COVID-19 vaccination for patients with epilepsy: A Chinese expert consensus.

Coronavirus disease-2019 (COVID-19) first emerged in late 2019 and has since spread worldwide. More than 600 million people have been diagnosed with COVID-19, and over 6 million have died. Vaccination against COVID-19 is one of the best ways to protect humans. Epilepsy is a common disease, and there are approximately 10 million patients with epilepsy (PWE) in China. However, China has listed "uncontrolled epilepsy" as a contraindication for COVID-19 vaccination, which makes many PWE reluctant to get COVID-19 vaccination, greatly affecting the health of these patients in the COVID-19 epidemic. However, recent clinical practice has shown that although a small percentage of PWE may experience an increased frequency of seizures after COVID-19 vaccination, the benefits of COVID-19 vaccination for PWE far outweigh the risks, suggesting that COVID-19 vaccination is safe and recommended for PWE. Nonetheless, vaccination strategies vary for different PWE, and this consensus provides specific recommendations for PWE to be vaccinated against COVID-19.

Persulfate activation with sodium alginate/sulfide coated iron nanoparticles for degradation of tetrabromobisphenol a in soil.

The accumulation of tetrabromobisphenol A (TBBPA) in soil posed a serious threat to ecosystem and human health. Sodium alginate/sulfide coated iron nanoparticles (SA@S-Fe NPs) was synthesized by a two-step modification of Fe NPs prepared with tung tree leaves extracting solution, and utilized as a persulfate (PS) activator to degrade TBBPA in soil. Response surface methodology (RSM) optimization showed a theoretical maximum TBBPA degradation reaching 99.79% at the 34.28 °C, SA@S-Fe NPs and PS additions of 3.57 g kg-1 and 36.35 mM, respectively. The degradation mechanism of TBBPA suggested that the main reactive species produced in the SA@S-Fe NPs/PS system were •OH, SO4•-, and O2•-. Proposed mechanisms for the degradation of TBBPA in soil involved debromination, benzene rings split, hydroxylation, demethylation, and complete mineralization to CO2 and H2O. We also further studied the effect to soil physicochemical properties and morphology structure during TBBPA degradation in SA@S-Fe NPs/PS system, which showed that SOM, TN, C/N and TOC slightly reduced, the heavy metals Fe, Cu and Zn still existed in stable residue form, and the soil morphology showed a certain degree of aggregation. Therefore SA@S-Fe NPs/PS technology can effectively degrade soil TBBPA, maintain soil fertility, curb the migration of heavy metals, and environmental risks.

Pharmacokinetics/pharmacodynamics of marbofloxacin in a Pasteurella multocida serious murine lung infection model.

BACKGROUND: Marbofloxacin is a third-generation fluoroquinolone developed solely for veterinary medicine with a broad spectrum of antibacterial activity against some Gram-positive and most Gram-negative bacteria, including the bovine respiratory tract pathogen, Pasteurella multocida. The objective of our study was to elucidate the pharmacokinetics and pharmacodynamics of marbofloxacin in a Pasteurella multocida infected murine lung model, and to estimate the magnitudes of pharmacokinetics-pharmacodynamics parameters associated with various effects. RESULTS: The pharmacokinetic studies revealed marbofloxacin kinetics in infected mice were linear over a dose ranging from 1.25 to 10 mg/kg of body weight. The protein binding in the plasma of neutropenic infected mice was 29.77 %. The magnitudes of the ratio of the free-drug area under the concentration-time curve over 24 h to MIC (fAUC 0-24h/MIC) associated with static effect, a 2 log10 reduction and a 3 log10 reduction of bacterial counts were 40.84, 139.34, and 278.08 h, respectively. CONCLUSIONS: Based on the dose range study, marbofloxacin exhibited concentration-dependent killing and the fAUC/MIC was the PK/PD index that correlated best with efficacy (R(2) = 83 %). On the basis of a bactericidal effect goal of fAUC 0-24h/MIC of 278.08 h, if marbofloxacin is used for the treatment of P. multocida serious lung infection with an MIC90 of 0.12 µg/ml, the current dose (2 mg/kg) would fail to achieve a bactericidal effect. It would benefit from higher doses (4 ~ 6 mg/kg) than those commonly used in clinical practice.

Epileptic seizures worsen the gait and motor abnormalities in adult patients with Dravet syndrome (with a case report and literature review).

Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is considered the most serious "epileptic encephalopathy." Here, we present a man with a de novo SCN1A mutation who was diagnosed with DS at the age of 29. In addition to pharmaco-resistant seizures and cognitive delay, he also developed moderate to severe motor and gait problems, such as crouching gait and Pisa syndrome. Moreover, it deteriorated significantly following an epileptic seizure. The patient presented with severe flexion of the head and trunk in the sagittal plane and fulfilled the diagnostic criteria for camptocormia and antecollis. After a week, it spontaneously alleviated partially. We applied levodopa to the patient and had a good response. Functional Gait Assessment (FGA) was assessed at three different times: 4 days after the seizure, 1 week after the seizure, and after taking levodopa for 2 years. The results were 4, 12, and 19 points, respectively. We postulated that: (1) gait and motor deficits are somehow influenced by recurrent epileptic episodes;(2) the nigrostriatal dopamine system is involved. To our knowledge, we were the ones who first reported this phenomenon.

Effects of estrogen receptor antagonist on biological behavior and expression of growth factors in the prolactinoma MMQ cell line.

The relationship between estrogen and pituitary prolactinoma is well documented. The biological effects of estrogen are mainly mediated by estrogen receptor α (ERα). Several lines of evidence demonstrate that growth factors such as pituitary tumor transforming gene (PTTG), basic fibroblast growth factor (bFGF), transforming growth factor ß1 (TGFß1), transforming growth factor ß3 (TGFß3), and transforming growth factor ß receptor type II (TGFßRII) play an important role in prolactinoma pathogenesis induced by estrogen, but the relationship between ERα and such growth factors is still unclear. The aims of this study are to investigate the functional role of ERα in proliferation, prolactin (PRL) secretion, and expression of the above-mentioned growth factors in MMQ cells in the absence of estrogen and to discuss the feasibility of using an estrogen receptor antagonist to treat prolactinoma. Fulvestrant, a "pure" antiestrogen without any estrogen-like activity, was used to block expression of ERα in the MMQ cell line. Proliferation and PRL secretion of MMQ cells were measured using CellTiter 96(®) AQueous One Solution Cell Proliferation Assay (MTS) and the enzyme-linked immunosorbent assay (ELISA) method. Levels of ERα, PTTG, bFGF, TGFß1, TGFß3, and TGFßRII were analyzed by real-time polymerase chain reaction (PCR) and Western blot. Fulvestrant significantly inhibited cell proliferation (up to 60.80%) and PRL secretion (up to 77.95%), and changed expression of TGFß3 and TGFßRII in the absence of estrogen. In conclusion, ERα plays an important functional role in proliferation and PRL secretion of pituitary prolactinomas and also can change expression of some growth factors even under the condition of no estrogen. Fulvestrant could potentially be an effective therapy for treating such tumors.

[Effect of the chelator BPCBG on the decorporation of uranium in vivo and uranium-induced damage of human renal tubular epithelial cells in vitro].

This study is to assess the efficacy of BPCBG on the decorporation of uranium (VI) and protecting human renal proximal tubular epithelial cells (HK-2) against uranium-induced damage. BPCBG at different doses was injected intramuscularly to male SD rats immediately after a single intraperitoneal injection of UO2(CH3COO)2. Twenty-four hours later uranium contents in urine, kidneys and femurs were measured by ICP-MS. After HK-2 cells were exposed to UO2(CH3COO)2 immediately or for 24 h followed by BPCBG treatment at different doses for another 24 or 48 h, the uranium contents in HK-2 cells were measured by ICP-MS, the cell survival was assayed by cell counting kit-8 assay, formation of micronuclei was determined by the cytokinesis-block (CB) micronucleus assay and the production of intracellular reactive oxygen species (ROS) was detected by 2',7'-dichlorofluorescin diacetate (DCFH-DA) oxidation. DTPA-CaNa3 was used as control. It was found that BPCBG at dosages of 60, 120, and 600 micromol kg(-1) resulted in 37%-61% increase in 24 h-urinary uranium excretion, and significantly decreased the amount of uranium retention in kidney and bone to 41%-31% and 86%-42% of uranium-treated group, respectively. After HK-2 cells that had been pre-treated with UO2(CH3COO)2 for 24 h were treated with the chelators for another 24 h, 55%-60% of the intracellular uranium was removed by 10-250 micromol L(-1) of BPCBG. Treatment of uranium-treated HK-2 cells with BPCBG significantly enhanced the cell survival, decreased the formation of micronuclei and inhibited the production of intracellular ROS. Although DTPA-CaNa3 markedly reduced the uranium retention in kidney of rats and HK-2 cells, its efficacy of uranium removal from body was significantly lower than that of BPCBG and it could not protect uranium-induced cell damage. It can be concluded that BPCBG effectively decorporated the uranium from UO2(CH3COO)2-treated rats and HK-2 cells, which was better than DTPA-CaNa3. It could also scavenge the uranium-induced intracellular ROS and protect against the uranium-induced cell damage. BPCBG is worth further investigation.

