Effects of robot-assisted gait training on motor performance of lower limb in poststroke survivors: a systematic review with meta-analysis.

OBJECTIVE: This study aimed to investigate the effects of robot-assisted gait training (RAGT) on improving walking ability, and to determine the optimal dosage of task-specific training based on RAGT for stroke patients. MATERIALS AND METHODS: Two investigators independently searched electronic databases, including PubMed, Embase, Cochrane Library, and Physiotherapy Evidence Database (PEDro) from inception to 31 January 2020. The study design was a systematic review with meta-analysis of randomized controlled trials (RCTs), comparing the intervention of RAGT plus conventional therapy to conventional therapy alone. RCTs mainly focus on lower limb motor function as the primary outcomes, while the secondary outcomes involve gait speed, walking distance, cadence, balance, and activities of daily living (ADL). Pooled effect estimates were calculated by comparing the change from baseline to the end of the study in each group. RESULTS: Twenty-eight RCTs were included. The pooled analysis showed that RAGT had a significantly short-term effect on improving lower limb function [standardized mean difference (SMD) 0.32, 95% CI 0.10 to 0.55]. Additionally, there were significant improvements in gait speed (MD 0.10, 95% CI 0.06 to 0.14) and ADL (SMD 0.17, 95% CI 0.02 to 0.32). Subgroup analyses indicated that RAGT lasting for 30-60 minutes per day over 4 weeks yielded a moderate effect size (SMD 0.53, 95% CI 0.16 to 0.90). Additionally, RAGT significantly promoted lower limb function recovery in the early stage after a stroke (SMD 0.33, 95% CI 0.07 to 0.58) or in non-ambulatory patients (SMD 0.35, 95% CI 0.10 to 0.59). CONCLUSIONS: RAGT demonstrated significant positive effects on lower limb function post-stroke. Our results provide additional evidence to support that RAGT is a potentially appropriate intervention to promote lower limb recovery in individuals who have had a stroke.

Scrotal heat stress causes a transient alteration in tight junctions and induction of TGF-ß expression.

Specialized junctions, which occur at sites of Sertoli-Sertoli and Sertoli-germ cell contact of seminiferous epithelium, play pivotal roles in spermatogenesis. Slight increase in scrotal temperature can induce oligospermia or azoospermia via increasing germ cell apoptosis. In this study, we demonstrated that the expression of tight junction (TJ) components, such as occludin, claudin-3 and zonula occludens-1 (ZO-1), was reduced 24-48h after a single mild scrotal heat exposure (43°C for 30min), whereas mRNA levels of claudin-11 were increased. Moreover, the protein localization of occludin and ZO-1 was lost from the blood-testis barrier (BTB) site, whereas claudin-11 immunostaining became diffuse and cytoplasmic 2days following heat exposure. Electron microscopic analysis showed that 2days after the heat treatment, the intercellular space between the two adjacent Sertoli cells was expanded, coupled with defragmentation of actin bundles and the endoplasmic reticulum. In addition, the TJ permeability increased significantly 2days after the heat exposure and recovered approximately 10days later. Heat-induced reversible BTB disruption was associated with a transient induction of transforming growth factor (TGF)-ß2, -3 and p38 mitogen-activated protein kinase activation. However, the TGF-ß antagonist only partially prevented the heat-induced BTB disruption. In conclusion, the expression of TJ-associated molecules and BTB were reversibly perturbed after mild testicular hyperthermia, and the induction of TGF-ß expression may be partially involved in heat-induced BTB damage.

LncRNA DNAJC3-AS1 functions as oncogene in renal cell carcinoma via regulation of the miR-27a-3p/PRDM14 axis.

