Exoskeleton rehabilitation robot training for balance and lower limb function in sub-acute stroke patients: a pilot, randomized controlled trial.

PURPOSE: This pilot study aimed to investigate the effects of REX exoskeleton rehabilitation robot training on the balance and lower limb function in patients with sub-acute stroke. METHODS: This was a pilot, single-blind, randomized controlled trial. Twenty-four patients with sub-acute stroke (with the course of disease ranging from 3 weeks to 3 months) were randomized into two groups, including a robot group and a control group. Patients in control group received upright bed rehabilitation (n = 12) and those in robot group received exoskeleton rehabilitation robot training (n = 12). The frequency of training in both groups was once a day (60 min each) for 5 days a week for a total of 4 weeks. Besides, the two groups were evaluated before, 2 weeks after and 4 weeks after the intervention, respectively. The primary assessment index was the Berg Balance Scale (BBS), whereas the secondary assessment indexes included the Fugl-Meyer Lower Extremity Motor Function Scale (FMA-LE), the Posture Assessment Scale for Stroke Patients (PASS), the Activities of Daily Living Scale (Modified Barthel Index, MBI), the Tecnobody Balance Tester, and lower extremity muscle surface electromyography (sEMG). RESULTS: The robot group showed significant improvements (P < 0.05) in the primary efficacy index BBS, as well as the secondary efficacy indexes PASS, FMA-LE, MBI, Tecnobody Balance Tester, and sEMG of the lower limb muscles. Besides, there were a significant differences in BBS, PASS, static eye-opening area or dynamic stability limit evaluation indexes between the robotic and control groups (P < 0.05). CONCLUSIONS: This is the first study to investigate the effectiveness of the REX exoskeleton rehabilitation robot in the rehabilitation of patients with stroke. According to our results, the REX exoskeleton rehabilitation robot demonstrated superior potential efficacy in promoting the early recovery of balance and motor functions in patients with sub-acute stroke. Future large-scale randomized controlled studies and follow-up assessments are needed to validate the current findings. CLINICAL TRIALS REGISTRATION: URL: https://www.chictr.org.cn/index.html.Unique identifier: ChiCTR2300068398.

ß-hydroxybutyrate alleviates neurological deficits by restoring glymphatic and inflammation after subarachnoid hemorrhage in mice.

BACKGROUND: Both glymphatic system dysfunction and inflammatory response aggravate neurological dysfunction after subarachnoid hemorrhage (SAH). Studies have shown that ß-hydroxybutyrate (BHB) may mitigate painful diabetic neuropathy (PDN) by upregulating SNTA1 expression and reinstating AQP4 polarity. However, the potential of BHB to ameliorate glymphatic system function and inflammatory response in SAH mice remains uncertain. METHODS: The SAH models were constructed by injection of arterial blood into cisterna Magana. Three groups of C57 mice were randomly assigned: Sham, SAH, and BHB. All mice were subjected to neurological function assessment, western blot, immunofluorescence double staining, and RNA-seq. Glymphatic system function was examined with tracer and immunofluorescence double staining, and the differential genes were examined with RNA-seq. In addition, the expression of related inflammation was detected. RESULTS: Compared with the SAH group, BHB reinstated AQP4 polarization by upregulating SNTA1 protein to enhance the glymphatic system. According to RNA-seq, the different genes were primarily connected to microglia activation, astrocytes, and inflammation. Western blot and immunofluorescence further confirmed that the related inflammatory protein expression levels were upregulated. BHB attenuated neuroinflammation after SAH. Ultimately, it can mitigate the neurological deficits in SAH mice. CONCLUSION: The study reveals a novel mechanism that BHB treatment mitigates neurologic impairment in SAH mice. We propose that BHB may play a neuroprotective effect by enhancing glymphatic system function and attenuating neuroinflammatory subarachnoid hemorrhage.

