Closed-loop electrical stimulation to prevent focal epilepsy progression and long-term memory impairment.

Interictal epileptiform discharges (IEDs) are ubiquitously expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes as most therapeutics target seizures. We show in a model of progressive hippocampal epilepsy that IEDs produce pathological oscillatory coupling which is associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expands the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human subjects with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation. One-Sentence Summary: Targeted closed-loop electrical stimulation prevents spread of the epileptic network and ameliorates long-term spatial memory deficits.

1,3-Dichloro-2-propanol-Induced Renal Tubular Cell Necroptosis through the ROS/RIPK3/MLKL Pathway.

1,3-Dichloro-2-propanol (1,3-DCP), as a food pollutant, exists in a variety of foods. Studies have shown that it has nephrotoxicity. In the study, we found that 1,3-DCP caused renal injury with necroptosis in C57BL/6J mice. The mechanism of 1,3-DCP-caused nephrotoxicity was further explored in NRK-52E cells in vitro. We found that 1,3-DCP caused cell necroptosis with the increase in lactate dehydrogenase (LDH) levels and the expressions of RIPK3 and MLKL. But pretreatment with a ROS inhibitor N-acetyl-l-cysteine (NAC), a RIPK3 inhibitor GSK'872, or RIPK3 gene silencing alleviated 1,3-DCP-induced cell necroptosis. The data indicated that 1,3-DCP induced necroptosis through the ROS/RIPK3/MLKL pathway in NRK-52E cells. In further mechanistic studies, we explored how 1,3-DCP induced ROS production. We found that 1,3-DCP inhibited the expressions of nuclear and cytoplasmic Nrf2. But pretreatment with an Nrf2 activator dimethyl fumarate (DMF) up-regulated the expressions of nuclear and cytoplasmic Nrf2 and down-regulated ROS levels and RIPK3 and MLKL expressions. We also examined the effects of mitophagy on 1,3-DCP-induced ROS. The data manifested that 1,3-DCP suppressed mitophagy in NRK-52E cells by decreasing LC3-II, Pink1, and Parkin levels, increasing p62 levels, and decreasing colocalization of LC3 and Mito-Tracker Red. Pretreatment with an autophagy activator rapamycin (Rapa) decreased 1,3-DCP-induced ROS. Taken together, our data identified that 1,3-DCP caused renal necroptosis through the ROS/RIPK3/MLKL pathway.

Daptomycin and linezolid for severe methicillin-resistant Staphylococcus aureus psoas abscess and bacteremia: A case report and review of the literature.

BACKGROUND: Vancomycin remains a first-line treatment drug as per the treatment guidelines for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. However, a number of gram-positive cocci have developed resistance to several drugs, including glycopeptides. Therefore, there is an urgent need for effective and innovative antibacterial drugs to treat patients with infections caused by drug-resistant bacteria. CASE SUMMARY: A 24-year-old male was admitted to hospital owing to lumbago, fever, and hematuria. Computed tomography (CT) results showed an abscess in the psoas major muscle of the patient. Repeated abscess drainage and blood culture suggested MRSA, and vancomycin was initiated. However, after day 10, CT scans showed abscesses in the lungs and legs of the patient. Therefore, treatment was switched to daptomycin. Linezolid was also added considering inflammation in the lungs. After 10 d of the dual-drug anti-MRSA treatment, culture of the abscess drainage turned negative for MRSA. On day 28, the patient was discharged without any complications. CONCLUSION: This case indicates that daptomycin combined with linezolid is an effective remedy for bacteremia caused by MRSA with pulmonary complications.

