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Abstract Acute myocardial ischaemia and reperfusion (I–R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA) has previously been shown to be antiarrhythmic in fetal hearts. This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium, and compares the effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague–Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery (10 min), followed by reperfusion (2 min), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p = 0.028), with a reduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment (10 ± 3 vs 58 ± 15, p = 0.036). No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias. The antiarrhythmic effect of UDCA may be partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity slowing (p = 0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia (p = 0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.

Freezing of gait is a disabling symptom with a complex episodic nature that is frequently experienced by people with Parkinson's disease (PD). Although China has the largest population with PD in the world, no Chinese version of the freezing of gait questionnaire (FOGQ), the instrument that has been most widely used to assess FOG, has yet been developed. This study aimed to translate and adapt the original version of FOGQ to create a Chinese version, the FOGQ-CH, then assess its reliability, calculate the Minimal Detectable Change (MDC) and investigate its validity. The forward-backwards translation model was adopted, and cultural adaptation included expert review and pretesting. For the reliability study, 31 Chinese native speaking patients with PD were assessed two times in a 7–10 days interval. Internal consistency and test-retest reliability of the FOGQ-CH were measured by Cronbach's alpha (Cα) and the Intraclass Correlation Coefficient (ICC). For the validity study, 34 native speakers of Chinese with PD were included. To explore the convergent validity, relationships between the FOGQ-CH and the Unified Parkinson's Disease Rating Scale Part II (UPDRS II) and Part III (UPDRS III), Timed Up and Go Test (TUGT), Timed Up and Go Test in cognitive task (TUGT-Cog), walking speed (10 MWT speed), and step length (10 MWT step length) in a 10-m Walk Test were tested. To explore predictive validity, the number of falls followed up for 6 months were assessed. The area under the ROC curve (AUC) was employed to test the capacity of FOGQ-CH to discriminate those with falls. From the reliability study, Cα = 0.823, ICC = 0.786. The MDC0.90 = 4.538. From the validity study, the FOGQ-CH showed moderate correlations with UPDRS II (rho = 0.560, p = 0.001), UPDRS III (rho = 0.451, p = 0.007), TUGT (rho = 0.556, p = 0.007), TUGT-Cog (rho = 0.557, p = 0.001), 10MWT-speed (rho = −0.478, p = 0.004), 10MWT-step length (rho = −0.419, p = 0.014), and the number of falls followed up for 6 months (rho = 0.356, p = 0.045). The AUC = 0.777 (p = 0.036) for predicting whether the participants will have multiple falls (two or more) in the following 6 months. The FOGQ-CH showed good reliability and validity for assessing Chinese native speaking patients with PD. In addition, the FOGQ-CH showed good efficacy for predicting multiple falls in the following 6 months.

Abstract Cu1.8S has been considered as a potential thermoelectric (TE) material for its stable electrical and thermal properties, environmental benignity, and low cost. Herein, the TE properties of nanostructured Cu1.8S1−x Te x (0 ⩽ x ⩽ 0.2) bulks fabricated by a facile process combining mechanical alloying (MA) and room-temperature high-pressure sintering (RT-HPS) technique were optimized via eliminating the volatilization of S element and suppressing grain growth. Experimentally, a single phase of Cu1.8S was obtained at x = 0, and a second Cu1.96S phase formed in all Cu1.8S1−x Te x samples when 0.05 ⩽ x ⩽ 0.125. With further increasing x to 0.15 ⩽ x ⩽ 0.2, the Cu2−z Te phase was detected and the samples consisted of Cu1.8S, Cu1.96S, and Cu2−z Te phases. Benefiting from a modified band structure and the coexisted phases of Cu1.96S and Cu2−z Te, the power factor is enhanced in all Cu1.8S1−x Te x (0.05 ⩽ x ⩽ 0.2) alloys. Combining with a drastic decrease in the thermal conductivity due to the strengthened phonon scatterings from multiscale defects introduced by Te doping and nano-grain boundaries, a maximum figure of merit (ZT) of 0.352 is reached at 623 K for Cu1.8S0.875Te0.125, which is 171% higher than that of Cu1.8S (0.130). The study demonstrates that doping Te is an effective strategy to improve the TE performance of Cu1.8S based materials and the proposed facile method combing MA and RT-HPS is a potential way to fabricate nanostructured bulks.

