Efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients: a meta-analysis.

OBJECTIVE: This study aims to determine the efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients. METHODS: We searched Cochrane Library, PubMed, Embase, and ClinicalTrials.gov databases until July 27, 2022. Both randomized control trials (RCTs) and cohort studies were included and analyzed separately. The outcomes included mortality, incidence of invasive mechanical ventilation (IMV), ventilation improvement rate (need oxygen therapy to without oxygen therapy), secondary infection, and adverse events (AEs). The odds ratio (OR) with a 95% confidence interval (CI) was calculated by a random-effects meta-analysis model. RESULTS: Five RCTs and 2 cohort studies with 1726 COVID-19 patients were recruited (n = 866 in the GM-CSF antibody group and n = 891 in the control group). GM-CSF antibodies treatment reduced the incidence of IMV, which was supported by two cohort studies (OR 0.16; 95% CI 0.03, 0.74) and three RCTs (OR 0.62; 95% CI 0.41, 0.94). GM-CSF antibodies resulted in slight but not significant reductions in mortality (based on two cohort studies and five RCTs) and ventilation improvement (based on one cohort study and two RCTs). The sensitive analysis further showed the results of mortality and ventilation improvement rate became statistically significant when one included study was removed. Besides, GM-CSF antibodies did not increase the risks of the second infection (based on one cohort study and five RCTs) and AEs (based on five RCTs). CONCLUSION: GM-CSF antibody treatments may be an efficacious and well-tolerant way for the treatment of COVID-19. Further clinical evidence is still warranted.

Analysis of brain metabolites by gas chromatography-mass spectrometry reveals the risk-benefit concerns of prednisone in MRL/lpr lupus mice.

OBJECTIVE: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common cause of disability in systemic lupus erythematosus (SLE). This study aims to investigate the metabolic changes in the hypothalamus and frontal cortex in lupus-prone MRL/lpr mice. METHODS: Metabolic changes were analyzed using gas chromatography-mass spectrometry (GC-MS). RESULTS: According to the principal component analysis (PCA), the metabolic profiles were different between the frontal cortex and hypothalamus, but they were comparable between MRL/lpr and MRL/MpJ mice (16 weeks of age). By OPLS-DA, eight cortical and six hypothalamic differential metabolites were identified in MRL/lpr as compared to MRL/MpJ mice. Among these differential metabolites, we found a decrease of N-acetyl-L-aspartate (NAA, a potential marker of neuronal integrity), an increase of pyruvate and a decrease of glutamate in the frontal cortex but not in the hypothalamus. Prednisone treatment (3 mg/kg from 8 weeks of age) relieved the decrease of NAA but further increased the accumulation of pyruvate in the frontal cortex, additionally affected eight enriched pathways in the hypothalamus, and led to significant imbalances between the excitation and inhibition in both the frontal cortex and hypothalamus. CONCLUSION: These results suggest that the frontal cortex may be more preferentially affected than the hypothalamus in SLE. Prednisone disrupted rather than relieved metabolic abnormalities in the brain, especially in the hypothalamus, indicating that the risk-benefit balance of prednisone for SLE or NPSLE remains to be further evaluated.

Low-frequency stimulation of the external globus palladium produces anti-epileptogenic and anti-ictogenic actions in rats.

AIM: To investigate the anti-epileptic effects of deep brain stimulation targeting the external globus palladium (GPe) in rats. METHODS: For inducing amygdala kindling and deep brain stimulation, bipolar stainless-steel electrodes were implanted in SD rats into right basolateral amygdala and right GPe, respectively. The effects of deep brain stimulation were evaluated in the amygdala kindling model, maximal electroshock model (MES) and pentylenetetrazole (PTZ) model. Moreover, the background EEGs in the amygdala and GPe were recorded. RESULTS: Low-frequency stimulation (0.1 ms, 1 Hz, 15 min) at the GPe slowed the progression of seizure stages and shortened the after-discharge duration (ADD) during kindling acquisition. Furthermore, low-frequency stimulation significantly decreased the incidence of generalized seizures, suppressed the average stage, and shortened the cumulative ADD and generalized seizure duration in fully kindled rats. In addition, low-frequency stimulation significantly suppressed the average stage of MES-induced seizures and increased the latency to generalized seizures in the PTZ model. High-frequency stimulation (0.1 ms, 130 Hz, 5 min) at the GPe had no anti-epileptic effect and even aggravated epileptogenesis induced by amygdala kindling. EEG analysis showed that low-frequency stimulation at the GPe reversed the increase in delta power, whereas high-frequency stimulation at the GPe had no such effect. CONCLUSION: Low-frequency stimulation, but not high-frequency stimulation, at the GPe exerts therapeutic effect on temporal lobe epilepsy and tonic-colonic generalized seizures, which may be due to interference with delta rhythms. The results suggest that modulation of GPe activity using low-frequency stimulation or drugs may be a promising epilepsy treatment.