OBJECTIVE: Renal cell carcinoma (RCC) is one of the most common urological malignancies worldwide. Although great advances have been made in the diagnosis and management of RCC, its prognosis remains unsatisfactory. Long noncoding RNAs (lncRNAs) have been found to be essential factors in the initiation and development of cancer. The current study aimed to measure the expression and functions of lncRNA DNAJC3-AS1 in the progression of clear cell RCC (ccRCC). PATIENTS AND METHODS: The expression of lncRNA DNAJC3-AS1 was detected in 30 pairs of ccRCC tissues and in cell lines by RT-PCR, and its prognostic association with ccRCC was evaluated by the Kaplan-Meier method. The proliferation, migration, invasion and apoptosis of ccRCC cells were measured after silencing DNAJC3-AS1. The interaction between DNAJC3-AS1, miR-27a-3p and PRDM14 was identified by Dual-Luciferase reporter assay. The protein levels were measured by Western blotting. RESULTS: The expression of DNAJC3-AS1 was upregulated in ccRCC tissues and cell lines compared to their normal counterparts. In vitro, silencing DNAJC3-AS1 reduced the proliferation, migration and invasion of ccRCC cells. Downregulation of DNAJC3-AS1 also led to the apoptosis of ccRCC cells. Moreover, we also found that DNAJC3-AS1 acted as a sponge of miR-27a-3p and identified PRDM14 as a target of miR-27a-3p. CONCLUSIONS: LncRNA DNAJC3-AS1 acts as an oncogene and plays an essential role in the tumorigenesis of ccRCC, possibly via the regulation of the miR-27a-3p/PRDM14 axis.

Prognostic and predictive values of CXCL10 in colorectal cancer.

BACKGROUND: The role of CXCL10 in progression and prognosis of colorectal cancer (CRC) has been studied for years, yet results remain controversial. AIM: This study aims to explore the relationship between CXCL10 and CRC progression and prognosis. METHODS: We evaluated plasma CXCL10 in CRC patients using ELISA. We also performed a meta-analysis of the associations between CXCL10 and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), relapse-free survival (RFS), and clinicopathological features. Finally, correlations between CXCL10 and methylation or immune infiltration were performed using TCGA data. RESULTS: ELISA analysis showed that CXCL10 was associated with age, red blood cells, blood platelets, and blood urea nitrogen. A separate analysis of 3,763 patients from 24 studies revealed that there were significant associations between low CXCL10 expression and OS (HR 1.25, 95% CI 1.01-1.53), DFS (HR 1.65, 95% CI 1.17-2.34), and RFS (HR 1.43, 95% CI 1.20-1.71) in CRC. Additionally, downregulated CXCL10 expression was significantly correlated with age [odds ratio (OR) 1.31, 95% CI 1.13-1.52], metastasis (OR 1.34, 95% CI 1.11-1.63), recurrence (OR 1.46, 95% CI 1.16-1.83), tumor location (OR 1.88, 95% CI 1.58-2.24), differentiation (OR 0.57, 95% CI 0.35-0.93), microsatellite instability (OR 0.23, 95% CI 0.15-0.35), BRAF mutation (OR 1.62, 95% CI 1.25-2.08), p53 mutation (OR 0.28, 95% CI 0.16-0.47), and CIMP (OR 0.27, 95% CI 0.17-0.43). Furthermore, significant associations were observed between CXCL10 and methylation and immune infiltration. CONCLUSIONS: The study suggests that CXCL10 might be a potential target for the treatment of CRC. TRIAL REGISTRATION: NCT03189992. Registered 4 June 2017, https://www.clinicaltrials.gov/ct2/show/study/NCT03189992?term=NCT03189992&rank=1 .

IMP3 promotes TNBC stem cell property through miRNA-34a regulation.

OBJECTIVE: To explore the expression and function of insulin-like growth factor II (IGFII) mRNA binding protein (IMP3) in the Triple Negative Breast Cancer (TNBC). MATERIALS AND METHODS: According to previously reported gene expression array, we found that IMP3 had significantly higher expression in the CD44+CD24-ESA+ cell cluster, tumor initiating cell or cancer stem cell (CSCs), compared to other tumor cells. Based on the GEO database (GEO accession No. GSE6883), we detected the mRNA levels of IMP 1,2 and 3 by quantitative polymerase chain reaction (q-PCR) in CD44+CD24-ESA+ cell cluster and other breast tumor cell clusters. Besides, we measured IMP3 expression in microsphere of breast cancer, which exerted more significant tumor stem cell properties. The effects of IMP3 on breast cancer cell stem cell properties were studied by RNA interference and overexpression approaches in vitro. Furthermore, we predicted and identified microRNA, which could target and regulate IMP3 from bioinformatics analysis, and verified the interaction by luciferase assays and rescue experiments. RESULTS: Previously reported data showed that IMP3 expression was significantly upregulated in CD44+CD24-ESA+ cell cluster from breast cancer tissues. Besides, we found IMP3 had higher expression in mesenchymal cells rather than epithelial cells, which was also significantly elevated in SUM159 and T49D cell lines cultured as microsphere rather than adherent cells or differentiated cells. CD44+CD24-ESA+ cell cluster proportion was significantly decreased after silencing IMP3 in SUM1315, and its ability to develop into microsphere was significantly inhibited. By re-expressing IMP3 in SUM315, we restored the self-renewal capacity and tumorigenesis potential of SUM315. Through relative predicting website, we found several miRNAs which could regulate IMP3. miR-34a with highest score was chosen for further analysis. Mimicking miR-34a significantly downregulated IMP3 expression and inhibited its ability to develop into microsphere, while overexpressing IMP3 could rescue this process. CONCLUSIONS: IMP3 plays a vital role in maintaining stem cell properties of breast cancer cells, which could be regulated by mir-34a.