Recommendations for the diagnosis and treatment of paroxysmal kinesigenic dyskinesia: an expert consensus in China.

Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different causes. Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesia and can be divided into primary and secondary types based on the etiology. Clinically, PKD is characterized by recurrent and transient attacks of involuntary movements precipitated by a sudden voluntary action. The major cause of primary PKD is genetic abnormalities, and the inheritance pattern of PKD is mainly autosomal-dominant with incomplete penetrance. The proline-rich transmembrane protein 2 (PRRT2) was the first identified causative gene of PKD, accounting for the majority of PKD cases worldwide. An increasing number of studies has revealed the clinical and genetic characteristics, as well as the underlying mechanisms of PKD. By seeking the views of domestic experts, we propose an expert consensus regarding the diagnosis and treatment of PKD to help establish standardized clinical evaluation and therapies for PKD. In this consensus, we review the clinical manifestations, etiology, clinical diagnostic criteria and therapeutic recommendations for PKD, and results of genetic analyses in PKD patients performed in domestic hospitals.

The value of rapid eye movement sleep in the localization of epileptogenic foci for patients with focal epilepsy.

PURPOSE: Our aim was to investigate the value of rapid eye movement (REM) during prolonged scalp video-electroencephalography (VEEG) in the localization of epileptogenic foci for patients with focal epilepsy. METHOD: We retrospectively studied a total of 59 patients with focal epilepsy and 31 of 59 received surgery. We assessed localization of interictal epileptiform discharges (IEDs) during REM, non-rapid eye movement sleep (NREM) and wakefulness to compare with the localization of ictal EEG, clinical semiology, magnetic resonance imaging (MRI) and positron emission tomography (PET) and stereo-electroencephalogram (SEEG). We graded postoperative follow-up outcome according to Engel criteria to further verify the accuracy of localization of epileptogenic foci in REM-IEDs. NREM-IEDs and Wakefulness-IEDs. Stepwise multiple logistic regression was carried out to assess for independent association of good prognosis with REM accurate localization, temporal lobe epilepsy and MRI accurate localization. RESULTS: Clinical semiology was concordant to REM-IEDs in 40 patients (72.7 %), NREM-IEDs in 27 (49.1 %), and Wakefulness-IEDs in 25 (45.5 %). MRI lesion was concordant with REM-IEDs in 35 patients (81.4 %), Wakefulness-IEDs in 26 (60.5 %), and NREM-IEDs in 25 (58.1 %). PET localization was concordant with REM-IEDs in 20 patients (76.9 %), Wakefulness-IEDs and NREM-IEDs in 11 (42.3 %). SEEG localization was concordant with REM-IEDs in 15 patients (65.2 %), Wakefulness-IEDs in 10 (43.5 %), and NREM-IEDs in 8 (34.8 %). Thirty-one patients received surgery, and 30 (96.8 %) of them achieved good seizure control (Engel I-III). The surgical site was concordant with REM-IEDs in 23 (74.2 %), Wakefulness-IEDs and NREM-IEDs in 14 (45.2 %). In addition, the accuracy of REM-IEDs localization in temporal epilepsy (90 %) was higher than that extra-temporal epilepsy (45.5 %). REM accurate localization of epileptogenic foci was an independent factor contributing to good prognosis (P = 0.025, OR = 12.368). CONCLUSIONS: Compared with NREM-IEDs and Wakefulness-IEDs, REM-IEDs had most value for localization of epileptogenic foci in patients with focal epilepsy. REM-IEDs- accurate localization of epileptogenic foci was an independent factor contributing to good prognosis for postsurgical patients with focal epilepsy.

The adverse-effect profile of lacosamide.