[Antiepileptic effect of low frequency stimulation in kindling rats].

OBJECTIVE: To investigate the antiepileptic effects of various stimulation modes of low-frequency stimulation(LFS) on the kindling rats. METHODS: Stimulating electrodes were implanted in the amygdala and current with constant intensity was applied to evoke kindling-induced seizures. The antiepileptic effect of LFS by open loop stimulation(before kindling), closed loop stimulation(immediately after kindling) and different forms of closed loop stimulation(whole stage after kindling and early stage after kindling) were investigated in amygdala kindled rats. RESULTS: The closed loop LFS of whole stage after kindling can significantly inhibited seizure stages(P<0.01) and reduced afterdischarge duration(P<0.05). The closed loop LFS of early stage after kindling can significantly suppress the seizure stages, mainly in stages 0-3(P<0.05 or P<0.01). The open loop low-frequency stimulation did not inhibit the seizure stage during kindling acquisition(P>0.05). CONCLUSION: The antiepileptic effect of low frequency stimulation may have a mode-dependent effect. It may be helpful for the deep brain stimulation as a promising approach applied to clinical antiepileptic therapy in the future.

[Antiepileptic effect of low-frequency electrical stimulation is waveform-dependent in hippocampal kindled mice].

OBJECTIVE: To investigate whether the waveform of electrical stimulus affects the antiepileptic effect of focal low-frequency stimulation (LFS). METHODS: The antiepileptic effects of the LFS in sine, monophase square and biphase square waves were investigated in hippocampal kindled mice, respectively. RESULTS: Compared to the control group, sine wave focal LFS (30 s) inhibited seizure stages (2.85 ± 0.27 vs 4.75 ± 0.12, P<0.05), lowered incidence of generalized seizures (53.6% vs 96.5%, P<0.01) and reduced afterdischarge durations [(16.2 2 ± 1.69)s vs (30.29 ± 1.12)s, P<0.01] in hippocampal kindled mice, while monophase or biphase square wave LFS (30 s) showed no antiepileptic effect. Monophase square LFS (15 min) inhibited seizure stages (3.58 ± 0.16, P<0.05) and incidence of generalized seizures (66.7%,P<0.01), but had weaker inhibitory effect on hippocampal afterdischarge durations than sine wave LFS. In addition, pre-treatment and 3 s but not 10 s post-treatment with sine wave LFS resulted in suppression of evoked seizures (P<0.05 or P<0.01). CONCLUSION: The antiepileptic effect of LFS is dependent on its waveform. Sine wave may be optimal for closed-loop LFS treatment of epilepsy.

Leptin attenuates the osteogenic induction potential of BMP9 by increasing ß-catenin malonylation modification via Sirt5 down-regulation.

BMP9 has demonstrated significant osteogenic potential. In this study, we investigated the effect of Leptin on BMP9-induced osteogenic differentiation. Firstly, we found Leptin was decreased during BMP9-induced osteogenic differentiation and serum Leptin concentrations were increased in the ovariectomized (OVX) rats. Both in vitro and in vivo, exogenous expression of Leptin inhibited the process of osteogenic differentiation, whereas silencing Leptin enhanced. Exogenous Leptin could increase the malonylation of ß-catenin. However, BMP9 could increase the level of Sirt5 and subsequently decrease the malonylation of ß-catenin; the BMP9-induced osteogenic differentiation was inhibited by silencing Sirt5. These data suggested that Leptin can inhibit the BMP9-induced osteogenic differentiation, which may be mediated through reducing the activity of Wnt/ß-catenin signalling via down-regulating Sirt5 to increase the malonylation level of ß-catenin partly.

Lanthionine synthetase C-like protein 1 interacts with and inhibits cystathionine ß-synthase: a target for neuronal antioxidant defense.

