Efficacy and safety of agomelatine in epilepsy patients with sleep and mood disorders: An observational, retrospective cohort study.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of agomelatine for treating the sleep and mood disorders in epilepsy patients. METHODS: Retrospective data were derived from 113 epilepsy patients for at least 8 weeks. All the subjects were divided into two groups, one was treated with agomelatine, the other was treated with escitalopram. Their depression and anxiety states were assessed by Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Scales. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The HAMA, HAMD and PSQI scores in both groups significantly declined after the treatments with agomelatine and escitalopram. However, the agomelatine group exhibited greater improvement in terms of HAMA and PSQI scores compared to the escitalopram group. No severe adverse events were observed in agomelatine group. SIGNIFICANCE: Agomelatine performed better in HAMA and PSQI scores compared to escitalopram, where no significant increase in seizure frequency or side effects were observed. Possibly, agomelatine presents a promising therapeutic option for treating the sleep or mood disorders in epilepsy patients.

Identification of disease-related genes in Plasmodium berghei by network module analysis.

BACKGROUND: Plasmodium berghei has been used as a preferred model for studying human malaria, but only a limited number of disease-associated genes of P. berghei have been reported to date. Identification of new disease-related genes as many as possible will provide a landscape for better understanding the pathogenesis of P. berghei. METHODS: Network module analysis method was developed and applied to identify disease-related genes in P. berghei genome. Sequence feature identification, gene ontology annotation, and T-cell epitope analysis were performed on these genes to illustrate their functions in the pathogenesis of P. berghei. RESULTS: 33,314 genes were classified into 4,693 clusters. 4,127 genes shared by six malaria parasites were identified and are involved in many aspects of biological processes. Most of the known essential genes belong to shared genes. A total of 63 clusters consisting of 405 P. berghei genes were enriched in rodent malaria parasites. These genes participate in various stages of parasites such as liver stage development and immune evasion. Combination of these genes might be responsible for P. berghei infecting mice. Comparing with P. chabaudi, none of the clusters were specific to P. berghei. P. berghei lacks some proteins belonging to P. chabaudi and possesses some specific T-cell epitopes binding by class-I MHC, which might together contribute to the occurrence of experimental cerebral malaria (ECM). CONCLUSIONS: We successfully identified disease-associated P. berghei genes by network module analysis. These results will deepen understanding of the pathogenesis of P. berghei and provide candidate parasite genes for further ECM investigation.

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.

Inhibition of TMEM16A improves cisplatin-induced acute kidney injury via preventing DRP1-mediated mitochondrial fission.

Acute kidney injury (AKI) is associated with high morbidity and mortality. Our previous study has demonstrated that TMEM16A, a Ca2+-activated chloride channel, contributes to renal fibrosis progression in chronic kidney disease. However, whether TMEM16A is involved in AKI is still unknown. In this study, we established cisplatin AKI mice model and found that TMEM16A expression was upregulated in the injured kidney. In vivo knockdown of TMEM16A effectively prevented cisplatin-induced tubular cell apoptosis, inflammation and kidney function loss. Western blot and transmission electron microscopy (TEM) revealed that TMEM16A knockdown inhibited Drp1 translocation from the cytoplasm to mitochondria and prevented mitochondrial fission in tubular cells. Consistently, in cultured HK2 cells, knockdown or inhibition of TMEM16A by shRNA or its specific inhibitor suppressed cisplatin-induced mitochondrial fission and its associated energy dysfunction, ROS accumulation, and cell apoptosis via inhibiting Drp1 activation. Further investigation showed that genetic knockdown or pharmacological inhibition of TMEM16A inhibited cisplatin-induced Drp1 Ser-616 site phosphorylation through ERK1/2 signaling pathway, whereas overexpression of TMEM16A promoted this effect. Treatment with Drp1 or ERK1/2 inhibitor could efficiently prevent cisplatin-induced mitochondrial fission. Collectively, our data suggest that TMEM16A inhibition alleviated cisplatin-induced AKI by preventing tubular cell mitochondrial fission through the ERK1/2 / Drp1 pathway. Inhibition of TMEM16A may be a novel therapeutic strategy for AKI.