The adrenergic system contributes to the stress‐induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE‐induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE‐induced phosphorylation of cAMP response element‐binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human colon cancer cells. The downstream effector of NE, CREB1, bound to the promoter of miR‐373 and transcriptionally activated its expression. miR‐373 expression was shown to be necessary for NE‐induced cell proliferation, invasion, and tumor growth. We confirmed that proliferation and invasion of colon cancer cells are regulated in vitro and in vivo by miR‐373 through targeting of the tumor suppressors TIMP2 and APC. Our data suggest that NE promotes colon cancer cell proliferation and metastasis by activating the CREB1–miR‐373 axis. The study of this novel signaling axis may provide mechanistic insights into the neural regulation of colon cancer and help in the design of future clinical studies on stress biology in colorectal cancer.

Background: Ankle complex proprioceptive ability, needed in active human movement, may change from childhood to elderly adulthood; however, its development across all life stages has remained unexamined. The aim of the present study was to investigate the across-the-lifespan trend for proprioceptive ability of the ankle complex during active ankle inversion movement. Methods: The right ankles of 118 healthy right-handed participants in 6 groups were assessed: children (6–8 years old), adolescents (13–15 years old), young adults (18–25 years old), middle-aged adults (35–50 years old), old adults (60–74 years old), and very old adults (75–90 years old). While the participants were standing, their ankle complex proprioception was measured using the Active Movement Extent Discrimination Apparatus. Results: There was no significant interaction between the effects of age group and gender on ankle proprioceptive acuity (F (5, 106) = 0.593, p = 0.705, η2p = 0.027). Simple main effects analysis showed that there was a significant main effect for age group (F (5, 106) = 22.521, p < 0.001, η2p = 0.515) but no significant main effect for gender (F (1,106) = 2.283, p = 0.134, η2p = 0.021) between the female (0.723 ± 0.092, mean ± SD) and the male (0.712 ± 0.083) participants. The age-group factor was associated with a significant linear downward trend in scores (F (1, 106) = 10.584, p = 0.002, η2p = 0.091) and a strong quadratic trend component (F (1,106) = 100.701, p < 0.001, η2p = 0.480), producing an asymmetric inverted-U function. Conclusion: The test method of the Active Movement Extent Discrimination Apparatus is sensitive to age differences in ankle complex proprioception. For proprioception of the ankle complex, young adults had significantly better scores than children, adolescents, old adults, and very old adults. The middle-aged group had levels of ankle proprioceptive acuity similar to those of the young adults. The scores for males and females were not significantly different. Examination of the range of the scores in each age group highlights the possible level that ankle complex movement proprioceptive rehabilitation can reach, especially for those 75–90 years of age. Keywords: Aging, Ankle complex, Development, Motor control, Proprioception

This study aimed to estimate the incidence of central nervous system (CNS) metastases in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) treated with trastuzumab. Studies were identified through a literature search of electronic databases. Random-effects meta-analyses were performed to estimate the incidence rate of CNS metastases, trastuzumab therapy duration, and time from trastuzumab therapy to CNS metastasis diagnosis. A meta-analysis of odds ratios was performed to evaluate the significance of a difference in CNS metastasis incidence between patients with and without trastuzumab treatment. Thirty studies (8121 trastuzumab-treated and 3972 control patients) were included. The follow-up duration was 18.9 months (95% confidence interval [CI]: 13.8, 24.1). The trastuzumab treatment duration was 9.0 months (95% CI: 7.0, 11.0). The median interval between the start of trastuzumab therapy and CNS metastasis diagnosis was 12.2 months (95% CI: 9.5, 14.7). The incidence of CNS metastasis after the start of trastuzumab therapy was 22% (95% CI: 16, 27). The incidence of CNS metastases was significantly higher in trastuzumab-treated than in non-trastuzumab-treated patients (odds ratio: 1.39 [95% CI: 1.06, 1.82], p=0.02). The survival time from the start of the study was 23.4 months (95% CI: 19.7, 27.1) in trastuzumab-treated patients and 18.4 months (95% CI: 12.7, 24.1) in patients treated with control regimens. The survival time after the development of CNS metastases in trastuzumab-treated patients was 19.2 months (95% CI: 15.6, 25.9). Approximately 22% of patients with HER2-positive MBC who were treated with trastuzumab developed CNS metastases. However, trastuzumab-treated patients had a longer survival than patients who were not treated with trastuzumab.