Timing of Acupuncture Treatment in Peripheral Facial Paralysis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Investigate the optimum time of acupuncture treatment in peripheral facial paralysis in order to provide evidence for clinical treatment. METHODS: CNKI, Wanfang, PubMed, Cochrane Library, and EMBASE databases were systematically searched from the inception dates to February 20, 2020. Studies limited to participants with acute peripheral facial paralysis treated with acupuncture and patients without information of the stage were excluded. The primary outcomes were effective rate and cure rate (based on facial nerve function scores). This meta-analysis is registered with PROSPERO, number CRD42020169870. RESULTS: 15 randomized controlled trials that enrolled 2847 participants met the selection criteria. There was no significant differences in the effective rate (RR, 1.22; 95% CI, 0.70-2.11) when comparing acupuncture to prednisone therapy in acute facial paralysis. Acupuncture treatment in the acute stage increased both the effective rate (RR, 1.03; 95% CI, 1.00-1.07) and the cure rate (RR, 1.34; 95% CI, 1.14-1.58) compared to that in the nonacute stage. CONCLUSIONS: In this meta-analysis, acupuncture showed a better effect in the acute stage than the nonacute stage for participants with peripheral facial paralysis. There was no statistical difference in the effective rate no matter the choice of acupuncture or prednisone therapies in the acute stage. These findings encourage early acupuncture treatment in peripheral facial paralysis.

1,3-dichloro-2-propanol induced hepatic lipid accumulation by inhibiting autophagy via AKT/mTOR/FOXO1 pathway in mice.

Our study investigated the effects of food contaminant 1,3-dichloro-2-propanol (1,3-DCP) on hepatic lipid metabolism and its mechanism. We found that triglyceride (TG), total cholesterol (TC) and the number of lipid droplets (LDs) were increased in the liver of C57BL/6 mice given intragastric administration of 1,3-DCP for 30 days. Meanwhile, 1,3-DCP inhibited autophagosomes and lysosomes formation, reflected by decreased LC3-II, LAMP1, LAMP2, CTSD, CTSB expression, increased p62 expression and decreased LC3 fluorescence. Subsequently, we detected the changes of hepatic lipid accumulation caused by 1,3-DCP using an autophagy inducer or inhibitor. In vivo, Hepatic lipid accumulation caused by 1,3-DCP was mitigated by the autophagy inducer Rapa. On the contrary, the autophagy inhibitor (chloroquine or 3-methyladenine) further exacerbated hepatic lipid accumulation caused by 1,3-DCP. 1,3-DCP reduced the number of autophagosomes encapsulated LDs, assessed by colocalization of LD and LC3. These data demonstrated that 1,3-DCP induced lipid accumulation by inhibiting autophagy. We further investigated the mechanism of 1,3-DCP-inhibited autophagy and found 1,3-DCP increased the ratios of p-AKT/AKT, p-mTOR/mTOR, p-FOXO1/FOXO1, decreased FOXO1 nuclear localization in vivo. These proteins may be involved in the regulation of 1,3-DCP-mediated autophagy. We detected the changes in autophagy marker protein LC3-II and lipid accumulation using an AKT inhibitor ARQ-092 or a mTOR inhibitor rapamycin in HepG2 cells. Compared with 1,3-DCP group, lipid accumulation was decreased, LC3-II and FOXO1 nuclear localization were increased, p-FOXO1 levels were decreased in HepG2 cells pretreated with ARQ-092 or rapamycin. Taken together, these data revealed that the effects of 1,3-DCP on lipid accumulation by inhibiting autophagy were dependent on AKT/mTOR/FOXO1 signaling pathway. Our study not only supplied the mechanism of 1,3-DCP toxicity, but also provided experimental basis for effective intervention measures of 1,3-DCP toxicity.

Investigating the correlation between serum albumin level and the prognosis of Bell's palsy.

ABSTRACT: To investigate the correlation between the serum albumin level and the prognosis of patients with Bell's palsy.We retrospectively analyzed the clinical records of 311 inpatients with Bell's palsy (BP) in our hospital between September 2018 and October 2019. The patients were divided into 2 groups: the recovered group (with the House-Brackmann grade ≤ 2) and the unrecovered group (with the House-Brackmann grade > 2), according to the follow-up results within 3 months after discharge. Blood test indicators (white blood cell count, neutrophil-to-lymphocyte ratio, red cell distribution width, serum albumin level, globulin level) and basic clinical data (age, sex, course of the disease, inpatient days, comorbidity of hypertension, diabetes, and hepatitis B) of the 2 groups were compared to explore whether they were correlated with the prognosis of patients with Bell's palsy.The serum albumin level of patients with BP in the unrecovered group was significantly lower than that of the recovered group (medians [interquartile range], 40.75 [38.40, 43.85] vs 44 [42.10, 46.20], P < .001). Multivariate binary logistic regression revealed that serum albumin (odds ratio 0.772, 95% confidence interval 0.711-0.839, P < .001) was a protective factor for BP prognosis.Serum albumin is a protective factor for the prognosis of BP. Although more prospective clinical controlled trials are needed, our study provides valuable and crucial prognostic information for physicians.