The Role of Continuous Theta Burst Stimulation on Primary Motor Cortex in Improving Bladder Function in Post-stroke Patients: A Case Report.

Neurogenic bladder (NB) is a frequently encountered post-stroke complication, characterized by symptoms, such as urinary incontinence, dysuria, increased frequency, and urgency. Here, we present a case of a 75-year-old male with urgent urination, frequent urination, urinary incontinence, conspicuous discomfort during urination, and an unpleasant smell in the urine following a stroke. By reviewing the patient's previous medical records of stroke and ruling out other potential causes for bladder dysfunction, a diagnosis of NB could be established. We implemented conventional physical therapy, pelvic floor muscle training with the electromyography biofeedback device, and continuous theta burst stimulation (cTBS) on the contralesional primary motor cortex area to manage bladder function. To the best of our knowledge, this is the first case report on cTBS applied to manage NB after stroke. Our treatment has demonstrated remarkable efficacy in enhancing bladder and kidney function, improving the overall quality of life, and alleviating anxiety and depression symptoms in this patient. This case study concludes that the noninvasive neuromodulation approach exhibits significant potential in the clinical field when addressing this specific patient population.

High-resolution magnetic resonance vessel wall imaging provides new insights into Moyamoya disease.

Moyamoya disease (MMD) is a rare condition that affects the blood vessels of the central nervous system. This cerebrovascular disease is characterized by progressive narrowing and blockage of the internal carotid, middle cerebral, and anterior cerebral arteries, which results in the formation of a compensatory fragile vascular network. Currently, digital subtraction angiography (DSA) is considered the gold standard in diagnosing MMD. However, this diagnostic technique is invasive and may not be suitable for all patients. Hence, non-invasive imaging methods such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are often used. However, these methods may have less reliable diagnostic results. Therefore, High-Resolution Magnetic Resonance Vessel Wall Imaging (HR-VWI) has emerged as the most accurate method for observing and analyzing arterial wall structure. It enhances the resolution of arterial walls and enables quantitative and qualitative analysis of plaque, facilitating the identification of atherosclerotic lesions, vascular entrapment, myofibrillar dysplasia, moyamoya vasculopathy, and other related conditions. Consequently, HR-VWI provides a new and more reliable evaluation criterion for diagnosing vascular lesions in patients with Moyamoya disease.

Effects of Priming Intermittent Theta Burst Stimulation With High-Definition tDCS on Upper Limb Function in Hemiparetic Patients With Stroke: A Randomized Controlled Study.

BACKGROUND: Preconditioning with cathodal high-definition transcranial direct current stimulation (HD-tDCS) can potentiate cortical plasticity induced by intermittent theta burst stimulation (iTBS) and enhance the after-effects of iTBS in healthy people. However, it is unclear whether this multi-modal protocol can enhance upper limb function in patients with stroke. OBJECTIVE: The aim of this study was to investigate whether priming iTBS with cathodal HD-tDCS over the ipsilesional M1 can augment upper limb motor recovery in poststroke patients. METHODS: A total of 66 patients with subacute stroke were randomly allocated into 3 groups. Group 1 received priming iTBS with HD-tDCS (referred to as the tDCS + iTBS group), Group 2 received non-priming iTBS (the iTBS group), and Group 3 received sham stimulation applied to the ipsilesional M1. One session was performed per day, 5 days per week, for 3 consecutive weeks. In Group 1, iTBS was preceded by a 20-minute session of cathodal HD-tDCS at a 10-minute interval. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score. Moreover, the secondary outcome measures for muscle strength and spasticity were the Motricity Index-Upper Extremity (MI-UE) and the Modified Ashworth Scale Upper-Extremity (MAS-UE), respectively, and the Hong Kong Version of the Functional Test for the Hemiplegic Upper Extremity (FTHUE-HK) and the Modified Barthel Index (MBI) for activity and participation. RESULTS: Significant differences were detected in the changes in FMA-UE, MI-UE, and MBI scores between the 3 groups from baseline to post-intervention (χ2FMA-UE = 10.856, P = .004; χ2MI-UE = 6.783, P = .034; χ2MBI = 9.608, P = .008). Post hoc comparisons revealed that the priming iTBS group demonstrated substantial improvements in FMA-UE (P = .004), MI-UE (P = .028), and MBI (P = 0.006) compared with those in the sham group. However, no significant difference was observed between the iTBS group and the sham group. Moreover, no significant differences were found in the changes in MAS-UE or FTHUE-HK between the groups. CONCLUSIONS: Priming iTBS with HD-tDCS over the ipsilesional M1 cortex had beneficial effects on augmenting upper limb motor recovery and enhancing daily participation among subacute stroke patients.