Introduction: Lacosamide has been used in epilepsy patients in the United States, Europe and Asia since it was approved by the FDA in 2008. Many patients have benefited from this drug as a new generation of sodium channel blocker. With the worldwide use of this drug, its adverse effects have gradually emerged, especially some rare adverse events.Areas covered: The present review aims to summarize the adverse effects of lacosamide reported in the literature in recent years to promote the safe clinical application of the drug.Expert opinion: In more than 10 years of experience in drug usage, adverse reactions of lacosamide have also been gradually discovered. The review showed that lacosamide is safe and effective in antiepileptic treatment, and its common side effects are dizziness, headache, drowsiness, diplopia, and cardiovascular abnormalities. Skin rashes, hematotoxicity and heart damage, psychological symptoms and suicide risk have also been reported and emphasized.

Effectiveness of Surgical Treatments for Basal Ganglia Hemorrhage and Imaging Factors Affecting Hematoma Evacuation Rate by Neuroendoscopic Surgery.

BACKGROUND: Basal ganglia hemorrhage (BGH) is a devastating neurologic disease with high morbidity and mortality, and its management is still controversial. We evaluated the effectiveness of surgical treatments for BGH and investigated computed tomography (CT) imaging features affecting the hematoma evacuation rate (ER) in patients treated with neuroendoscopic surgery. MATERIALS AND METHODS: A total of 104 BGH patients who underwent craniotomy, burr-hole drainage, or neuroendoscopic surgery were analyzed retrospectively. Clinical characteristics, imaging features, and postoperative complications were compared. Univariate and multivariate regression analyses were applied to identify imaging factors associated with ER. RESULTS: A significant difference in ER was observed: 78.4% in patients treated with neuroendoscopic surgery, 33.6% in patients treated with burr-hole drainage, and 82.5% in patients treated with craniotomy (p < 0.001). Similar results were observed for operative time (p < 0.001). Five cases (12.5%) of rebleeding were found in patients treated with burr-hole drainage (p = 0.020). No significant difference was found for pneumonia, intracranial infection, gastrointestinal bleeding, hospital mortality, hospital stay, expenses, 3-day Glasgow Coma Scale (GCS) scores after surgery, or GCS at discharge. The CT imaging feature, the island sign (p = 0.004), was observed as an independent factor correlated with lower ER for neuroendoscopic surgery. CONCLUSIONS: The benefits and drawbacks of surgical treatments confirmed they have their own indications, and neuroendoscopic surgery may be relatively beneficial for BGH treatment. The island sign was an independent factor affecting ER for neuroendoscopic surgery. Therefore, comprehensive assessment of clinical data, especially the island sign, should be performed preoperatively in BGH patients.

Effect of bone marrow stromal cell-conditioned medium on the glutamate uptake of peroxide-injured astrocytes.

We aimed to investigate the effect of bone marrow stromal cell-conditioned medium (BCM) on glutamate uptake of peroxide (H(2)O(2))-injured astrocytes. Bone marrow stromal cells (BMSC) were isolated from rat bone marrow. Confluent BMSC cultures were incubated with serum-free Dulbecco's Modified Eagle's Medium to create the BCM. Astrocytes were isolated from 1-day-old rats. H(2)O(2)-injured astrocytes were cultured in BCM (experimental group) or serum-free medium (control group). The labeled glutamate ((3)H-L-glutamate) uptake by H(2)O(2)-injured astrocytes with or without BCM was compared after 1 and 3 days. We found that astrocytes cultured in BCM exhibited increased glutamate uptake compared to those cultured in serum-free medium following H(2)O(2)-induced injury (p<0.01) and concluded that BCM increased the glutamate uptake capability of H(2)O(2)-injured rat astrocytes. The therapeutic benefits associated with BMSC transplantation following brain injury might be partly due to increased glutamate uptake by astrocytes.

Effects of valproic acid on bone mineral density and bone metabolism: A meta-analysis.