High molecular weight fibroblast growth factor 2 induces apoptosis by interacting with complement component 1 Q subcomponent-binding protein in vitro.

Fibroblast growth factor 2 (FGF2) is a multifunctional cell growth factor that regulates cell proliferation, differentiation, adhesion, migration, and apoptosis. FGF2 has multiple isoforms, including an 18-kDa low molecular weight isoform (lo-FGF2) and 22-, 23-, 24-, and 34-kDa high molecular weight isoforms (hi-FGF2). Hi-FGF2 overexpression induces chromatin compaction, which requires the mitochondria and leads to apoptosis. Complement component 1 Q subcomponent-binding protein (C1QBP) plays an important role in mitochondria-dependent apoptosis by regulating the opening of the mitochondrial permeability transition pore. However, the interaction between C1QBP and hi-FGF2 and its role in hi-FGF2-mediated apoptosis remain unclear. Here, we found that hi-FGF2 overexpression induced depolarization of the mitochondrial membrane, cytochrome c release into the cytosol, and a considerable increase in C1QBP messenger RNA and protein expression. Furthermore, coimmunoprecipitation results showed that the mitochondrial protein, C1QBP, interacts with hi-FGF2. C1QBP knockdown using small interfering RNA significantly decreased the localization of hi-FGF2 to the mitochondria and increased the rate of apoptosis. Our results highlight a novel mechanism underlying hi-FGF2-induced, mitochondria-driven cell death involving the direct interaction between hi-FGF2 and C1QBP and the upregulation of C1QBP expression.

[Small interfering RNA-mediated LPXN silencing suppresses proliferation and enhances drug sensitivity of human acute monocytic leukemia SHI-1 cells in vitro].

OBJECTIVE: To investigate the effect of silencing LPXN expression by RNA interference on the proliferation and drug sensitivity of human acute monocytic leukemia SHI-1 cells in vitro. METHODS: Small interfering RNA (siRNA) sequences targeting LPXN were designed and transiently transfected in SHI-1 cells via Lipofectamine 2000, and the most efficient siRNA sequence for LPXN silencing was identified using Western blotting. The protein expression levels of LPXN, p-JNK, p-P38 MAPK and p-ERK were in the cells transfected with the selected siRNA were detected using Western blotting, and the cell proliferation changes were assessed using CCK-8 reagent. RESULTS: LPXN silencing by siRNA transfection resulted in significant proliferation suppression in SHI-1 cells with an inhibition rate of(27.04±2.05) % (P < 0.05). Western blotting showed that treatment of the siRNA-transfected SHI-1 cells with 0-25 µmol/L curcumin or with 0-2.0 µmol/L Ara-C further increased the cell inhibition rate and obviously enhanced the expressions of p-P38 MAPK and p-JNK without significantly affecting p-ERK expression. CONCLUSIONS: Down-regulation of LPXN expression by siRNA transfection can suppress the proliferation and increase the drug sensitivity of SHI-1 cells probably by activating JNK and P38 MAPK.

Microfabrication of polydimethylsiloxane phantoms to simulate tumor hypoxia and vascular anomaly.

We introduce a microfluidic approach to simulate tumor hypoxia and vascular anomaly. Polydimethylsiloxane (PDMS) phantoms with embedded microchannel networks were fabricated by a soft lithography process. A dialysis membrane was sandwiched between two PDMS slabs to simulate the controlled mass transport and oxygen metabolism. A tortuous microchannel network was fabricated to simulate tumor microvasculature. A dual-modal multispectral and laser speckle imaging system was used for oxygen and blood flow imaging in the tumor-simulating phantom. The imaging results were compared with those of the normal vasculature. Our experiments demonstrated the technical feasibility of simulating tumor hypoxia and vascular anomalies using the proposed PDMS phantom. Such a phantom fabrication technique may be potentially used to calibrate optical imaging devices, to study the mechanisms for tumor hypoxia and angiogenesis, and to optimize the drug delivery strategies.