Down-regulation of the mitochondrial fusion protein Opa1/Mfn2 promotes cardiomyocyte hypertrophy in Su5416/hypoxia-induced pulmonary hypertension rats.

BACKGROUND: Maladaptive right ventricular (RV) remodeling is the most important pathological feature of pulmonary hypertension (PH), involving processes such as myocardial hypertrophy and fibrosis. A growing number of studies have shown that mitochondria-associated endoplasmic reticulum membranes (MAMs) are involved in various physiological and pathological processes, such as calcium homeostasis, lipid metabolism, inflammatory response, mitochondrial dynamics, and autophagy/mitophagy. The abnormal expression of MAMs-related factors is closely related to the occurrence and development of heart-related diseases. However, the role of MAM-related factors in the maladaptive RV remodeling of PH rats remains unclear. METHODS AND RESULTS: We first obtained the transcriptome data of RV tissues from PH rats induced by Su5416 combined with hypoxia treatment (SuHx) from the Gene Expression Omnibus (GEO) database. The results showed that two MAMs-related genes (Opa1 and Mfn2) were significantly down-regulated in RV tissues of SuHx rats, accompanied by significant up-regulation of cardiac hypertrophy-related genes (such as Nppb and Myh7). Subsequently, using the SuHx-induced PH rat model, we found that the downregulation of mitochondrial fusion proteins Opa1 and Mfn2 may be involved in maladaptive RV remodeling by accelerating mitochondrial dysfunction. Finally, at the cellular level, we found that overexpression of Opa1 and Mfn2 could inhibit hypoxia-induced mitochondrial fission and reduce ROS production in H9c2 cardiomyocytes, thereby retarded the progression of cardiomyocyte hypertrophy. CONCLUSIONS: The down-regulation of mitochondrial fusion protein Opa1/Mfn2 can accelerate cardiomyocyte hypertrophy and then participate in maladaptive RV remodeling in SuHx-induced PH rats, which may be potential targets for preventing maladaptive RV remodeling.

Cerebellin-2 promotes endothelial-mesenchymal transition in hypoxic pulmonary hypertension rats by activating NF-κB/HIF-1α/Twist1 pathway.

AIMS: Endothelial-mesenchymal transition (EndMT) is one of the critical factors leading to vascular remodeling in pulmonary hypertension (PH). Recent studies found that the expression of Cerebellin-2 (CBLN2) is significantly increased in the lung tissue of patients with PH, suggesting that CBLN2 may be closely related to the development of PH. This study aims to investigate the role and potential mechanism of CBLN2 in the hypoxia-induced EndMT of PH rats. MATERIAL AND METHODS: Hypoxia-induced PH rat model or EndMT cell model was constructed to investigate the role of CBLN2 in the process of endothelial mesenchymal transition during PH. The effects of CBLN2 siRNA, KC7F2 (HIF-1α inhibitor), and PDTC (NF-κB inhibitor) on hypoxia-induced EndMT were observed to evaluate the potential mechanism of CBLN2 in promoting EndMT. KEY FINDINGS: The right ventricular systolic pressure and pulmonary vascular remodeling index in hypoxia-treated rats were significantly increased. The transformation of endothelial cells (marked by CD31) to mesenchymal cells (marked by α-SMA) can be observed in the pulmonary vessels of PH rats, and the expression of CBLN2 in the intima was also significantly up-regulated. In the hypoxia-induced HPAECs, endothelial cell markers such as VE-cadherin and CD31 expression were significantly down-regulated, while mesenchymal-like cell markers such as α-SMA and vimentin were increased considerably, along with the increased expressions of CBLN2, p-p65, HIF-1α, and Twist1; CBLN2 siRNA, PDTC, and KC7F2 could inhibit those phenomena. SIGNIFICANCE: CBLN2 can promote EndMT by activating NF-κB/HIF-1α/Twist1 pathway. Therefore, CBLN2 may be a new therapeutic target for PH.

Specific Selective Neck Dissection for Isolated Regional Failure in Nasopharyngeal Carcinoma after Radiation.