Cytokines/chemokines and immune checkpoint molecules in anti-leucine-rich glioma-inactivated 1 encephalitis.

OBJECTIVE: We aimed to investigate levels of cytokines/chemokines and immune checkpoint molecules in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis. METHODS: The study recruited 12 patients with anti-LGI1 encephalitis and six non-inflammatory controls from the Qilu Hospital of Shandong University treated between January 2019 and December 2020. Serum levels of 30 cytokines/chemokines and 10 checkpoint molecules were measured in participants of both the groups. RESULTS: In contrast to those in the control group, 24 cytokines/chemokines and 5 immune checkpoint molecules were differentially expressed in patients with anti-LGI1 encephalitis, with 14 cytokines being upregulated and 10 being downregulated. There were 1033 enriched biological processes and 61 enriched Kyoto Encyclopedia of Genes and Genomes signaling pathways. CONCLUSION: A wide range of cytokines/chemokines and immune checkpoint molecules are implicated in immune regulation in anti-LGI1 encephalitis, indicating that they may serve as important targets in the development and treatment of the disease.

Long-acting tunable release of amlodipine loaded PEG-PCL micelles for tailored treatment of chronic hypertension.

Hypertension is a chronic condition that requires lifelong therapeutic management. Strict adherence to drug administration timing improves efficacy, while poor adherence leads to safety concerns. In light of these challenges, we present a nanofluidic technology that enables long-acting drug delivery with tunable timing of drug administration using buried gate electrodes in nanochannels. We developed a poly(ethylene glycol) methyl ether-block-poly(ε-caprolactone) (PEG-PCL)-based micellar formulation of amlodipine besylate, a calcium channel blocker for hypertension treatment. The electrostatically charged PEG-PCL micellar formulation enhanced drug solubility and rendered amlodipine responsive to electrostatic release gating in nanochannels for sustained release at clinically relevant therapeutic dose. Using a low-power (<3 VDC) gating potential, we demonstrated tunable release of amlodipine-loaded micelles. Additionally, we showed that the released drug maintained biological activity via calcium ion blockade in vitro. This study represents a proof of concept for the potential applicability of our strategy for chronotherapeutic management of hypertension.

Platforms to test the temporospatial capabilities of carrier systems in delivering growth factors to benefit vascular bioengineering.

In this study we produced a set of in vitro culture platforms to model vascular cell responses to growth factors and factor delivery vehicles. Two of the systems (whole vessel and whole lung vascular development) were supported by microfluidic systems facilitating media circulation and waste removal. We assessed vascular endothelial growth factor (VEGF) delivery by Pluronic F-127 hydrogel, 30 nm pore-sized microparticles (MPs), 60 nm pore-sized MP or a 50/50 mixture of 30 and 60 nm pore-sized MP. VEGF was delivered to porcine acellular lung vascular scaffolds (2.5 cm2 square pieces or whole 3D segments of acellular blood vessels) as well as whole acellular lung scaffolds. Scaffold-cell attachment was examined as was vascular tissue formation. We showed that a 50/50 mixture of 30 and 60 nm pore-sized silicon wafer MPs allowed for long-term release of VEGF within the scaffold vasculature and supported vascular endothelial tissue development during in vitro culture.

Effect of high-pressure pre-soaking on texture and retrogradation properties of parboiled rice.

BACKGROUND: The poor palatability, low digestibility, and unpleasant color of parboiled rice (PR) have severely hampered its acceptance by consumers. It is hence necessary and urgent to develop a new method for producing high-quality PR. In the current study, the effect of high hydrostatic pressure (HHP) pre-soaking on the color, textural properties, and the degree of retrogradation of PR was investigated. RESULTS: With HHP from 100 to 500 MPa, the water adsorption rate increased and cooking time decreased. Parboiled rice samples presented higher lightness scores (L) and had lower color intensity (B). Compared with a control group, PR samples treated with high-pressure pre-soaking showed a reduction of hardness values from 0.69% to 32.99%, and gumminess values also decreased from 8.58% to 33.62%. The differential scanning calorimetry (DSC) results indicated that the enthalpy values of PR samples decreased after high pressure pre-soaking. The molecular structure of PR characterized by Fourier transform infrared spectrometry confirmed that HHP pre-soaking could decrease the retrogradation level. CONCLUSION: The findings outlined above suggest that the texture and retrogradation properties of PR were improved after high-pressure pre-soaking. © 2021 Society of Chemical Industry.