Previous studies have demonstrated that Yueju-Ganmaidazao (YG) decoction induces rapid antidepressant-like effects, and the antidepressant response is mostly dependent on the suppression of nitric oxide-cyclic guanosine monophosphate signaling in male mice. This study aimed to investigate the sex difference mediated by calcium/calmodulin-dependent protein kinase II (CaMKII)-neuronal nitric oxide synthase (nNOS) signaling involved in the antidepressant-like effect of YG in mice. We found that the immobility times in the tail suspension test (TST) were found to be decreased after the single injection of YG in male and female mice with the same dosage. Additionally, chronic administration for 4 days of subthreshold dosage of YG and escitalopram (ES) also significantly decreased the immobility time in mice of both sexes. Chronic subthreshold dosage of YG and ES in LPS-treated mice and in chronic unpredictable stress (CUS) mice both decreased the immobility time, which was increased by stress. Meanwhile, in CUS-treated mice, sucrose preference test, forced swimming test, and open field test were applied to further confirm the antidepressant-like effects of YG and ES. Moreover, CUS significantly decreased the expression of nNOS and CaMKII, and both YG and ES could enhance the expression in the hippocampus of female mice, which was opposite to that in male mice, while endothelial nitric oxide synthase expression was not affected by stress or drug treatment neither in male mice nor in female mice. Finally, subthreshold dosage of YG combined with 7-nitroindazole (nNOS inhibitor) induced the antidepressant-like effects both in female and in male mice, while the single use of YG or 7-NI did not display any effect. However, pretreatment with KN-93 (CaMKII inhibitor) only blocked the antidepressant-like effect of high-dosage YG in female mice. Meanwhile, in CUS mice, chronic stress caused NR1 overexpression and inhibited cAMP response element binding protein action, which were both reversed by YG and ES in male and female mice, implying that YG and ES produced the same antidepressant-like effect in mice of both sexes. The study revealed that chronic treatment with a subthreshold dose of YG also produced antidepressant-like effects in female mice, and these effects depended on the regulation of the CaMKII-nNOS signaling pathway.

Eltrombopag is an orally administered, non-peptide, thrombopoietin receptor agonist which initiates thrombopoietin signaling and stimulates the production of normally functioning platelet. We aimed to do a systematic review and meta-analysis of currently available published data to verify whether eltrombopag treatment in patients with chronic immune-mediated thrombocytopenia can prolong survival. We searched for published, randomized, controlled trials in PubMed, Cochrane and Scopus databases using the following search strategy (“Eltrombopag” OR “Benzoates” OR “Hydrazines”) AND (“Idiopathic Thrombocytopenic Purpura” OR “immune thrombocytopenia” OR “Idiopathic Thrombocytopenic Purpuras” OR “Immune Thrombocytopenia” OR “Autoimmune Thrombocytopenia” OR “Werlhof”). The pooled relative risk (RR) showed that eltrombopag group has significantly higher overall platelet response than placebo group (MD = 3.42, 95% CI [2.51, 4.65], P > .0001); pooled results were homogenous ( P = .27, I 2 = 22%). The pooled relative risk showed that eltrombopag group has lower incidence of any bleeding than placebo group (MD = 0.65, 95% CI [0.48, 0.87], P = .003); pooled results were heterogenous ( P = .001, I 2 = 75%) and the detected heterogeneity was best resolved after excluding Bussel et al ( P = .10). Homogeneous results were still favored eltrombopag group (MD = 0.75, 95% CI [0.60, 0.93], P = .008).