BACKGROUND: To assess whether specific selective neck dissection (SND) with involved levels is a feasible treatment for isolated regional failure in nasopharyngeal carcinoma (NPC) after radiation. MATERIAL AND METHODS: Between January 2011 and December 2019, a total of 46 patients were assigned to undergo SND in the Department of Head and Neck Surgery at our center. The dissection extent of specific SND usually only involved levels of lymph node sites for isolated regional failure; in addition, lesions of level II or III involved removing both level II and III lymph nodes. The patients' clinical, MRI and pathological characteristics, overall survival (OS), disease-free survival (DFS) and regional-free survival (RFS) were evaluated and analyzed. RESULTS: Level II was the most commonly involved cervical nodal region in 28 neck dissection specimens (54.9%), followed by level III with positive nodes in 11 specimens (21.6%). Eleven patients (34.8%) had post-SND locoregional recurrence without distant metastasis. Of the patients, 7 patients (30.4%) had regional recurrence, and only one patient (2.8%) had lymph node recurrence on the side of SND. In addition, 8 patients (17.4%) had post-SND distant metastasis. The OS, DFS, and RFS of the patients were 76.1%, 58.7%, and 69.6%, respectively, at 3 years. The OS, DFS, and RFS values of patients who underwent SND were similar to those of patients who underwent comprehensive neck dissection (CND) and/or SND in published articles. CONCLUSION: Specific SND was shown to be an effective and feasible treatment for isolated regional failure in NPC.

Evaluating the therapeutic role of selected active compounds in Plumula Nelumbinis on pulmonary hypertension via network pharmacology and experimental analysis.

Excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) are critical factors leading to vascular remodeling in pulmonary hypertension (PH). This study aimed to explore the effect and potential mechanism of Plumula Nelumbinis on PH by using network pharmacology and experimental analysis. Network pharmacology and molecular docking results indicated that the potential active components of Plumula Nelumbinis against PH were mainly alkaloid compounds, including neferine, liensinine, and isoliensinine. Subsequently, by constructing a Su5416 plus hypoxia (SuHx)-induced PH rat model, we found that the total alkaloids of Plumula Nelumbinis (TAPN) can reduce the right ventricular systolic pressure, delay the process of pulmonary vascular and right ventricular remodeling, and improve the right heart function in PH rats. In addition, TAPN can effectively reverse the upregulation of collagen1, collagen3, MMP2, MMP9, PCNA, PIM1, and p-SRC protein expression in lung tissue of PH rats. Finally, by constructing a hypoxia-induced PASMCs proliferation and migration model, we further found that TAPN, neferine, liensinine, and isoliensinine could inhibit the proliferation and migration of PASMCs induced by hypoxia; reverse the upregulation of collagen1, collagen3, MMP2, MMP9, PCNA, PIM1 and p-SRC protein expression in PASMCs. Based on these observations, we conclude that the alkaloid compounds extracted from Plumula Nelumbinis (such as neferine, liensinine, and isoliensinine) can inhibit the abnormal proliferation and migration of PASMCs by regulating the expression of p-SRC and PIM1, thereby delaying the progression of PH.

Magnolol alleviates hypoxia-induced pulmonary vascular remodeling through inhibition of phenotypic transformation in pulmonary arterial smooth muscle cells.

Phenotypic transformation and excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) play an important role in vascular remodeling during pulmonary hypertension (PH). Magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) is the major bioactive constituent isolated from the bark of Magnolia Officinalis, which has anti-inflammatory, antioxidant, and cardiovascular protection effects. However, the effect of magnolol on the phenotypic transformation of PASMCs is still unknown. This study aims to evaluate the effects of magnolol on the phenotypic transformation of PASMCs induced by hypoxia. In vivo, Sprague Dawley rats were exposed to hypoxia (10% O2) for four weeks to establish a PH model. The results showed that hypoxia treatment led to an increase in right ventricle systolic pressure, Fulton index, collagen production, accompanied by upregulation in the expression of collagen Ⅰ, collagen Ⅲ, OPN, PCNA, CyclinD1, p-JAK2, and p-STAT3, as well as decreases in expression of SM-22α; these changes were attenuated by magnolol. In vitro, the primary cultured PASMCs were exposed to 3% O2 for 48 h to induce phenotypic transformation. Consistent with the findings in vivo, magnolol treatment could prevent the phenotypic transformation and hyperproliferation of PASMCs induced by hypoxia, accompanied by downregulation in the expression of p-JAK2 and p-STAT3. In summary, this study demonstrated that the protective effect of magnolol on PH vascular remodeling is related to the inhibition of phenotypic transformation and hyperproliferation of PASMCs by inhibiting the JAK2/STAT3 pathway.