TGN-020 Alleviate Inflammation and Apoptosis After Cerebral Ischemia-Reperfusion Injury in Mice Through Glymphatic and ERK1/2 Signaling Pathway.

Post-stroke acute inhibition of aquaporin 4 (AQP4) is known to exacerbate inflammation and apoptosis, yet the underlying mechanisms are not fully understood. The objective of this study was to investigate the specific mechanism of inflammation and apoptosis following cerebral ischemia-reperfusion (I/R) injury using the AQP4-specific inhibitor, N-(1,3,4-thiadiazol-2-yl) pyridine-3-carboxamide dihydrochloride (TGN-020). Ischemic stroke was induced in mice using the middle cerebral artery occlusion (MCAO) model. The C57/BL6 mice were randomly divided into three groups as follows: sham operation, I/R 48 h, and TGN-020 + I/R 48 h treatment. All mice were subjected to a series of procedures. These procedures encompassed 2,3,5-triphenyltetrazolium chloride (TTC) staining, neurological scoring, fluorescence tracing, western blotting, immunofluorescence staining, and RNA sequencing (RNA-seq). The glymphatic function in the cortex surrounding cerebral infarction was determined using tracer, glial fibrillary acid protein (GFAP), AQP4 co-staining, and beta-amyloid precursor protein (APP) staining; differential genes were detected using RNA-seq. The influence of TGN-020 on the extracellular signal-regulated kinase 1/2 (ERK) 1/2 pathway was confirmed using the ERK1/2 pathway agonists Ro 67-7467. Additionally, we examined the expression of inflammation associated with microglia and astrocytes after TGN-020 and Ro 67-7467 treatment. Compared with I/R group, TGN-020 alleviated glymphatic dysfunction by inhibiting astrocyte proliferation and reducing tracer accumulation in the peri-infarct area. RNA-seq showed that the differentially expressed genes were mainly involved in the activation of astrocytes and microglia and in the ERK1/2 pathway. Western blot and immunofluorescence further verified the expression of associated inflammation. The inflammation and cell apoptosis induced by I/R are mitigated by TGN-020. This mitigation occurs through the improvement of glymphatic function and the inhibition of the ERK1/2 pathway.

Limb Remote Ischemic Postconditioning Improves Glymphatic Dysfunction After Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: Delayed neuronal damage can be caused or aggravated after cerebral ischemia-reperfusion (I/R) injury. Recent studies have shown that glymphatic system dysfunction after cerebral ischemia-reperfusion injury is involved in ischemic brain edema and neuroinflammation, thereby regulating cerebral ischemia-reperfusion injury. The aim of this study is to investigate the changes of glymphatic system after cerebral ischemia-reperfusion injury and whether limb remote ischemic postconditioning (LRIP) can improve the function of glymphatic system to protect the brain. METHODS: To establish a focal brain I/R injury mouse model, this study utilized the middle cerebral artery occlusion/reperfusion (MCAO/R) method. The present study classified eight-week-old C57BL/6 male mice into three groups. The changes in glymphatic function in different periods of ischemia and reperfusion were analyzed through immunofluorescence, transmission electron microscopy (TEM), and Western-Blot (WB) assays. The contents of the evaluation included cerebrospinal fluid flow, swelling degree of brain tissue, aquaporin-4 (AQP4) expression and polarization, and amyloid-ß (Aß) excretion. RESULTS: In the early stages of cerebral ischemia, cerebrospinal fluid (CSF) flow is disturbed, accompanied by a decrease in AQP4 polarization. The polarity of AQP4 decreased from 12 h to 72 h of reperfusion, the Aß deposition. LRIP can increase the expression of ß-DG and AQP4 polarization, reduce the deposition of Aß, improve the function of the glymphatic system, and reduce the expression of AQP4 to play A protective role in brain. CONCLUSION: Glymphatic system impaired after cerebral ischemia-reperfusion injury in mice. LRIP may play a neuroprotective role by improving glymphatic function after I/R.