The finding that eukaryotic lanthionine synthetase C-like protein 1 (LanCL1) is a glutathione-binding protein prompted us to investigate the potential relationship between LanCL1 and cystathionine ß-synthase (CBS). CBS is a trans-sulfuration enzyme critical for the reduced glutathione (GSH) synthesis and GSH-dependent defense against oxidative stress. In this study we found that LanCL1 bound to CBS in mouse cortex and HEK293 cells. Mapping studies revealed that the binding region in LanCL1 spans amino acids 158-169, and that in CBS contains N-terminal and C-terminal regulatory domains. Recombinant His-LanCL1 directly bound endogenous CBS from mouse cortical lysates and inhibited its activity. Overexpression of LanCL1 inhibited CBS activity in HEK293 cells. CBS activity is reported to be regulated by oxidative stress. Here we found that oxidative stress induced by H(2)O(2) or glutamate lowered the GSH/GSSG ratio, dissociated LanCL1 from CBS, and elevated CBS activity in primary rat cortical neurons. Decreasing the GSH/GSSG ratio by adding GSSG to cellular extracts also dissociated LanCL1 from CBS. Either lentiviral knockdown of LanCL1 or specific disruption of the LanCL1-CBS interaction using the peptide Tat-LanCL1(153-173) released CBS activity in neurons but occluded CBS activation in response to oxidative stress, indicating the major contribution of the LanCL1-CBS interaction to the regulation of CBS activity. Furthermore, LanCL1 knockdown or Tat-LanCL1(153-173) treatment reduced H(2)O(2) or glutamate-induced neuronal damage. This study implies potential therapeutic value in targeting the LanCL1-CBS interaction for neuronal oxidative stress-related diseases.

Metabolic profiles in plasma of patients with herpes labialis based on GC-MS.

OBJECTIVE: This study aims to compare the plasma metabolic profiles of patients with herpes labialis with healthy controls and identify the biomarkers of herpes labialis. SUBJECTS AND METHODS: We collected 18 patients with herpes labialis and 20 healthy individuals. Plasma samples from both groups were analyzed using gas chromatography-mass spectrometry (GC-MS). RESULTS: According to the principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), we found that metabolic profiles had changed in patients with herpes labialis compared to the controls. By further selecting the different metabolites according to the variable importance in the projection (VIP) and p valve of t-tests, we found that acetic acid, pyroglutamic acid, alanine, ethanedioic acid, cyclohexaneacetic acid, pyruvic acid, d-mannose, phosphoric acid, l-amphetamine, and citric acid were decreased in patients with herpes labialis, while sedoheptulose and ethylamine were increased. Pathway analysis showed that herpes labialis may affect the amino acid and energy metabolism. CONCLUSIONS: Our findings may contribute to elucidating the metabolic basis of herpes labialis and provide a new perspective for further research on the "Shang-Huo" state in traditional Chinese medicine (TCM).

Wide therapeutic time-window of low-frequency stimulation at the subiculum for temporal lobe epilepsy treatment in rats.

Low-frequency stimulation (LFS) has been considered as an option for the treatment of intractable epilepsy. However, previous data showed that LFS of certain brain regions only exerts its effect within a very narrow therapeutic time window, which lasts from seconds to tens of seconds, thus restricting its clinical application. The present study was designed to determine whether there exists a target with a wider therapeutic window for LFS treatment. Therefore, evoked seizures in the rat were induced by amygdala kindling and spontaneous seizures were induced by pilocarpine. The effects of different modes of LFS at the subiculum on the progression and severity of evoked seizures and the frequency of spontaneous seizure were evaluated. We found that (i) LFS at 1Hz delivered to the subiculum before and immediately after the kindling stimulations, or after the cessation of afterdischarge (afterdischarge duration, ADD) decreased the seizure stages and shortened the ADD both in seizure acquisition and expression in amygdaloid-kindled seizures. In addition, even LFS delivered after duration of double the ADD prolonged the kindling progression. (ii) LFS delivered at 1Hz, but not 0.5, 3 or 130Hz, immediately after the cessation of kindling stimulations retarded the progression of kindling seizures. (iii) Pilocarpine-induced spontaneous seizures were completely inhibited by 1Hz LFS. Thus, these results demonstrated that LFS of the subiculum has a wide therapeutic time-window for temporal lobe epilepsy treatment in rats, suggesting that the subiculum may be a promising and suitable target for clinical application.

Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement.

