees were at greater risk of developing CTS.

Physician practices in the diagnosis of carpal tunnel syndrome at a medical center in southern Taiwan.

Carpal tunnel syndrome (CTS) is the most common neurologic entrapment disorder diagnosed in the upper limb. Nevertheless, there is still debate about the most reliable test that should be performed to diagnose CTS. Much of the argument has been drawn from the opinions of individuals or groups with varying degrees of expertise in the field; little has been based on actual data. The purpose of this study was to investigate the diagnostic patterns of CTS in an academic medical setting in southern Taiwan. The charts of 1,050 patients with a diagnosis of CTS over a 1-year period (2001-2002) were retrospectively reviewed. Data on 622 patients with new-onset CTS were included in the analysis. On the patient's initial visit, physicians made a diagnosis of CTS in 34.9% of cases solely on the basis of the history of symptoms without resort to provocative tests, while 8.7% of cases were diagnosed on the basis of symptom characteristics alone in spite of negative provocative tests. A CTS diagnosis was given according to symptoms and positive provocative tests in 55% of cases. Apart from these, CTS diagnosis remained unchanged in 27.3% of cases without electrodiagnostic signs of CTS during follow-up visits. An average of 1.6 diagnostic maneuvers were conducted for CTS patients, with nerve conduction velocity (NCV) studies (516 cases) being the most frequently performed, followed by Tinel's sign (350 cases) and Phalen's test (102 cases). Our findings imply that physicians are inclined to base their diagnosis on clinical history and physical examination for patients with suspected CTS. Clear guidelines regarding the indications for referral for NCV studies should be established in response to the increased concerns about the cost effectiveness of diagnostic tests.

Relationship between neurogenic bowel dysfunction and health-related quality of life in persons with spinal cord injury.

OBJECTIVE: To assess the relationship between the severity of neurogenic bowel and health-related quality of life in persons with various degrees of spinal cord injury. DESIGN: Cross-sectional. SUBJECTS: A total of 128 people with spinal cord injury. METHODS: Two questionnaires were sent out by post. One included demographic characteristics and a neurogenic bowel dysfunction score to evaluate the severity of neurogenic bowel dysfunction. The other was a Short-Form 36-Item Health Survey that evaluated the quality of life in persons with spinal cord injury. RESULTS: Approximately half of the persons with spinal cord injury (46.9%) had moderate to severe degrees of neurogenic bowel dysfunction, the severity of which was associated with the physical functioning and physical component summary score in health-related quality of life. The results also showed that more severe neurological classifications led to lower physical component summary scores for impaired physical function and bodily pain. There was no correlation between the length of time elapsed since injury and health-related quality of life. Persons with more severe neurogenic bowel conditions were also found to be more likely to receive rehabilitative therapy. CONCLUSION: Neurogenic bowel dysfunction is associated with health-related quality of life expression in persons with spinal cord injury, especially in physical functioning and physical component summary.

Association of C-reactive protein and insulin resistance in patients with chronic spinal cord injury.

OBJECTIVE: To study the association between C-reactive protein levels and insulin resistance in patients with spinal cord injury. DESIGN: Cross-sectional study. SUBJECTS: Forty-two subjects who had sustained spinal cord injuries at least 6 months before enrollment. METHODS: Circulating glucose, insulin and C-reactive protein levels were measured after 12 hours' fasting. The homeo-stasis model insulin resistance index was used to evaluate insulin resistance. Insulin resistance and C-reactive protein levels were compared between complete/incomplete patients and between paraplegic/tetraplegic patients. The subjects were then divided into 3 groups (C-reactive protein levels < 1, 1-3, > 3 mg/l) to compare insulin resistance. RESULTS: Eighteen (43%) subjects had C-reactive protein levels > 3 mg/l. The C-reactive protein levels and insulin resistance did not significantly differ between complete/incomplete or between paraplegic/tetraplegic subjects. However, insulin resistance in the high C-reactive protein group (>3 mg/l) differed significantly from that of the other 2 groups, and there was a significant correlation between C-reactive protein and insulin resistance, with r=0.7745. CONCLUSION: Most young and middle-aged patients with chronic spinal cord injury with high C-reactive protein levels also have high insulin resistance, and their C-reactive protein levels have well correlated with insulin resistance.