Reliability of TMS measurements using conventional hand-hold method with different numbers of stimuli for tibialis anterior muscle in healthy adults.

Objective: The objective of this study was to determine the reliability of corticomotor excitability measurements using the conventional hand-hold transcranial magnetic stimulation (TMS) method for the tibialis anterior (TA) muscle in healthy adults and the number of stimuli required for reliable assessment. Methods: Forty healthy adults participated in three repeated sessions of corticomotor excitability assessment in terms of resting motor threshold (rMT), slope of recruitment curve (RC), peak motor evoked potential amplitude (pMEP), and MEP latency using conventional TMS method. The first two sessions were conducted with a rest interval of 1 h, and the last session was conducted 7-10 days afterward. With the exception of rMT, the other three outcomes measure elicited with the block of first 3-10 stimuli were analyzed respectively. The within-day (session 1 vs. 2) and between-day (session 1 vs. 3) reliability for all four outcome measures were assessed using intraclass correlation coefficient (ICC), standard error of measurement, and minimum detectable difference at 95% confidence interval. Results: Good to excellent within-day and between-day reliability was found for TMS-induced outcome measures examined using 10 stimuli (ICC ≥ 0.823), except in pMEP, which showed between-day reliability at moderate level (ICC = 0.730). The number of three stimuli was adequate to achieve minimum acceptable within-day reliability for all TMS-induced parameters and between-day reliability for MEP latency. With regard to between-day reliability of RC slope and pMEP, at least seven and nine stimuli were recommended respectively. Conclusion: Our findings indicated the high reliability of corticomotor excitability measurement by TMS with adequate number of stimuli for the TA muscle in healthy adults. This result should be interpreted with caveats for the specific methodological choices, equipment setting, and the characteristics of the sample in the current study. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR2100045141.

Small GTPase FoSec4-Mediated Protein Secretion Is Important for Polarized Growth, Reproduction and Pathogenicity in the Banana Fusarium Wilt Fungus Fusarium odoratissimum.

Apical secretion at hyphal tips is important for the growth and development of filamentous fungi. In this study, we analyzed the role of the Rab GTPases FoSec4 involved in the secretion of the banana wilt fungal pathogen Fusarium odoratissimum. We found that the deletion of FoSEC4 affects the activity of extracellular hydrolases and protein secretion, indicating that FoSec4 plays an important role in the regulation of protein secretion in F. odoratissimum. As a typical Rab GTPase, Sec4 participates in the Rab cycle through the conversion between the active GTP-bound state and the inactive GDP-bound state, which is regulated by guanine nucleate exchange factors (GEFs) and GTPase-activating proteins (GAPs). We further found that FoSec2 can interact with dominant-negative FoSec4 (GDP-bound and nucleotide-free form, FoSec4DN), and that FoGyp5 can interact with dominant active FoSec4 (GTP-bound and constitutively active form, FoSec4CA). We evaluated the biofunctions of FoSec4, FoSec2 and FoGyp5, and found that FoSec4 is involved in the regulation of vegetative growth, reproduction, pathogenicity and the environmental stress response of F. odoratissimum, and that FocSec2 and FoGyp5 perform biofunctions consistent with FoSec4, indicating that FoSec2 and FoGyp5 may work as the GEF and the GAP, respectively, of FoSec4 in F. odoratissimum. We further found that the amino-terminal region and Sec2 domain are essential for the biological functions of FoSec2, while the carboxyl-terminal region and Tre-2/Bub2/Cdc16 (TBC) domain are essential for the biological functions of FoGyp5. In addition, FoSec4 mainly accumulated at the hyphal tips and partially colocalized with Spitzenkörper; however, FoGyp5 accumulated at the periphery of Spitzenkörper, suggesting that FoGyp5 may recognize and inactivate FoSec4 at a specific location in hyphal tips.