PURPOSE: Numerous studies have shown that the risk of fracture is increased by long-term antiepileptic drugs (AEDs). Valproic acid (VPA) is one of the most commonly used AEDs. In this meta-analysis, we aimed to assess the effects of VPA on bone mineral density (BMD) and bone metabolism. METHODS: PubMed, Embase, Cochrane and Web of Science databases were searched from inception to January 2019 for articles focusing on the effects of VPA on BMD and bone metabolism in adults or children. A meta-analysis was performed using RevMan 5. 3 software. RESULTS: 18 studies were included in the meta-analysis. The BMD of lumber spine (MD= -0.06, 95%CI: -0.09 to -0.03, P < 0.0001) and femoral neck (MD= -0.05, 95% CI= -0.08 to -0.01, P = 0.02) was markedly decreased in the VPA group compared to healthy controls. Serum bone-specific alkaline phosphatase (BALP) level (SMD = 0.85, 95% CI: 0.30-1.40, P = 0.002) was notably increased in the VPA group compared to healthy groups. In the child group, the serum parathyroid hormone (PTH) level was higher than in healthy groups (SMD= -0.22, 95% CI: -0.40 to -0.04, P = 0.02); besides, the serum 25-hydroxy vitamin D3 (25(OH)D3) level was decreased (SMD= -0.22, 95% CI: -0.40 to -0.04, P = 0.02), while no significant alteration of these parameters was noted in the adult VPA group (P ≥ 0.05). CONCLUSIONS: VPA may reduce the BMD of lumbar spine and femoral neck in patients with epilepsy while increasing the serum BALP level. Serum PTH level are increased and serum 25(OH)D3 level decreased in children with epilepsy treated with VPA. These parameters were unaltered in adults.

The effects of lamotrigine and ethosuximide on seizure frequency, neuronal loss, and astrogliosis in a model of temporal-lobe epilepsy.

OBJECTIVE: The putative neuroprotective and disease-modifying effects of lamotrigine (LTG) and ethosuximide (ESM) were investigated in the lithium-pilocarpine (Li-Pc) model of temporal-lobe epilepsy (TLE) in rats. Then, spontaneous recurrent seizures (SRS), neuronal loss and astrogliosis were assessed. METHODS: Status Epilepticus (SE) was induced by Li-Pc in five experimental groups: 24 h after SE, all rats received twice daily either a low (10 mg/kg) or high (20 mg/kg) dose of LTG, or a low (25 mg/kg) or high (50 mg/kg) dose of ESM, or solvent. The sixth group (control) did not receive Li-Pc and was given twice daily injections with solvent only. Drug administration lasted for 7 d. Rats were systematically observed in the 5th and 6th weeks, after that the brains were prepared for histology. RESULTS: LTG dose-dependently decreased the frequency of SRS, and restricted neuronal loss, as well as astrogliosis in the hippocampus compared with the untreated SE control group. However, ESM had none of the above-mentioned effects. CONCLUSION: LTG had protective as well as disease-modifying effects in this TLE model. It was revealed that the disease-modifying effects were accompanied by the prevention of neuronal loss and astrogliosis. ESM was devoid of antiepileptogenic and its accompanying histological effects in this TLE model, in contrast to the antiepileptogenic effects found in the genetic absence epilepsy models, suggesting that different mechanisms are involved in the different models for epileptogenesis and antiepileptogenesis.

Reversion of multidrug resistance in human glioma by RNA interference.

OBJECTIVE: To explore whether the vector construction of short hairpin in vivo could make human glioma cell line BT325 produce RNA interference (RNAi) duplexes and reverse the expression of the MDR1 gene. METHODS: Three 62nt oligonucleotide fragments (shRNA) were constructed according to GeneBank MDR1 sequence and were cloned to the retrovirus-delivered vectors. After these vectors were transfected directly to the BT325 cell by Lipofectamine 2000 with enhanced green fluorescent protein (EGFP) co-transfection, the MDR1 gene silence effects were detected by the changing levels of mRNA and P-glycoprotein (P-gp) including real-time PCR (RT-PCR), Northern blot and Western blot analysis. For assessing multidrug resistance against doxorubicin (DOX) and vincristine (VCR), cell proliferation assays were performed by cell counting kit-8 and IC50 was calculated. RESULTS: The RNAi plasmid vectors were constructed successfully. The gene silence became the strongest after 48 hour transfection from Northern blot; Western blot analysis demonstrated that P-gp expression reduced to 12.9, 30.3 and 4.8%. The chemosensitivity assays showed that the transfected cell could increase the sensitivity of DOX and VCR. Based on the value of IC50, BT325 cells increased sensitivity to drugs obviously. The sequence specific RNAi could inhibit MDR1 mRNA and P-gp expression of the glioma cell line. And it may reverse multidrug resistance phenotype, which may provide promising therapeutic modalities in the treatment of human glioma.

A ditopic colorimetric sensor for fluoride ion based on thiourea mercury complex.

