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Background & Aims Rapid gastric epithelial progenitor cell (EPC) proliferation and inflammatory response inhibition play key roles in promoting the repair of gastric mucosal damage. However, specific targets inducing these effects are unknown. In this study, we explored the effects of a potential target, Ankyrin repeat domain 22 (ANKRD22). Methods An acute gastric mucosal injury model was established with Ankrd22-/- and Ankrd22+/+ mice by intragastric administration of acidified ethanol. Organoid culture and flow cytometry were performed to evaluate the effects of ANKRD22 on leucine-rich repeat-containing G-protein–coupled receptor 5–positive (Lgr5+) gastric EPC proliferation. The mechanisms by which ANKRD22 affects gastric EPC proliferation and inflammatory responses were explored by mitochondrial Ca2+ influx and immunoblotting. Candidate ANKRD22 inhibitors then were screened virtually and validated in vitro and in vivo. Results After acute gastric mucosal injury, the number of Lgr5+ gastric EPCs was increased significantly in Ankrd22-/- mice compared with that in Ankrd22+/+ mice. Moreover, Ankrd22 knockout attenuated inflammatory cell infiltration into damaged gastric tissues. ANKRD22 deletion also reduced mitochondrial Ca2+ influx and cytoplasmic nuclear factor of activated T cells in gastric epithelial cells and macrophages, which further induced Lgr5+ gastric EPC proliferation and decreased macrophage release of tumor necrosis factor-α and interleukin 1α. In addition, a small molecule, AV023, was found to show similar effects to those produced by ANKRD22 deletion in vitro. Intraperitoneal injection of AV023 into the mouse model promoted the repair of gastric mucosal damage, with increased proliferation of Lgr5+ gastric EPCs and visible relief of inflammation. Conclusions ANKRD22 inhibition is a potential target-based therapeutic approach for promoting the repair of gastric mucosal damage., Graphical abstract

Introduction Deep brain stimulation (DBS) is an effective treatment for patients with Parkinson’s disease (PD). On time follow-up and timely programing of symptoms are important measures to maintain the effectiveness of DBS. Due to the highly contagious nature of 2019-nCoV, patients were quarantined. With the help of Internet technologies, we continued to provide motor and non-motor symptom assessment and remote programming services for postsurgical PD-DBS patients during this extraordinary period. Methods A retrospective analysis was performed on postsurgical PD-DBS patients who could not come to our hospital for programming due to the impact of the 2019-nCoV. The differences between the pre- and post-programming groups were analyzed. We designed a 5-level Likert rating scale to evaluate the effects and convenience of the remote programming and Internet self-evaluation procedures. Results Of the 36 patients engaged in the remote programming, 32 patients met the inclusion criteria. Four of the 32 patients set initiated stimulation parameters, and the other 28 patients had significant improvement in UPDRS-III. Nearly all the 28 patients were satisfied with the effect of the remote programming. Most of the patients were willing to use remote programming again. Conclusion Remote programming based on the online evaluation of patient’s symptoms can help improve motor symptoms of postsurgical DBS patients with PD during the quarantine period caused by 2019-nCoV. Electronic supplementary material The online version of this article (10.1007/s00415-020-10273-z) contains supplementary material, which is available to authorized users.

Electroconvulsive therapy (ECT) has known beneficial effects on the core motor symptoms of Parkinson's disease (PD), likely through induction of dopamine release and sensitivity of dopamine receptors. Mesenchymal stem cells (MSCs) can salvage loss of dopamine in PD through their differentiation into dopaminergic neurons. However, it is not known if combined ECT and MSC transplantation may have a synergistic effect against PD. Here, we showed that ECT significantly increased the differentiation of the transplanted MSCs into dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. On the other hand, transplantation of MSCs significantly increased dopamine levels after ECT. Co-application of ECT and MSC transplantation generated a synergistic effect through increases in dopamine and decreases in pro-inflammatory cytokines, resulting in significantly attenuated defect in stepping test and rotational behavior in MPTP-mice. Together, our data suggest that combined ECT and MSC transplantation can be a valuable treatment of PD.