Cerebellar Continuous Theta Burst Stimulation for Aphasia Rehabilitation: Study Protocol for a Randomized Controlled Trial.

Background: Language recovery is limited in moderate to severe post-stroke aphasia patients. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool in improving language dysfunctions caused by post-stroke aphasia, but the treatment outcome is as yet mixed. Considerable evidence has demonstrated the essential involvement of the cerebellum in a variety of language functions, suggesting that it may be a potential stimulation target of TMS for the treatment of post-stroke aphasia. Theta burst stimulation (TBS) is a specific pattern of rTMS with shorter stimulation times and better therapeutic effects. The effect of continuous TBS (cTBS) on the cerebellum in patients with aphasia with chronic stroke needs further exploration. Methods: In this randomized, sham-controlled clinical trial, patients (n = 40) with chronic post-stroke aphasia received 10 sessions of real cTBS (n = 20) or sham cTBS (n = 20) over the right cerebellar Crus I+ a 30-min speech-language therapy. The Western Aphasia Battery (WAB) serves as the primary measure of the treatment outcome. The secondary outcome measures include the Boston Diagnostic Aphasia Examination, Boston Naming Test and speech acoustic parameters. Resting-state fMRI data were also obtained to examine treatment-induced changes in functional connectivity of the cerebro-cerebellar network. These outcome measures are assessed before, immediately after, and 12 weeks after cerebellar cTBS intervention. Discussion: This protocol holds promise that cerebellar cTBS is a potential strategy to improve language functions in chronic post-stroke aphasia. The resting-state fMRI may explore the neural mechanism underlying the aphasia rehabilitation with cerebellar cTBS.

Effects of the Intermittent Theta Burst Stimulation of the Cerebellar Vermis on Balance Recovery After Stroke: A Study Protocol for a Randomized Controlled Trial.

Background: The recovery of balance function is a critical segment in the rehabilitation treatment of stroke. The cerebellum is considered as the key structure involved in balance and motor control. The cerebellar vermis plays an important role in integrating vision, proprioception, and sensory skin input and may be a candidate stimulation target for regulating the motor network related with balance. However, evidence that the intermittent theta burst stimulation (iTBS) of cerebellar vermis can promote the recovery of balance function after stroke remains insufficient. Therefore, this study aims to explore the efficacy of the cerebellar vermis iTBS for the treatment of balance function in patients with stroke. Methods and Analysis: Forty patients with stroke will be recruited in this prospective, randomized, sham-controlled trial. Participants will be randomized in a 1:1 ratio to receive either 15 sessions of cerebellar vermis iTBS (600 pulses) or sham stimulation. Additionally, a routine rehabilitation therapy follows the intervention. The primary outcome is the Berg Balance Scale, and the secondary outcomes are the Fugl-Meyer assessment of the lower extremity and modified Barthel index. The above outcomes will be assessed before intervention and at the end of each week. Pre- and post-iTBS resting-state functional magnetic resonance imaging (rs-fMRI) will be acquired, and the regional homogeneity, fractional amplitude of low-frequency fluctuation and functional connectivity will be calculated and analyzed. Discussion: This protocol holds promise as a potential method to improve balance function in patients with stroke. If the outcomes of patients improve after the intervention, the study will provide new insights into improving balance function. Ethics and Dissemination: This study has been approved by the Medical Research Ethics Committee of Wuxi Mental Health Center (Wuxi Tongren Rehabilitation Hospital). Results will be disseminated through (open-access) peer-reviewed publications, networks of scientists, professionals, and the public and presented at conferences. Clinical Trial Registration Number: www.chictr.org.cn, identifier ChiCTR2100052590.