Sepsis is a heterogeneous syndrome caused by a dysregulated host response during the process of infection. Neutrophils are involved in the development of sepsis due to their essential role in host defense. COVID-19 is a viral sepsis. Disfunction of neutrophils in sepsis has been described in previous studies, however, little is known about the role of microRNA-let-7b (miR-let-7b), toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) activity in neutrophils and how they participate in the development of sepsis. In this study, we investigated the regulatory pathway of miR-let-7b/TLR4/NF-κB in neutrophils. We also explored the downstream cytokines released by neutrophils following miR-let-7b treatment and its therapeutic effects in cecal ligation and puncture (CLP)-induced septic mice. Six-to-eight-week-old male C57BL/6 mice underwent CLP following treatment with miR-let-7b agomir. Survival (n=10), changes in liver and lungs histopathology (n=4), circulating neutrophil counts (n=4), the liver-body weight ratio (n=4–7), and the lung wet-to-dry ratio (n=5–6) were recorded. We found that overexpression of miR-let-7b could significantly down-regulate the expression of human-derived neutrophilic TLR4 at a post-transcriptional level, a decreased level of proinflammatory factors including interleukin-6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), and an upregulation of anti-inflammatory factor IL-10 in vitro. After miR-let-7b agomir treatment in vivo, neutrophil recruitment was inhibited and thus the injuries of liver and lungs in CLP-induced septic mice were alleviated (p=0.01 and p=0.04, respectively), less weight loss was reduced, and survival in septic mice was also significantly improved (p=0.013). Our study suggested that miR-let-7b could be a potential target of sepsis.

Introduction: Low back pain (LBP) is associated with altered somatosensory perception, which is involved in both involuntary and voluntary control of posture. Currently, there is a lack of methods and tools for assessing somatosensory acuity in patients with LBP. The purpose of this study was (1) to assess the reliability of the sway discrimination apparatus (SwayDA) (2) to evaluate the differences in somatosensory acuity between patients with LBP and pain-free individuals, and (3) to examine relationships between somatosensory acuity, severity of LBP, and mobility in patients with LBP. Methods: Twenty participants (10 patients with LBP and 10 matched asymptomatic controls) were recruited in a test–retest reliability test. Another 56 participants were recruited for this study with 28 individuals presenting with LBP and a further twenty-eight being asymptomatic. The SwayDA was custom-built to measure somatosensory perception during voluntary anterior–posterior (SwayDA-AP), medial-lateral to the dominant side (SwayDA-ML-D), and non-dominant side (SwayDA-ML-ND) postural sway control. Participants also completed mobility tests, including 10 times and 1-min sit-to-stand tests (10-STS, 1 m-STS). The area under the receiver operating characteristic curve (AUC) was calculated to quantify somatosensory acuity in discriminating different voluntary postural sway extents. Results: The ICC (2.1) for the SwayDA-AP, SwayDA-ML-D, and SwayDA-ML-ND were 0.741, 0.717, and 0.805 with MDC95 0.071, 0.043, and 0.050. Patients with LBP demonstrated significantly lower SwayDA scores (tSwayDA-AP = −2.142, p = 0.037; tSwayDA-ML-D = -2.266, p = 0.027) than asymptomatic controls. The AUC values of the SwayDA-AP test were significantly correlated with ODI (rSwayDA-AP-ODI = −0.391, p = 0.039). Performances on the 1 m-STS and the 10-STS were significantly correlated with the AUC scores from all the SwayDA tests (−0.513 ≤ r ≤ 0.441, all p < 0.05). Discussion: The SwayDA tests evaluated showed acceptable reliability in assessing somatosensory acuity during voluntary postural sway. Somatosensory acuity was diminished in patients with LBP compared to asymptomatic controls. In patients with LBP, lower somatosensory acuity was associated with increased LBP-related disability. Future research could focus on investigating the factors contributing to the decreased somatosensory perception and mobility in individuals with LBP. [ABSTRACT FROM AUTHOR]