Magnetic resonance angiography manifestations and prognostic significance in HIV-negative tuberculosis meningitis.

OBJECTIVE: To evaluate the patterns, related factors and prognostic value of abnormal magnetic resonance angiography (MRA) in human immunodeficiency virus negative tuberculous meningitis. MATERIALS AND METHODS: We performed a prospective study in patients aged >14 years. Abnormality on MRA was correlated with clinical, laboratory and magnetic resonance imaging findings. Modified Barthel index was used to assess outcome at 6 months after inclusion. RESULTS: Of 101 patients included, MRA was abnormal in 45 (44.6%). The distribution of MRA abnormality was classified as disseminated irregular calibres of intracranial arteries with or without reduction in distant branches (29.7%, pattern 1) and localised stenosis at the base of the brain (26.7%, pattern 2). In logistic regression analysis, pattern 2 was related to stage of the disease (P = 0.002), basal exudates (P = 0.03) and infarction (P = 0.000), while pattern 1 was related to duration of disease (P = 0.050), hydrocephalus (P = 0.032) and age (P = 0.002). Pattern 1 was also correlated with infarction (P = 0.000), particularly infarction in the tubercular zone (P = 0.035) in univariate analysis. MRA abnormality was associated with paradoxical worsening (P = 0.022) and poor prognosis in univariate analysis (P = 0.035). CONCLUSION: MRA abnormality is associated with stroke and poor outcomes. Although it indicates mild vascular injury, pattern 1 MRA abnormality is nevertheless associated with infarction and needs proper intervention.

Distinct modifications of convergent excitatory and inhibitory inputs in developing olfactory circuits.

The interaction between excitatory and inhibitory inputs is critical to neuronal signal processing. However, little is known about this fundamental property, largely due to the inability to clearly isolate the respective inputs. Here we took advantage of the characteristic stereotypical architecture of synaptic connections in the main olfactory bulb, which enabled us to entirely separate excitatory and inhibitory inputs. Using paired stimulation of two glomeruli located apart at different intensities, we separately elicited excitatory and inhibitory inputs and mimicked stimulation of competing mitral cells (MCs) with different odorants. We performed dual whole-cell patch recording of evoked excitatory postsynaptic responses (EPSPs) and inhibitory postsynaptic responses (IPSPs) in current-clamp mode from two competitive MCs that are connected to the two stimulated glomeruli in slices of the main olfactory bulb in 2-3-week-old rats. We deliberately held the recorded cells at a relative hyperpolarized potential. This manipulation not only suppressed action potential generation but also excluded the possible contamination of inhibitory components in excitatory inputs. We found that in weakly activated MCs repetitive EPSP-IPSP interactions (5 Hz, 180 times) induced long-term potentiation (LTP) and long-term depression (LTD) in convergent excitatory and inhibitory inputs, respectively. Unexpectedly, these forms of plasticity depend on activity of somatic (mainly non-synaptic) NMDA receptors (NMDARs). In contrast, the same repetitive stimulation induced the LTP of excitatory inputs in strongly activated MCs (MC2) that require activity of synaptic NMDARs. These distinct forms of plasticity in the developing olfactory circuit may represent a novel rule of modification in convergent inputs that leads to decorrelation of inputs and facilitates odor discrimination.

Characterizing the membrane properties of capsules flowing in a square-section microfluidic channel: effects of the membrane constitutive law.