Magnolol Attenuates Right Ventricular Hypertrophy and Fibrosis in Hypoxia-Induced Pulmonary Arterial Hypertensive Rats Through Inhibition of the JAK2/STAT3 Signaling Pathway.

Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol (6, 6', 7, 12-tetramethoxy-2,2'-dimethyl-1-ß-berbaman, C18H18O2) is a compound isolated from Magnolia Officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. In vivo, male Sprague Dawley rats were exposed to 10% O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of Fulton index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3; these changes were attenuated by treating with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3% O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagen Ⅰ, collagen Ⅲ, and α-SMA). Administration of magnolol and TG-101348 or JSI-124 (both JAK2 selective inhibitors) could prevent myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. Based on these observations, we conclude that magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway. Magnolol may possess the potential clinical value for PAH therapy.

Effects of acellular dermal matrix on the prevention of complications and esthetic outcome after parotidectomy: A propensity score matched analysis.

OBJECTIVE: The present study was designed to investigate whether acellular dermal matrix (ADM) grafts could prevent Frey's syndrome (FS) and improve esthetic scores following parotidectomy. METHODS: From January 2015 to December 2019, 175 patients underwent parotidectomy. We divided the patients into two groups: the ADM group and the control group. We included in each group 30 patients according to a propensity score matched analysis. RESULTS: FS was subjective in 1 patient (3%) from the ADM group and 9 patients (30%) from the control group (P=0.015). Patients in the ADM group had a subjective esthetic score of 6.1 + 1.7 compared with 5.2 + 1.7 in the control group. The subjective esthetic score for patients in the ADM group was higher than that for patients in the control group (P =0.040). CONCLUSION: The present clinical study suggests that ADM grafts are effective in preventing FS and improving esthetic scores after parotidectomy.

Changing trends of deep neck infections in southern China: A review of 127 cases.

This study aimed to review our experience with the clinical characteristics and management of deep neck infections (DNIs) and determine the changing trends of their characteristics over time in southern China. Patients diagnosed with a DNI between January 2009 and December 2018 were screened retrospectively for their demographic characteristics, etiology of infection, site of infection, microbiology, treatment, and complications. In total, 127 patients were included: 41 (32.3%) were treated between 2009 and 2013 (group A), and 86 (67.7%) were treated between 2014 and 2018 (group B). The most common site of infection in group A was the parapharyngeal space (15 patients, 36.6%), while that in group B involved multiple spaces (36 patients, 41.9%). The leucocyte count (×109 cells/L) was 13.23 ± 4.19 in group A and 16.04 ± 4.33 in group B (p < 0.001). Streptococcus viridans was the most common bacteria in both groups. The mean hospital stay was 21.46 ± 33.09 days in group A and 10.44 ± 6.19 days in group B. The rate of diabetes mellitus (DM) in group A was lower than that in group B (8/41 and 33/86, respectively; p = 0.034). Airway obstruction was the most common complication in both groups. DNIs are more likely to show multi-space involvement, affect more DM patients, and be associated with higher leucocyte counts over time. We infer that the duration from morbidity to admission and that from admission to operation play roles in the successful management of DNIs, possibly causing fewer complications, lower mortality rates, and shorter hospital stays. DM patients require increased attention.

[Diagnosis and treatment of 12 patients with deep neck infection and inferior mediastinal infection].