Objective. To explore the optimal time points for deep brain stimulation (DBS) on the treatment of morphine addiction and its possible mechanisms by investigating how high-frequency stimulation (HFS) in bilateral nucleus accumbens (NAc) at different time points influences the addictive behaviors of rats with drug addiction. Methods. The rats were randomly divided into extinction stimulation group (n = 20) and postextinction stimulation group (n = 20). Ten rats in the extinction stimulation group were treated using 120 Hz HFS during extinction stage while another 10 rats with pseudostimulation were served as control group. The CPP scores were evaluated at the second day after intervention, with total 9 sections accomplished. The CPP scores were evaluated at the second day of the intervention. In the postextinction stimulation group, 120 Hz HFS was intervened during the postextinction stage in 10 experimental rats and pseudostimulation was performed in 10 control rats. Stimulation was performed for 7 days continuously, and a small dose of morphine was administrated to induce relapse after the postextinction period. Results. During the extinction phase, CPP scores after HFS were significantly higher. During the postextinction phase, relapse CPP scores after HFS were dramatically lower. Conclusion. HFS of bilateral NAc inhibits the extinction of addictive behavior during the extinction phase, and HFS during the postextinction period suppresses relapse of drug seeking behavior.

Objective This study aimed to analyze the risk factors of intracranial hemorrhage (ICH) after deep brain stimulation (DBS) for idiopathic Parkinson’s disease (PD). Methods Patients who received DBS from March 2014 to December 2016 were retrospectively analyzed. The hemorrhage index was derived by combining the hemorrhagic volume and clinical manifestations of ICH. All patients with IHC were followed up for 2 years. Results Computed tomography showed 13 events of ICH in 11 patients (nine cases in the subthalamic nucleus), including eight cases with symptomatic hemorrhage (seven cases in the subthalamic nucleus). Hemorrhage was characterized by intracranial hematoma in the electrode puncture tract. Male sex and hypertension were significant risk factors for ICH. Hemorrhage in the preferred puncture side was significantly higher than that in the non-preferred puncture side. The mean hemorrhage index was 2.23 ± 0.83 in 11 patients, and no permanent neurological impairment was found during the 2-year follow-up. The effect of DBS on motor symptoms was similar in patients with and without ICH. Conclusion Male sex and hypertension are risk factors of ICH after DBS in PD. The risk of hemorrhage on the first puncture site is significantly higher than that on the second puncture site.

Background. Stimulation-induced transient nonmotor psychiatric symptoms (STPSs) are side effects following bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients. We designed algorithms which (1) determine the electrode contacts that induce STPSs and (2) provide a programming protocol to eliminate STPS and maintain the optimal motor functions. Our objective is to test the effectiveness of these algorithms. Materials and Methods. 454 PD patients who underwent programming sessions after STN-DBS implantations were retrospectively analyzed. Only STPS patients were enrolled. In these patients, the contacts inducing STPS were found and the programming protocol algorithms used. Results. Eleven patients were diagnosed with STPS. Of these patients, two had four episodes of crying, and two had four episodes of mirthful laughter. In one patient, two episodes of abnormal sense of spatial orientation were observed. Hallucination episodes were observed twice in one patient, while five patients recorded eight episodes of hypomania. There were no statistical differences between the UPDRS-III under the final stimulation parameter (without STPS) and previous optimum UPDRS-III under the STPSs (p=1.000). Conclusion. The flow diagram used for determining electrode contacts that induce STPS and the programming protocol employed in the treatment of these symptoms are effective.

Prostate cancer is a common malignant tumor in elderly men. As a novel metabolic-reprogramming molecule, the role of ankyrin repeat domain 22 (ANKRD22) in the tumorigenesis and progression of prostate cancer remains unknown. In the present study, mouse monoclonal antibodies against human ANKRD22 were prepared using recombinant ANKRD22 from prokaryotic expression and validated. Subsequently, these antibodies were used to evaluate ANKRD22 levels via immunohistochemical staining in prostate cancer tissues. Finally, the association between ANKRD22 levels and prostate cancer progression was analyzed in 636 samples of prostate cancer using The Cancer Genome Atlas (TCGA) database. A total of four anti-ANKRD22 monoclonal antibodies were generated and validated, which could be effectively blocked by recombinant ANKRD22 protein. Using these antibodies for immunohistochemical staining, ANKRD22 was detected in prostate cancer cells in both the cytoplasm and nucleus. Bioinformatics analysis demonstrated that the mRNA level of ANKRD22 was inversely associated with prostate cancer stage (P