BACKGROUND: Rheumatoid arthritis patients usually suffer from arthritic chronic pain. However, due to an incomplete understanding of the mechanisms underlying autoimmune disorders, the management of arthritic pain is unsatisfactory. Here, we investigated the analgesic effect and underlying mechanism of the natural flavonoid naringenin (NAR) in collagen-induced arthritis (CIA) pain. METHODS: NAR was injected (i.p.) once per day for 42 days after initial immunization, and rats were sacrificed on the 28th (the 21st day after final immunization, PID 21) and 42nd days (PID 35). The inflammatory factors, central sensitization indicators, and CRMP2 phosphorylation, as well as the anti-rheumatoid activity and analgesic effect of NAR, were further investigated. RESULTS: We found that NAR decreased the arthritis score and paw swelling, as well as the mechanical and thermal pain. The immunofluorescence results also showed a dose dependent effect of NAR on reducing the expressions of spinal cFos, IBA-1, and GFAP on the 28th (PID 21) and 42nd day (PID 35). NAR decreased the phosphorylation of CRMP2 S522 and the expression of the kinase CDK5 in the spinal dorsal horn, but pCRMP2 Y479 was unchanged. In addition, CRMP2 was co-localized with NEUN, but not IBA-1 or GFAP, indicating the involvement of neural CRMP2 phosphorylation in CIA-related pain. Finally, CRMP2 S522 phosphorylation selective inhibitor (S)-lacosamide also alleviated arthritic pain. CONCLUSIONS: Taken together, our results demonstrate that NAR alleviates inflammation and chronic pain in CIA model, which might be related to its inhibition of neuronal CRMP2 S522 phosphorylation, potentially mitigating the central sensitization. Our study provide evidence for the potential use of NAR as non-opioid-dependent analgesia in arthritic pain.

Inconsistent Time-Dependent Effects of Tetramethylpyrazine on Primary Neurological Disorders and Psychiatric Comorbidities.

The aim of this study was to investigate the time dependent effects of tetramethylpyrazine (TMP, main activity compound of Ligusticum chuanxiong Hort) on two neurological disorders and their neuropsychiatric comorbidities. 6 Hz corneal rapid kindling was used to induce epileptogenesis and the inflammatory pain was induced by intra-articular Complete Freund's adjuvant (CFA) injection. The mechanical pain thresholds were measured using von Frey hair (D4, D11, D18, D25 after CFA first injection), and the vertical rearings of the mice was observed. To test the neuropsychiatric comorbidities, anxiety-like behaviors of mice were examined by open field and elevated plus maze tests. Two behavioral despair models, tail suspension test and forced swimming test were also used to evaluate the depressive like behaviors. The results showed that TMP administered from the initial day (D1-D35 in kindling model, D0-D14 and D0-D28 in CFA model) of modeling retarded both the developments of 6 Hz corneal rapid kindling epileptogenesis and the CFA induced inflammatory pain. In comparison, late periods administration of TMP (D21-D35 in kindling and D14-D28 in CFA model) showed no effect on the epileptogenesis and the generalized seizures (GS) of kindling, but alleviated maintenance of CFA induced inflammatory pain. Furthermore, we also found all TMP treatments from the initial day of modeling alleviated the co-morbid depressive and anxiety-like behaviors in both models; however, late periods treatments did not, either in kindling or the CFA induced inflammatory pain. BDNF/ERK signaling impairment was also tested by western blot, and the results showed that TMP administered from the initial day of modeling increased the hippocampal BDNF/ERK expression, whereas late period administration showed no effects. Overall, our findings reveal the inconsistent time dependent effects of Tetramethylpyrazine on neurological disorders and their relative neuropsychiatric comorbidities, and provide novel insight into the early application of TMP that might enhance hippocampal BDNF/ERK signaling to alleviate neuropsychiatric comorbidities in neurological diseases.

A meta-analysis of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody treatment for COVID-19 patients.

OBJECTIVE: This meta-analysis aims to assess the efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies on COVID-19. METHODS: Relevant literatures about GM-CSF antibody treatment in COVID-19 patients were searched from the PubMed, Cochrane Library, Embase, Google scholar, and Baiduscholar databases from the COVID-19 outbreak in December 2019 until 1 January 2021. The primary outcomes included the death, intensive care unit (ICU) admission risk, ventilation requirement, and secondary infection. RESULTS: A total of 12 eligible literature involving 8979 COVID-19 patients were recruited, and they were divided into experimental group (n = 2673) and control group (n = 6306). Using a random-effect model, it is found that the GM-CSF antibody treatment was associated with a 23% decline of the risk of death [odd's ratio (OR): 0.34, 95% confidence interval (CI): 0.21-0.56, p < 0.0001] and a 20% enhancement of ventilation (OR: 1.47, 95% CI: 1.19, 1.80, p = 0.0002). GM-CSF antibody treatment did not have a significant correlation to secondary infection and increased risk of ICU admission in COVID-19 patients, which may be attributed to the older age and the length of stay. CONCLUSIONS: Severe COVID-19 patients can benefit from GM-CSF antibodies.