Effects of Sodium Valproate Combined with Lamotrigine on Quality of Life and Serum Inflammatory Factors in Patients with Poststroke Secondary Epilepsy.

BACKGROUND: We sought to explore the effects of sodium valproate combined with lamotrigine on quality of life and serum inflammatory factors in patients with poststroke secondary epilepsy. METHODS: A total of 145 patients with post-stroke secondary epilepsy admitted to our hospital from January 2017 to June 2018 were collected: 76 treated with sodium valproate combined with lamotrigine (study group) and 69 patients treated with sodium valproate alone (control group). The levels of serum high-mobility group protein B1, matrix metalloproteinase 9, and interleukin 6 were detected before and after treatment, and the therapeutic efficacy and adverse reactions were compared between the 2 groups. RESULTS: The total effective rate of the study group was higher than that of the control group. Both groups decreased in epileptiform discharges or in the number of involved leads after treatment, with the results of the study group being lower than those of the control group. The quality of life scores in both groups was increased after treatment, albeit the scores of the study group were higher than those of the control group. In terms of the levels of serum inflammatory factors, the 2 groups were reduced after treatment; the levels of the study group were lower than those of the control group. Regarding the incidence of adverse reactions, no significant difference was seen between the 2 groups. CONCLUSIONS: Sodium valproate combined with lamotrigine has better clinical efficacy and higher safety in the treatment of poststroke secondary epilepsy and is able to reduce the expression levels of serum inflammatory factors.

Inhibitory effect of Xiaochuan pill on obstinate cough and its role in regulation of TLR4-MyD88-NF-κBp65 signaling pathway. / å“®å–˜ä¸¸æŠ‘åˆ¶é¡½å›ºæ€§å’³å—½åŠå ¶å¯¹TLR4-MyD88-NF-κBp65信号通路的调控作用.

OBJECTIVES: Cough variant asthma (CVA) is the main cause of obstinate cough. This study aimed to observe the therapeutic effect of Xiaochuan pill on CVA in a rat model, and to explore the mechanisms. METHODS: The rats were sensitized and challenged with 4% ovaibumin (OA) and 2% Al(OH)3 to establish the CVA models. They were treated with Xiaochuan pill (at the dose of 0.9, 1.8, 3.6 g/kg) or montelukast sodium once a day for 14 days. After 7 and 14 days of intervention, 5 and 10 rats were randomly selected from each group to collect bronchoalveolar lavage fluid (BALF), trachea, and lungs. The number of white blood cells (WBC) and eosinophils (EOS), and the levels of IL-1ß, TNF- α, and IFN-γ in BALF were detected. Histopathological examination of lung tissue was performed to observe the histomorphological changes. The expressions of TLR4, MyD88, NF-κBp65, and p-p65 in lung tissue were detected by Western blotting. RESULTS: The numbers of WBC and EOS in BALF of CVA rats were significantly decreased by Xiaochuan pill (P<0.05 or P<0.01). The hyperplasia of tracheal, bronchial mucosa and the infiltration of inflammatory cells in lung were alleviated obviously. After 14 d of intervention, high dose of Xiaochuan pill significantly increased the level of IFN- γ (P<0.01), reduced the levels of IL-1ß (P<0.05) and TNF-α (P<0.05), and decreased the expressions of TLR4, MyD88, p65, and p-p65 (P<0.05 or P<0.01). CONCLUSIONS: Xiaochuan pill exerts the significant therapeutic effect on obstinate cough in rats. The mechanism of action may be related to the regulation of TLR4-MyD88-NF-κBp65 signaling pathway as well as the inflammation and immune response.