A novel ditopic chromogenic receptor, N-5-(8-hydroxy)quinoline-N'-4'-nitro-phenyl thiourea (1), was synthesized. The metal complex 1-Hg(2+) showed sensitive and highly selective responses to F(-) over other anions such as CH(3)CO(2)(-), H(2)PO(4)(-), HSO(4)(-) and Cl(-). 1-Hg(2+)-F(-) complex formed, which promoted the intramolecular charge transfer and led to a dramatic spectral change. The color of 1-Hg(2+) solution changed from colorless to red upon addition of F(-). Thus, a colorimetric assay of F(-) was developed in acetonitrile by naked-eye detection. F(-) behaved linearly in the 8.0 x 10(-6) to 2.0 x 10(-5) mol L(-1) concentration range with LOD as 1.4 x 10(-6) mol L(-1).

Preeclampsia and maternal risk of breast cancer: a meta-analysis of cohort studies.

BACKGROUND: Pregnancy-related hypertensive disorders, including preeclampsia (PE) and pregnancy-induced hypertension (PIH), may influence the maternal risk of breast cancer. However, results of the cohort studies were inconsistent. METHODS: An updated meta-analysis of cohort studies was performed to evaluate the association between PE, PIH and maternal breast cancer incidence. Relevant studies were identified via searching of PubMed and Embase databases. A random effect model was applied to synthesize the results. Stratified analyses were performed to evaluate the potential influence of parity, gender of offspring, and study design on the association between PE and maternal breast cancer incidence. RESULTS: Ten cohort studies with 2,417,899 pregnant women were included. Maternal risk of breast cancer was not significantly affected by PE (risk ration [RR] = 0.93, 95% confidence interval [CI]: 0.82-1.06, p = .27), or PIH (RR = 0.95, 95% CI: 0.81-1.12, p = .54). Interestingly, PE was associated with significantly lowered maternal incidence of breast cancer in women who give birth to male offspring (RR = 0.79, p < .01), and in those of prospective cohort studies (RR = 0.87, p < .01). However, no significant association between PE and maternal breast cancer was detected in primiparous women, those who gave birth to female offspring, or those of retrospective cohorts. CONCLUSIONS: Current evidence did not support a conclusive association between PE, PIH and the maternal risk of breast cancer. Gender of the offspring may influence the association between PE and maternal breast cancer incidence.

Pharmacokinetics and Pharmacodynamics of Tildipirosin Against Pasteurella multocida in a Murine Lung Infection Model.

Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound (f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect Imax model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC (fAUC0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log10 kill and 2-log10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle.

[Effects of cyclin dependent protein kinase inhibitor olomoucine on the neuronal apoptosis after status epilepticus: experiment with rats].

OBJECTIVE: To investigate the effects of olomoucine, a cyclin dependent protein kinase (CDK) inhibitor, on the neuronal apoptosis after status epilepticus (SE). METHODS: Lithium chloride was injected intraperitoneally, and pilocarpine was injected intraperitoneally after 18 h to 24 SD rats so as to cause SE. Twenty-two of the 24 rats developed SE and 2 of them died. The surviving 20 rats were then randomly divided into 2 equal groups: olomoucine group, injected intracerebroventricularly after the SE was terminated by diazepam and chloral hydrate once a day for 3 days, and SE group, infused intracerebroventricularly with DMSO solution Another 10 rats were injected intraperitoneally with normal saline and then infused intracerebroventricularly with DMSO solution to be used as control group. Six hours after SE attack 5 rats from each group were killed respectively with their brains taken out. Semiquantitative RT-PCR was used to detect the mRNA expression of anti-inflammatory cytokines, such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. Three days later the other 5 rats in each group were killed with their entorhinal cortex and hippocampus taken out. TUNEL was used to observe the apoptosis. Immunofluorescence (IF) staining was used to detect the expression of neuronal nuclear nucleoprotein (NeuN) and cyclin B1. RESULTS: TUNEL showed that apoptotic neurons were rare in the control group and were numerous in the SE group, especially in the entorhinal cortex and the hylus of dentate gyrus, and the number of apoptotic neurons in the hylus of dentate gyrus of the olomoucine group was not significantly different from that of the control group (P < 0.05), however, the number of apoptotic cells in the entorhinal cortex of the olomoucine group was still significantly higher than that of the control group (P < 0.05). IF staining demonstrated that in the control group the co-expression of NeuN and TUNEL-labeled cells was weak; and in the SE group the co-expression of NeuN and TUNEL was significantly increased compared with that in the control group (P < 0. 05). The number of cyclin B1 positive cells in the olomoucine group was 18.22 +/- 3.99, significantly lower than that of the SE group (24.57 +/- 6.78, P < 0.05). Semiquantitative RT-PCR showed that the IL-1beta and TNF-alpha mRNA expression levels of the SE group were both significantly higher than those of the control group (both P < 0.05), and the IL-1beta and TNF-alpha mRNA expression levels of the olomoucine group, except the TNF-alpha mRNA expression in the cortex, were all significantly lower than those of the SE group (all P < 0.05), and not significantly different from those of the control group (all P > 0.05). CONCLUSION: Olomoucine treatment can inhibits cell cycle protein B1 expression, anti-inflammatory cytokines such as IL-1beta and TNF-alpha secretion, thus decreasing neuronal death and providing neuroprotection after SE, which suggests a potential promising therapeutic way for epilepsy treatment.