Objectives. To analyze the hyperhidrosis neural network structure induced by subthalamic nucleus (STN) - deep brain stimulation (DBS). Materials and Methods. Patients with Parkinson’s disease treated with STN-DBS in Changhai Hospital between July 1, 2015, and December 1, 2016, were analyzed retrospectively. Using records of side effects of the intraoperative macrostimulation test, patients with skin sweats were selected as the sweating group. Based on the number of cases in the sweating group, the same number of patients was randomly selected from other STN-DBS patients without sweating to form the control group. The study standardized electrode position with Lead-DBS software to Montreal Neurological Institute (MNI) standard stereotactic space to compare the differences in three-dimensional coordinates of activated contacts between groups. Results. Of 355 patients, 11 patients had sweats during intraoperative macrostimulation tests. There was no significant difference in the preoperative baseline information and the postoperative UPDRS-III improvement rate (Med-off, IPG-on) between groups. Contacts inducing sweat were more medial (X-axis) (11.02 ± 0.69 mm vs 11.98 ± 0.84 mm, P=0.00057) and more upward (Z-axis) (−7.15 ± 1.06 mm VS −7.98 ± 1.21 mm, P=0.032) than those of the control group. The straight-line distance between the center of the sweat contact and the nearest voxel of the red nucleus was closer than that of the control group (2.72 ± 0.65 mm VS 3.76 ± 0.85 mm, P=0.00012). Conclusions. STN-DBS-induced sweat indicated that the contact was at superior medial of STN.

Proteomics and postgenomic technologies have found growing recent applications in reproductive biology and fertility research. Mice deficient in the wild-type p53-induced phosphatase 1 (WIP1) exhibit defects in reproductive organs. In this study, we aimed to understand how Wip1 deficiency affects spermatogenesis and sperm maturation using the Wip1-/- mouse model and gel-free isobaric tags for relative and absolute quantitation liquid chromatography-tandem mass spectrometry quantitative proteomic analysis of the whole epididymis, including somatic tissue and sperm. A total of 8763 proteins were identified, of which 91 were significantly differentially expressed proteins (DEPs) in Wip1-/- mice. Of note, four reproduction-related DEPs (PRM2, ODF1, PIWIL1, and KLHL10) were confirmed by western blotting. Pathway analysis suggested that the Smac/Diablo-mediated apoptotic pathway and the SERPINA3-mediated inflammatory process may contribute to the atrophy and marked reduction of sperm in the epididymis. Network analysis of reproduction-related DEPs revealed possible interactions of WIP1 that may affect sperm maturation, such as reduced ODF1 and PRM2 expression and increased PIWIL1 expression by p53. Histological analysis showed a spermatid deficiency in the epididymis and was further confirmed in testis in Wip1-/- mice. Immunohistochemistry showed that testicular expressions of PRM2 and PIWIL1 were down- and upregulated, respectively. In summary, WIP1 deficiency seems to cause impaired spermatogenesis in the testis and damaged sperm maturation in the epididymis. These may be attributed in part to regulation of PRM2, ODF1, PIWIL1, and associated pathways as well as the inflammatory and apoptotic pathways. Further preclinical and clinical studies of male fertility using proteomics and multiomics research are called for.

Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer-like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble β-amyloid (Aβ) which could be significantly inhibited by fluoxetine (FLX) via activating serotonin 5-HT2 receptors. FLX could also protect hippocampal neurons against astrocyte-induced neuronal damage in vitro. In the same APP/PS1 mice, FLX inhibited activation of astrocytes, lowered Aβ products, ameliorated neurotoxicity, and improved behavioral performance. These findings may provide a basis for the clinical application of FLX in patients, and may also lay the groundwork for exploration of other novel astrocyte-based therapies of AD.