Effectiveness of a Novel Contralaterally Controlled Neuromuscular Electrical Stimulation for Restoring Lower Limb Motor Performance and Activities of Daily Living in Stroke Survivors: A Randomized Controlled Trial.

Background: Contralaterally controlled neuromuscular electrical stimulation (CCNMES) is a novel electrical stimulation treatment for stroke; however, reports on the efficacy of CCNMES on lower extremity function after stroke are scarce. Objective: To compare the effects of CCNMES versus NMES on lower extremity function and activities of daily living (ADL) in subacute stroke patients. Methods: Forty-four patients with a history of subacute stroke were randomly assigned to a CCNMES group and a NMES group (n = 22 per group). Twenty-one patients in each group completed the study per protocol, with one subject lost in follow-up in each group. The CCNMES group received CCNMES to the tibialis anterior (TA) and the peroneus longus and brevis muscles to induce ankle dorsiflexion motion, whereas the NMES group received NMES. The stimulus current was a biphasic waveform with a pulse duration of 200 µs and a frequency of 60 Hz. Patients in both groups underwent five 15 min sessions of electrical stimulation per week for three weeks. Indicators of motor function and ADL were measured pre- and posttreatment, including the Fugl-Meyer assessment of the lower extremity (FMA-LE) and modified Barthel index (MBI). Surface electromyography (sEMG) assessments included average electromyography (aEMG), integrated electromyography (iEMG), and root mean square (RMS) of the paretic TA muscle. Results: Values for the FMA-LE, MBI, aEMG, iEMG, and RMS of the affected TA muscle were significantly increased in both groups after treatment (p < 0.01). Patients in the CCNMES group showed significant improvements in all the measurements compared with the NMES group after treatment. Within-group differences in all post- and pretreatment indicators were significantly greater in the CCNMES group than in the NMES group (p < 0.05). Conclusion: CCNMES improved motor function and ADL ability to a greater extent than the conventional NMES in subacute stroke patients.

Continuous theta burst stimulation-induced suppression of the right fronto-thalamic-cerebellar circuit accompanies improvement in language performance in poststroke aphasia: A resting-state fMRI study.

Background: Continuous theta burst stimulation (cTBS) is a specific paradigm of repetitive transcranial magnetic stimulation (rTMS) with an inhibitory effect on cortical excitability for up to 60 min after less than 1 min of stimulation. The right posterior superior temporal gyrus (pSTG), homotopic to Wernicke's area in the left hemisphere, may be a potential stimulation target based on its critical role in semantic processing. The objective of this study was to explore whether cTBS over the right pSTG can promote language improvements in aphasic patients and the underlying mechanism. Methods: A total of 34 subjects with aphasia were randomly assigned to undergo 15 sessions of either 40-s inhibitory cTBS over the right pSTG (the cTBS group) or sham stimulation (the sham group), followed by 30 min of speech and language therapy. Subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI), and the aphasia quotient (AQ) of the Chinese version of the Western Aphasia Battery (WAB) was calculated before and after the intervention. This randomized controlled trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR210052962). Results: After treatment, the language performance of the cTBS group was higher than that of the sham group in terms of the WAB-AQ score (p = 0.010) and the WAB scores for auditory comprehension (p = 0.022) and repetition (p = 0.035). The fractional amplitude of low-frequency fluctuations (fALFF) was significantly decreased in the pars triangularis of the inferior frontal gyrus (IFG), right middle frontal gyrus, right thalamus, and left cerebellar crus I. Clusters in the left orbitofrontal cortex exhibited increased fALFF. The change in WAB comprehension scores were significantly correlated with the change in the fALFF of the right IFG pars triangularis in both groups. Greatly increased functional connectivity was observed between the right pars triangularis and left paracingulate gyrus and between the right pSTG and right angular gyrus and the posterior cingulate gyrus with pre-and post-treatment between the two groups. Conclusion: Our findings indicate that cTBS of the right pSTG may improve language production by suppressing intrinsic activity of the right fronto-thalamic-cerebellar circuit and enhancing the involvement of the right temporoparietal region.