Objective:To summarize the clinical manifestations and treatment of patients with deep neck infection with descending mediastinal infection. Methods:The clinical data of 12 patients with deep neck infection with descending mediastinal infection were reviewed. The clinical manifestations, infection origin, bacterial culture results, related systemic diseases, surgical drainage methods and treatment results were analyzed. Results:The typical clinical features of descending mediastinal infection were chest pain and subcutaneous crackling, diagnosis can confirmed by CT scan detected gas and abscess in the neck and mediastinal space. The main origin of infection was pharyngeal infection, followed by odontogenic infection. Systemic diseases were mainly diabetes mellitus. The positive rate of purulent secretion culture was 58.3%（7/12）, streptococcus account for the highest proportion. Surgical treatment included 9 patients undergoing neck surgery alone and 3 patients undergoing combined neck and chest surgery. Chest drainage was performed by thoracic surgery through mediastinoscopy or thoracoscopic surgery or B-ultrasound guided puncture, and no patient underwent open surgery. Ten patients were cured and two died, with a mortality rate of 16.7%. Conclusion:The deep neck infection with descending mediastinal infection has no specificity in the early stage. Timely abscess drainage, effective airway protection, antimicrobial therapy, and management of potentially life-threatening complications such as sepsis, mediastinitis, and pneumonia are the key to successful treatment.

Exosomal Delivery of AntagomiRs Targeting Viral and Cellular MicroRNAs Synergistically Inhibits Cancer Angiogenesis.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated cancer characterized by a high degree of recurrence, angiogenesis, and metastasis. The importance of alternative pro-angiogenesis pathways including viral factors has emerged after decades of directly targeting various signaling components. Using NPC as a model, we identified an essential oncogenic pathway underlying angiogenesis regulation that involves the inhibition of a tumor suppressor, Spry3, and its downstream targets by EBV-miR-BART10-5p (BART10-5p) and hsa-miR-18a (miR-18a). Overexpression of EBV-miR-BART10-5p and hsa-miR-18a strongly promotes angiogenesis in vitro and in vivo by regulating the expression of VEGF and HIF1-α in a Spry3-dependent manner. In vitro or in vivo treatment with iRGD-tagged exosomes containing antagomiR-BART10-5p and antagomiR-18a preferentially suppressed the angiogenesis and growth of NPC. Our findings first highlight the role of EBV-miR-BART10-5p and oncogenic hsa-miR-18a in NPC angiogenesis and also shed new insights into the clinical intervention and therapeutic strategies for nasopharyngeal carcinoma and other virus-associated tumors.

Comparison of Ultrasonography and CT for Determining the Preoperative Benign or Malignant Nature of Thyroid Nodules: Diagnostic Performance According to Calcification.

BACKGROUND: The present study was designed to investigate the presence or absence of calcification and whether calcification size affect the diagnostic accuracy of ultrasonography (US) and computed tomography (CT) in predicting the benign or malignant nature of thyroid nodules. MATERIAL AND METHODS: From May 2014 to April 2019, 445 patients underwent thyroid US and neck CT before thyroid surgery. In each case, US and CT were retrospectively examined by radiologists. We divided the patients into 3 groups according to the type of calcification: no calcification, microcalcification, and macrocalcification. And macrocalcification group divided into rim calcifications and non-rim calcifications groups. We evaluated the diagnostic accuracy of US and CT for differentiating malignant from benign thyroid nodules using histopathological results as a reference standard. RESULTS: In the overall population, adding CT to US resulted in greater sensitivity, lower specificity, and lower accuracy in the prediction of the benign or malignant nature of nodules. In the group with no calcification, US had a significantly greater accuracy than CT and combined US/CT. In the group with macrocalcification, especially in rim calcifications, adding CT to US resulted in greater sensitivity than US, and CT exhibited greater sensitivity and accuracy than US. CONCLUSION: US is superior to CT for the prediction of the benign or malignant nature of nodules in thyroid lesions according to calcification and CT is also currently not recommended as a routine imaging tool for thyroid nodules. However, the superior sensitivity and accuracy of CT in lesions with macrocalcification especially in rim calcifications may enable CT to play a complementary role in identifying benign and malignant nodules.