[Reversion of multidrug resistance (MDR) in human glioma cells by RNA interference (RNAi)].

OBJECTIVE: To explore whether the constructed vector of short haprin in vivo can induce human glioma cell line BT325 to produce RNAi duplexes and reverse the expression of MDR1 gene. METHODS: Three 62nt oligonucleotide fragments (shRNA) were constructed according to GenBank MDR1 sequence and were cloned to the retrovirus-delivered vectors. After transfected these vectors directly into the human malignant glioma BT325 cells by lipofectamine 2000 with enhanced green fluorescence protein (EGFP) co-transfecting, the MDR1 gene silence effects were detected by the changing level of mRNA and P-glycoprotein including real time PCR (RT-PCR), Northern blot and Western blot analysis. To assess the multidrug resistance against adriamycin (ADR) and VCR, cell proliferation assays were performed by cell counting kit-8. RESULTS: The RNAi plasmid vectors were constructed successfully. RT-PCR showed MDR1 mRNA was significantly reduced (P < 0.05). Northern blot analysis showed that the gene silence became most intense at 48 hours after transfection. Western blot analysis demonstrated that P-gp expression was reduced at different time to 12.9%, 30.3% and 4.8%, respectively. The chemosensitivity assays indicated that the transfected cells showed an enhanced sensitivity to ADR and VCR. Based on the value of IC(50), BT325 cells had significantly increased sensitivity to the drugs. CONCLUSION: The sequence specific RNAi can inhibit MDR1 mRNA and P-gp expression in the glioma cell line. It may reverse multidrug resistance phenotype, therefore, may provide promising therapeutic modalities in the treatment of human glioma.

Effect of Chaihu-Shugan-San on the mRNA expression of the 5-HT1A receptor and cellular proliferation in the hippocampus of epileptic rats with depression.

Chaihu-Shugan-San (CHSGS) is a herbal preparation that has been shown to effectively relieve neurologic impairment and reduce depression. However, the efficacy of CHSGS in the treatment of patients with epilepsy with depression is unknown. Therefore, in the present study, adult rats were exposed to chronic mild stress following the establishment of chronic pilocarpine-induced epilepsy. Subsequently, a sucrose consumption test and open-field test (OFT) were performed to assess depression-like behavior. Rats were randomly divided into four groups: Control, model, fluoxetine (1.8 g/kg) and CHSGS (2.7 g/kg) groups. The control and model groups received normal saline. The mRNA expression levels of the 5-hydroxytryptamine 1A (5-HT1A) receptor and the number of 5-bromo-2'-deoxyuridine (BrdU)-labeled cells in the hippocampal dentate gyrus were detected using reverse transcription-quantitative polymerase chain reaction and immunohistochemical analysis, respectively. Treatment administration was conducted by once daily intragastric perfusion for 28 days. The mRNA expression levels of the 5-HT1A receptor, the number of BrdU-labeled cells in the hippocampal dentate gyrus, the consumption of sucrose, and frequency of vertical and horizontal movement scores in the OFT were enhanced in the fluoxetine and CHSGS groups compared with the model group (P<0.05). However, no statistically significant difference was detected between the fluoxetine and CHSGS groups. These data suggest that CHSGS is able to increase the expression of 5-HT1A receptor mRNA and cellular proliferation in the hippocampal dentate gyrus in epileptic rats with depression, and thus effectively improve certain symptoms of depression.