Influence of aging on chronic unpredictable mild stress-induced depression-like behavior in male C57BL/6J mice.

Depression is a common psychiatric disorder that can occur throughout an individual's lifespan. Chronic unpredictable mild stress (CUMS) protocol is currently the most commonly used to develop an animal model of depression. Due to the variable duration and procedure of CUMS, it is difficult to reproduce and explore the mechanism of CUMS-induced depression effectively. In the present study, the CUMS-induced behavioral phenotypes were assessed in male C57BL/6J mice at the age of 9-18 weeks. The mice stressed for 3-8 weeks exhibited lower body weight as well as longer immobility time of forced swim and tail suspension test compared to control mice. Moreover, lessening and impairment of hippocampal neurons was found in stressed mice at the age of 18 weeks, which was correlated with increased relative mRNA expression levels of inflammatory cytokines BDNF, Htr1a, and IL-6 in the hippocampus. Nevertheless, no difference between stressed and control mice was observed neither in the sucrose preference nor in the open field test (except for vertical activity in OFT) at the age of 18 weeks. These findings reveal that 3-8 weeks of chronic stress could induce depression-like alterations in male C57BL/6J mice and the behavioral adaptation of aged mice might fail to the availability of the depression model.

Depression-/Anxiety-Like Behavior Alterations in Adult Slit2 Transgenic Mice.

Background: Slit2 is a member of the Slit family of secreted glycoproteins that plays highly conserved roles in neuronal axon guidance and cellular migration. Our previous experimental results showed Alzheimer's disease-like alterations and increased permeability of the blood-brain barrier in Slit2-overexpressing transgenic (Slit2-Tg) mice aged 8-9 months. Nevertheless, relatively little is known about behavioral alterations in adult Slit2-Tg mice (2-6 months of age). To observe the age-related behavioral effects of Slit2 overexpression in adult mice, we performed a battery of behavioral tests with adult Slit2-Tg mice at 2-6 months of age. Results: The body weight of Slit2-Tg mice was lower than that of the wild-type mice from 15 weeks of age. Compared with the control mice, depression-like behaviors were found in Slit2-Tg mice from 15 to 21 weeks of age in the sucrose preference test, although Slit2-Tg mice were hyperactive in the tail suspension test. The anxiety-like behaviors were found in Slit2-Tg mice in the open field test, as well as increased locomotor activity. The anxiety-like behaviors were also found in adult Slit2-Tg mice in the elevated plus maze. Compared to wild-type mice at 23 weeks old, impairment of the hippocampal neurons were found in Slit2-Tg mice at the same age in hematoxylin-eosin staining (H&E), including some eccentric dispersion and expansion of neuronal bodies. In addition, the messenger RNA (mRNA) expression of TNF-α was elevated in the hippocampus of adult Slit2-Tg mice. Conclusions: Slit2 overexpression causes depression-/anxiety-like behaviors in adult mice that may be related to an increase in inflammatory factors and damage to hippocampal neurons.

Gastric precancerous lesions present in ApcMin/+ mice.