The role of DNMT1/hsa-miR-124-3p/BCAT1 pathway in regulating growth and invasion of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer with high aggressiveness and poor prognosis. There is an urgent need for understanding the molecular mechanism underlying the development and progression of ESCC. METHODS: ESCC tissues and corresponding non-neoplastic tissues were collected. The expression and function of miR-124-3p and BCAT1 in two cell lines KYSE-150 and Eca109 were determined. RESULTS: We show downregulation of miR-124-3p expression in ESCC tissues, which is highly correlated with proliferation and migration of ESCC cell lines KYSE-150 and Eca109. miR-124-3p show high correlation with TNM stage and differentiation grade. Furthermore, miR-124-3p directly targets mRNA 3'UTR region of BCAT1, which results in upregulation of BCAT1 expression as observed in ESCC tissues and cell lines. Also, our data indicates that BCAT1 high expression is strongly linked to the disease-free survival, tumor size, pathologic stage, T classification and differentiation grade. On the other hand, we clarified the upstream mechanism regulating miR-124-3p expression in ESCC, which involves in the hypermethylation-silencing regulation mediated by DNA methyltransferase 1(DNMT1), which is of high expression in ESCC tissues and cell lines in the present study. In addition, DNMT1 knockdown or inhibition of DNMT1 function contributes to downregulation of miR-124-3p and BCAT1 expression. CONCLUSIONS: Our study thus clarifies a new mechanism that DNMT1/miR-124/BCAT1 axis regulates the development and progression of ESCC.

MiRNA-mRNA crosstalk in laryngeal squamous cell carcinoma based on the TCGA database.

BACKGROUND: The functional characterization of non-coding microRNAs (miRNAs) has been shown to be associated with the pathophysiology of the disease, but it is still a challenging task to elucidate the pathogenesis of microRNAs and disease. In addition, the understanding of the role of miRNAs in the development of LSCC still needs further exploration. MATERIALS AND METHODS: In this study, to identify miRNAs that play a key role in LSCC, we analyzed miRNA and mRNA sequence data from 162 LSCC samples from the TCGA database, and screened specific miRNAs and mRNAs by differential gene expression analysis. And then, construct a differentially expressed miRNAs and mRNAs interaction network. RESULTS: In our investigation, 23 miRNAs (P < 0.01, log2FoldChange > 2) and 331 mRNAs (P < 0.01, log2FoldChange > 4) were identified differentially expressed in LSCC and reduced the number of loosely linked miRNAs and mRNAs according to appropriate thresholds. Finally, 13 miRNAs and 35 mRNAs were enriched in a network. CONCLUSIONS: Our study provides the most comprehensive information on the expression of miRNAs in LSCC and identifies the known oncogenic miRNAs (such as miR-163a), as well as aberrant expression of novel miRNAs involved in cell regulation and metabolic defects that occur during development of LSCC.

[Therapeutic effect of submental flap in repairing of approaching circumferential defects after hypopharyngeal cancer ablation with laryngeal function unpreserved].

OBJECTIVE: To study the effectiveness of repairing nearly circumferential defect with the submental flaps after resection of laryngeal function unpreserved hypopharyngeal cancer. METHOD: All the cases were treated with the submental flaps after resection of hypopharyngeal cancer with laryngeal function unpreserved. RESULT: All 13 flaps were alive. Hypopharyngeal fistula occurred in 2 cases. All patients had normal swallowing function. The patients were followed up 6-42 months. Of 13 cases,3 had recurrence at neck Lymph node, but no local hypopharyngeal recurrence was found. Seven cases were followed up more than 3 years, and only 3 of them survived. CONCLUSION: Submental flap is an ideal tissue flap submental flap in repairing of approaching circumferential defects after hypopharyngeal cancer ablation with laryngeal function unpreserved for the repairment of after approaching circumferential defects after hypopharyngeal cancer ablation with laryngeal function unpreserved, For it is close to the defect region, safe, easy-to-obtain and easy-to-survive.