Therapeutic time window of low-frequency stimulation at entorhinal cortex for amygdaloid-kindling seizures in rats.

The present study was designed to determine whether low-frequency stimulation (LFS) of the entorhinal cortex(EC) has an anticonvulsive effect, and whether LFS delivered at different times plays different roles. We found that LFS of the EC immediately or 4 s after kindling stimulation had an anticonvulsive effect, and that the latter had a better effect on both kindling and kindled seizures. However, LFS delivered after the cessation of afterdischarge or 10 s after the kindling stimulation, augmented the epileptic activity. So the EC is a potential target for LFS to interfere with epilepsy. Our findings suggest that even in the duration of afterdischarge, there exists a "time window" for LFS treatment, indicating that the time delay of closed-loop stimulation is crucial for LFS treatment.

Comparative efficacy and safety of mycophenolate mofetil and cyclophosphamide in the induction treatment of lupus nephritis: A systematic review and meta-analysis.

BACKGROUND: Lupus nephritis (LN) remains a predominant cause of morbidity and mortality in SLE. Here we performed a meta-analysis to evaluate the efficacy and safety of the induction treatment with mycophenolate mofetil (MMF) and cyclophosphamide (CYC) for LN. METHODS: Relevant literature was searched by computer from the establishment of the database to November 2019. A meta-analysis was conducted to analysis the efficacy and safety between mycophenolate mofetil and cyclophosphamide as induction therapy in LN patients. The primary end-point was response to urine protein, serum creatinine (Scr) and serum complement C3, and the secondary end-points were complete remission and adverse reactions. RESULTS: Eighteen articles were selected for the final meta-analysis, involving 1989 patients with LN, of which the renal biopsy result could be classified into class III-V according to the standards of WHO/ISN. The results revealed that MMF was superior to CYC in increasing the level of serum complement C3 [SMD = 0.475, 95%CI (0.230-0.719)] and complete remission [RR = 1.231, 95%CI (1.055-1.437)]. Furthermore, the subgroup analysis showed that it was in Asian patients, rather than in Caucasian patients, that CYC exerted a better effect on lowering the level of urine protein (UPRO) than MMF [SMD = 0.405, 95%CI (0.081-0.730)]. Besides, when the initial UPRO level was less than 4 g/day, the effect of CYC was better than MMF [SMD = 0.303, 95%CI (0.014-0.591)]. There was no significant difference between MMF and CYC in improving Scr [SMD = 0.090, 95%CI (-0.060-0.239)]. When it came to the comparison of safety between MMF and CYC, the meta-analysis showed that MMF was superior to CYC in decreasing infection in Caucasian patients [RR = 0.727, 95%CI (0.532-0.993)], reducing the risk of leukopenia and menstrual abnormalities in Asian patients and lowering the frequency of gastrointestinal symptoms [RR = 0.639, 95%CI (0.564-0.724)], independent of race. CONCLUSIONS: MMF precedes CYC in improving serum complement C3 and complete remission regardless of race, as well as shows fewer adverse drug reactions in the induction treatment of LN belonging to type III-V. But for Asian patients or those initial UPRO levels are less than 4 g/day, CYC may be superior to MMF.

[Intranasal administration of low dosage recombinant human erythropoietin inhibits seizure in rats].

OBJECTIVE: To investigate the effect of intranasal administration of low dosage recombinant human erythropoietin (r-HuEPO) on seizure in rats. METHODS: After intranasal or intraperitoneal administration of r-HuEPO, the behavioral and electroencephalographic changes were observed in pentylenetetrazol (PTZ) and maximal electroshock (MES) induced seizure or electrical amygdaloid-kindled seizure of rats. RESULT: Intranasal administration of low dosage r-HuEPO increased the seizure latency, and decreased the seizure grade and duration, and the number of convulsive episodes in PTZ induced seizure, with the most potential dosage of 2.4 IU. Intraperitoneal administration of r-HuEPO (3 000, 4 000 IU/kg) only decreased the seizure duration and number of convulsive episodes. The seizure grade, forelimb or hindlimb extension duration were decreased in MES-induced seizure by intranasal administration of 2.4 IU r-HuEPO. In addition, intranasal administration of 2.4 IU r-HuEPO decreased the seizure grade, generalized seizure duration and afterdischarge in electrical amygdaloid-kindled rats stimulated with generalized seizure threshold. CONCLUSION: Intranasal administration of low dosage r-HuEPO can inhibit the seizure in rats.