In the present paper, twin roll strip casting was applied to fabricating the strips of low carbon steels containing different P contents. P was spontaneously segregated near strip surfaces by the deformation in mushy zone during strip casting. Uniform surface layers enriched in P can be formed after subsequent processing of cold rolling and annealing, which can be used as surface coatings for the improvement of both weathering resistance and mechanical properties including toughness and elongation. In terms of plasticity, the elongation of conventional strips started drastically decreasing with P content beyond 0.15% by weight. By contrast, the elongation of the cast strips containing 0.26% P remained at the level of about 30%, with the tolerated ability of P being increased by about 0.1% by weight by twin roll strip casting. The ductile–brittle transition temperatures (DBTT) for the cast strips after cold rolling and annealing were measured to be lower than those for the conventional strips after hot rolling, cold rolling and annealing by 10–15°C. For 120 cycles of corrosion exposure, the weight gains of the 0.15 and 0.26P cast strips were reduced by more than 30% as compared with that on the conventional strip containing 0.08% P. It has been demonstrated that phosphate enriched layers could be formed beneath the corrosion scales of the 0.15 and 0.26P cast strips after cold rolling and annealing, which reduced the corrosion rate and improved the corrosion resistance.

Holmium laser enucleation of the prostate (HoLEP) is a well established procedure for the treatment of benign prostatic hyperplasia. Here we report our experience of the learning curve, efficacy, and safety of HoLEP.We retrospectively reviewed data from 190 consecutive patients who had undergone HoLEP for benign prostatic hyperplasia. The patients were divided into three groups: group 1--patients 1 to 50; group 2--patients 51 to 100; and group 3--patients 101 to 190. This analysis included our initial experience with the technique reflecting our learning curve. All patients were assessed preoperatively and 12 months postoperatively. Patient baseline characteristics, perioperative data, and postoperative outcome were compared in the three groups. All complications were noted.HoLEP resulted in a significant improvement in voiding symptoms and urodynamic parameters. The improvements in peak urinary flow rate, post-void residual urine, International Prostate Symptom Score, and quality-of-life index did not change significantly as experience increased. However, the operative time decreased significantly as experience increased. The surgeon became more confident with the HoLEP technique after about 15 cases in those with moderate-sized prostates. The postoperative rates for complications such as bladder mucosal injury, recatheterization and transient urinary incontinence were higher in group 1 than in the other two groups.Holmium laser enucleation of the prostate is a safe and effective treatment option for benign prostatic hyperplasia, even when performed by inexperienced surgeons. The incidence of complications decreases with increasing experience with the procedure.

Strips of low carbon steels containing high contents of P and Cu have been produced by twin roll strip casting. The as-cast strips containing more than 0.1 mass% P exhibited obvious inverse surface segregation, which was difficult to be eliminated by the subsequent annealing treatments. After cold rolling and annealing treatment at 625°C for 30 min, the strip containing 0.1 mass% P exhibited similar plastic deformation and rupture behaviors with the strip containing 0.01% P, showing no obvious deteriorating effects of P on the ductility of as-cast strip. With increasing P content in steel, more cleavage cracks, micro voids and inter-granular rapture were observed in the fractured areas after tensile testing, which are believed to have been induced by the segregation of P in as cast strips. These results provide primary guidance for recycling dirty steel scraps.

Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer-like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble β-amyloid (Aβ) which could be significantly inhibited by fluoxetine (FLX) via activating serotonin 5-HT2 receptors. FLX could also protect hippocampal neurons against astrocyte-induced neuronal damage in vitro. In the same APP/PS1 mice, FLX inhibited activation of astrocytes, lowered Aβ products, ameliorated neurotoxicity, and improved behavioral performance. These findings may provide a basis for the clinical application of FLX in patients, and may also lay the groundwork for exploration of other novel astrocyte-based therapies of AD.

A 57-year-old male patient with gastric carcinoma underwent radical distal gastrectomy type II + Braun anastomosis, and received total parenteral nutrition for 10 days after surgery, followed by small amounts of semi-liquid nutrition for 3 days and liquid nutrition for 2 days. The patient developed refractory hypotension for more than 1 week in the early course of disease, and on Day 15 after surgery presented with characteristic signs of Wernicke's encephalopathy, including diplopia and mental confusion. The hypotension did not improve despite appropriate fluid replacement soon after admission. Treatment with moderate dose of thiamine for 3 months partly relieved ophthalmoplegia and confusion, but not Korsakoff syndrome. This extraordinary presentation with refractory hypotension and the unusual course of the disease encouraged us to present this case.