[Clinical analysis of low grade myofibroblastic sarcoma in head and neck].

OBJECTIVE: To explore the clinical characteristic, the CT, MRI features, diagnosis and treatment of low grade myofibroblastic sarcoma in head and neck. METHOD: Six cases of low grade myofibroblastic sarcoma in head and neck were diagnosis and reviewed retrospectively. Routine preoperative CT and MRI examination were performed. RESULT: All cases were operated one case with radiotherapy before operation was given with a total dose of 60 Gy. The patients were follow-up for 6 months to 5 year and no recurrence was found. No complications occurred in 6 cases. CONCLUSION: It has been confirmed in this research that LGMS is a low-grade malignangt tumor. It was difficult to make early diagnosis through frozen section. The final diagnosis depend on paraffin section and immunohistochemisty. Extended local excision with tumor-free margin is the treatment of choice.

[Expression of SOX2 protein and its clinical significance in laryngeal carcinoma].

OBJECTIVE: To investigate the expression of SOX2 in laryngeal carcinoma and analyze the relation of SOX2 and clinical factors. METHOD: We measured the expression of SOX2 protein in 45 laryngeal carcinoma fresh samples and 45 paracarcinoma tissues (cutting margin > 0.5 cm) with flow cytometer (Epics-XL II), 20 normal laryngeal mucosa samples were also studied as controls. RESULT: The quantitative and qualitative expression of SOX2 protein in laryngeal carcinoma tissues was obviously higher than those in paracarcinoma and in normal laryngeal mucosa tissues respectively (P < 0 05). There was no significant difference between the expression of paracarcinoma and normal laryngeal mucosa tissues. In laryngeal carcinoma, the expression of SOX2 protein wasn't significantly related to patients' clinical classification, tumor size, smoking history, patients' age and sex but related to metastasis, pathological grade and clinical stage. CONCLUSION: The high expression of SOX2 may contribute to the carcinogenesis and development of laryngeal carcinoma. It is an important index of judging metastasis and staging and prognosis of laryngeal carcinoma to measure the expression of SOX2 protein.

Conduction and morphological changes in wrist nerves immediately after bilateral sanding exercises in hemiparetic subjects.

OBJECTIVE: To investigate the immediate effects of bilateral upper-extremity sanding exercises on conduction and morphologic characteristics of the median and ulnar nerves at the wrist in hemiparetic subjects and control subjects. DESIGN: Case control study using a pretest-post-test design. SETTING: Inpatient rehabilitation department affiliated with a teaching hospital. PATIENTS (OR PARTICIPANTS): Thirty hemiparetic subjects and 21 matched control subjects who met our inclusion criteria and had no history of diseases that may have predisposed them to peripheral neuropathies were recruited for this study. METHODS: Bilateral nerve conduction tests and ultrasonographic evaluations were performed on each subject before and immediately after a 30-minute bilateral sanding exercise with a frequency of 5 repetitions per minute. MAIN OUTCOME MEASUREMENTS: The effects of exercises on bilateral median and ulnar wrist nerves were assessed with the use of sensory and motor nerve conduction velocity tests and by width/thickness ratios in ultrasonographic evaluations. RESULTS: In the hemiparesis group, the pre-exercise amplitude of the motor component for the median and ulnar nerves were respectively lower than the corresponding values in the control group (P < .05), whereas the pre-exercise amplitude and velocity of the sensory component were lower than the corresponding values in the control group (P < .01). After the exercise, the assessments for the affected side showed reductions in the conduction velocity of the sensory component and an increase in the width/thickness ratio for the median nerve (P < .05). CONCLUSIONS: The median and ulnar nerves at the wrist in hemiparetic subjects before sanding exercises showed different conduction characteristics compared with control subjects. Their affected side also demonstrated significant conduction and morphologic changes after the exercises. These subclinical findings may be attributed to different mechanisms such as overuse, spasticity, and demyelinating changes. Prevention of these subclinical changes is recommended to enhance exercise safety in hemiparetic patients.