A microfluidic method is presented to measure the elastic membrane properties of a population of microcapsules with diameter of order 60 µm. The technique consists of flowing a suspension of capsules enclosed by a polymerized ovalbumin membrane through a square-section microfluidic channel with cross dimension comparable with the capsule mean diameter. The deformed profile and the velocity of a given capsule are recorded. A full mechanical model of the motion and deformation of an initially spherical capsule flowing inside a square-section channel is designed for different flow strengths, confinement ratios, and membrane constitutive laws. The experimental deformed profiles are analyzed with the numerical model. This allows us to find the ratio between the viscous and elastic forces and thus the shear elastic modulus of the membrane. We show that the ovalbumin membrane tends to have a strain-softening behavior under the conditions studied here.

Clinical efficacy and immunological impact of tacrolimus in Chinese patients with generalized myasthenia gravis.

In this multicenter, open-label pilot study, the efficacy, safety, and immunological impact of tacrolimus in Chinese patients with generalized myasthenia gravis are assessed. Forty-seven generalized myasthenia gravis (MG) patients were enrolled into this study and given 3mg/day tacrolimus for 24 weeks. The primary efficacy measurements used to monitor response to tacrolimus in MG patients were the Osserman grade, the quantitative MG score (QMGS) recommended by the MGFA, the MG-specific manual muscle testing (MMT) score, and the MG-related activities of daily living (MG-ADL) scale. Also, reduction in steroid doses was used to monitor the effect of tacrolimus. Clinical evaluations were conducted at weeks 4, 8, 12, 16, 20, and 24, while immunological parameters were measured at weeks 4, 12, and 24. Measurements of the Osserman grade, QMGS, MMT, and MG-ADL all suggested improvement in patient health by the fourth week of treatment. Steroid dosage was reduced during the course of the study in 74.2% of the forty-three patients who completed the study. There were thirty-one reported adverse events in the study. Only one was considered serious. We found that tacrolimus reduced levels of the IFN-γ, IL-2, IL-10, and IL-13 cytokines and induced the proliferation of tolerogenic plasmacytoid dendritic cells after treatment. Tacrolimus did not change the population of T cell subtypes but did steadily reduce the population of BAFF-R(+) CD19(+) B cells over the course of the study. Our results show that tacrolimus improves the clinical condition of MG patients and is well tolerated. The decrease in IL-13 and reduction of BAFF-R(+) CD19(+) B cells may be related to the therapeutic effect of tacrolimus.

Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit.

BACKGROUND AND PURPOSE: Alcohol produces its behavioural effects in part due to inhibition of N-methyl-d-aspartate (NMDA) receptors in the CNS. Previous studies have identified amino acid residues in membrane-associated domains 3 (M3) and 4 (M4) of the NMDA receptor that influence ethanol sensitivity. In addition, in other alcohol-sensitive ion channels, sedative-hypnotic agents have in some cases been shown to act at sites distinct from the sites of ethanol action. In this study, we compared the influence of mutations at these sites on sensitivity to ethanol and trichloroethanol, a sedative-hypnotic agent that is a structural analogue of ethanol. EXPERIMENTAL APPROACH: We constructed panels of mutants at ethanol-sensitive positions in the GluN2A (NR2A) NMDA receptor subunit and transiently expressed these mutants in human embryonic kidney 293 cells. We used whole-cell patch-clamp recording to assess the actions of ethanol and trichloroethanol in these mutant NMDA receptors. KEY RESULTS: Ethanol sensitivity of mutants at GluN2A(Ala825) was not correlated with any physicochemical measures tested. Trichloroethanol sensitivity was altered in two of three ethanol-insensitive mutant GluN2A subunits: GluN2A(Phe637Trp) in M3 and GluN2A(Ala825Trp) in M4, but not GluN2A(Met823Trp). Trichloroethanol sensitivity decreased with increasing molecular volume at Phe637 or increasing hydrophobicity at Ala825 and was correlated with ethanol sensitivity at both sites. CONCLUSIONS AND IMPLICATIONS: Evidence obtained to date is consistent with a role of GluN2A(Ala825) as a modulatory site for ethanol and trichloroethanol sensitivity, but not as a binding site. Trichloroethanol appears to inhibit the NMDA receptor in a manner similar, but not identical to, that of ethanol.