The ApcMin/+ mouse is an animal model for familial adenomatous polyposis, and aged ApcMin/+ mice also spontaneously develop multiple tumors in their stomachs. However, gastric premalignant lesions in ApcMin/+ mice have not been well characterized. The stomachs of ApcMin/+ mice were compared with those of their wild type littermates at 24 weeks with hematoxylin and eosin (H&E) staining and alcian blue staining. Ki67, CD68 and CA199 expression was analyzed by immunohistochemistry. The results revealed the presence of epithelial proliferation and inflammatory infiltration in the forestomachs, glandular atrophy and intestinal metaplasia in the gastric bodies, and dysplasia in the gastric antra. The effect of mutations in the Apc gene on chronic gastritis and gastric precancerous lesions was characterized in ApcMin/+ mice. These results suggest that ApcMin/+ mice represent a genetic model for mechanistic studies and drug discovery in gastric precancerous lesions.

[Electroacupuncture Relieves Visceral Hypersensitivity by Down-regulating Mast Cell Number，PAR-2/TRPV 1 Signaling, etc. in Colonic Tissue of Rats with Irritable Bowel Syndrome].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Shangjuxu" (ST 37, Lower Confluent point) and "Tianshu" (ST 25, Front-Mu point) on visceral pain and expression of colonic tryptase(Try), proteinase-activated receptor 2(PAR-2)，transient receptor potential channel vanilloid subfamily member 1 (TPRV 1)，substance P (SP) and calcitonin gene-related peptide (CGRP) in rats with irritable bowel syndrome (IBS), so as to explore its mechanisms underlying improvement of IBS. METHODS: Forty male Sprague Dawley rats were equally randomized into normal control (control), model, medication and EA groups (n＝10 in each). The IBS model was established by chronic acute combining stress (CACS, water deprivation, fasting, tail clamping, forced swimming in ice water, restraint, etc.) for 21 days. Rats of the medication group were treated by gavage of Pinaverium Bromide (1 mg/mL, 15 mg/kg), once daily for 14 d. EA (10 Hz/50 Hz, 0.2－0.3 mA) was applied to bilateral ST 37 and ST 25 for 30 min, once daily for 14 d. The muscular withdrawal reflex (AWR) of both abdomen and buttock was detected by colorectal distension (CRD) with a water-filled balloon for examining the visceral hypersensitivity. The number of mast cells in the colonic tissue was counted after toluidine blue stain. The immunoactivity of colonic Try was determined by immunochemistry and the expression of colonic PAR-2, TRVP 1, SP and CGRP proteins detected by Western blot. RESULTS: After modeling, the body weight was significantly decreased in IBS rats of the model, medication and EA groups compared with their own individual pre-treatment and with the control group (P<0.01), and markedly higher in both medication and EA groups than in the model group (P<0.05, P<0.01). The intra-colonic volume thresholds for inducing abdominal and hip AWR were significantly lower in the model group than in the normal control group (P<0.01), and obviously higher in both medication and EA groups than in the model group (P<0.05，P<0.01). The AWR scores of intra-colorectal balloon at volumes of 0.5, 1.0 and 1.5 mL of water were significantly higher in the model group than in the control group (P<0.01), and considerably lower in the EA and medication groups than in the model group (P<0.01). The number of colonic MC and the expression levels of colonic Try, PAR-2, TRPV 1, SP and CGRP proteins were significantly higher in the model group than in the control group (P<0.01), and obviously decreased in both medication and EA groups relevant to the model group (P<0.01). Comparison between the medication and EA groups showed that the decreased expression levels of colonic PAR-2, TRPV 1, SP and CGRP proteins were significantly lower in the EA group than in the medication group (P<0.05), but no significant differences were found between the two groups in intra-colonic volumes for inducing AWR, AWR scores, body weight, and colonic MC number and Try immunoactivity levels (P>0.05)．. CONCLUSION: EA of ST 37 and ST 25 can relieve visceral hypersensitivity in IBS rats, which may be associated with its effects in down-regulating the number of MC and the expression of PAR-2, TRVP 1, SP, CGRP and Try proteins in the colonic tissue.