[Fast catalogue of alien invasive weeds by Vis/NIR spectroscopy].

The feasibility of visible and short-wave near-infrared spectroscopy (VIS/WNIR) techniques as means for the nondestructive and fast detection of alien invasive weeds was evaluated. Selected sensitive bands were found validated. In the present study, 3 kinds of alien invasive weeds, Veronica persica, Veronica polita, and Veronica arvensis Linn, and one kind of local weed, Lamiaceae amplexicaule Linn, were employed. The results showed that visible and NIR (Vis/NIR) technology could be introduced in classification of the alien invasive weeds or local weed with the similar outline. Thirty x 4 weeds samples were randomly selected for the calibration set, while the remaining 20 x 4 samples for the prediction set. Smoothing methods of moving average and standard normal variate (SNV) were used to pretreat spectra data. Based on principal components analysis, soft independent models of class analogy (SIMCA) were applied to make the model. Four frontal principal components of each catalogues were applied as the input of SIMCA, and with a significance level of 0.05, recognition ratio of 78.75% was obtained. The average prediction result is 90% except for Veronica polita. According to the modeling power of each spectra data in SIMCA, some possible sensitive bands, 496-521, 589-626 and 789-926 nm, were founded. By using these possible sensitive bands as the inputs of least squares support vector machine (LS-SVM), and setting the result of LS-SVM as the object function value of genetic algorithm (GA), mutational rate, crossover rate and population size were set up as 0.9, 0.5 and 50 respectively. Finally recognition ratio of 95.63% was obtained. The prediction results of 95.63% indicated that the selected wavelengths reflected the main characteristics of the four weeds, which proposed a new way to accelerate the research on cataloguing alien invasive weeds.

Time-dependent effect of low-frequency stimulation on amygdaloid-kindling seizures in rats.

Low-frequency stimulation (LFS) has been considered as a new option for the treatment of intractable epilepsy. The present study was designed to determine whether LFS of the kindling focus given at different time points after seizures exert different roles on kindling seizures. Our results showed that: (i) In kindling animals, LFS delivered immediately after cessation of the kindling stimulus inhibited the seizure stage during kindling acquisition, whereas LFS delivered after the cessation of afterdischarge accelerated the kindling progression to stages 1 and 2. (ii) In fully kindled animals, when using the generalized seizure threshold current as the kindling stimulus, immediate LFS decreased the incidence of generalized seizures and the average seizure stage as well as shortened the cumulative generalized seizure duration (GSD). However, delayed LFS prolonged the cumulative GSD and afterdischarge duration. Our study indicates that there is a time-dependent aspect of LFS treatment, and immediate LFS has anti-epileptogenic action.

Correction to: Gender difference in acquired seizure susceptibility in adult rats after early complex febrile seizures.

In the original publication of the article, the representative EEG of female rat pups with FS in Figure 1 C and D was incorrectly intercepted from that of male rat pups. This correction does not affect the conclusions of the paper. Figure 1 has been corrected on the online PDF version and displayed below.

Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.

Proinflammatory cytokine interleukin-1 beta (IL-1ß) may accumulate in the brain during status epilepticus, but whether it contributes to the progressive refractoriness of SE remains unclear. By using a kainic acid-induced SE mice model, we tested whether pharmacological blockade or knock-out of interleukin-1 receptor type 1 (IL-1R1) could influence the diazepam-refractory phenomenon of prolonged SE. We confirmed diazepam failed to terminate prolonged SE (allowed to continue for 40min before diazepam administration). The expression level of IL-1ß in the hippocampus during prolonged SE was significantly higher than that of baseline. Interestingly, prolonged SE was not diazepam-refractory in IL-1R1 knock-out mice. Moreover, administration of interleukin-1 receptor antagonist (IL-1RA) combined with diazepam terminated established prolonged SE, while IL-1RA alone is not capable to terminate prolonged SE. On the contrary, administration of recombinant human IL-1ß weakens the efficacy of diazepam by prolonging its latency to terminate non-prolonged SE. Thus, the present study provides direct evidence that accumulated IL-1ß contributed to the diazepam refractoriness of prolonged SE, and suggests that interleukin-1 receptor is a target for adjunctive control of diazepam-refractory SE.