Microfluidic device for the analysis of MDR cancerous cell-derived exosomes' response to nanotherapy.

Exosomes are membrane-enclosed extracellular vesicles which have been indicated as important biomarkers of cancerous cell functionality, such as multiple drug resistance (MDR). Nanoparticles based chemotherapy is a promising strategy to overcome MDR by interfering the production and composition of exosomes. Therefore, tumor-derived exosomes post-treatment by nanotherapy are implied to play critical roles of biomarkers on cancer MDR analysis. However, the efficient isolation of such exosomes from extracellular environment for their therapeutic response analysis remains challenging. In this study, we presented a microfluidic device featured exosome specific anti-CD63 immobilized ciliated micropillars, which were capable to isolate cancer-derived exosomes from cell culture medium. The captured exosomes can be recovered intact by dissolving the cilia on the micropillars using PBS soaking. Owing to the immobilized antibody in the microfluidic device, nearly 70% of exosome from the biofluid could be isolated. So the secreted exosomes of the MDR and ordinary human breast cancer cells pre-treated by free drug or nanotherapy could be isolated with high purity. The drug contents of the isolated exosomes were measured to analysis of the exosomal pathway response of MDR cells to different chemotherapeutic formulations. Such analyses and further definition of the biomarkers of these exosomes could benefit the future investigations of accurately and reliably determine design principle, functional activity, and mechanisms of nanotherapy for MDR overcoming.

Investigation of parameters that determine Nano-DC vaccine transport.

Effective migration of dendritic cells into the lymphatic system organs is the prerequisite for a functional dendritic cell vaccine. We have previously developed a porous silicon microparticle (PSM)-based therapeutic dendritic cell vaccine (Nano-DC vaccine) where PSM serves both as the vehicle for antigen peptides and an adjuvant. Here, we analyzed parameters that determined dendritic cell uptake of PSM particles and Nano-DC vaccine accumulation in lymphatic tissues in a murine model of HER2-positive breast cancer. Our study revealed a positive correlation between sphericity of the PSM particles and their cellular uptake by circulating dendritic cells. In addition, the intravenously administered vaccines accumulated more in the spleens and inguinal lymph nodes, while the intradermally inoculated vaccines got enriched in the popliteal lymph nodes. Furthermore, mice with large tumors received more vaccines in the lymph nodes than those with small to medium size tumors. Information from this study will provide guidance on design and optimization of future therapeutic cancer vaccines.

Clinical features of patients with anti-leucine-rich glioma inactivated-1 protein associated encephalitis: a Chinese case series.

Purpose: Antibodies against leucine-rich glioma inactivated 1 (LGI1) are associated with limbic encephalitis and faciobrachial dystonic seizures (FBDS). We present a large series of Han Chinese patients for further clinical refinement. Materials and methods: Serum and cerebrospinal fluid samples from patients were tested. Clinical information of patients with serum anti­LGI1antibody positivity was retrospectively reviewed, and descriptive statistical analysis was performed. Results: The median onset age of the 24 patients was 56.9 years. Among these cases, 18 (75%) patients presented with new­onset refractory seizures, 18 (75%) patients had memory deficits, eight (33.3%) patients had a personality changes and five (20.8%) patients had a disturbance of consciousness. FBDS was observed in nine (37.5%) patients and five of them presented with FBDS as the initial symptom. No cancer was detected in any patient by CT scans. Fourteen (58.3%) patients had hyponatremia. Lymphocytic pleocytosis and protein concentration elevation in CSF were detected in four (16.7%) and six (25%) patients, respectively. Twelve (50%) patients showed paroxysmal sharp/spike waves and slow waves on EEG and seven (29.2%) patients showed mesial temporal region abnormalities by MRI scans. All patients received antiepileptic drugs and immunotherapy. After treatments, the modified Rankin scores of all patients were decreased. Conclusions: Our study showed that Han Chinese patients with anti­LGI1 antibody associated encephalitis had prominent clinical manifestations including seizures, memory deficits and FBDS. They showed neurological improvement with timely immunotherapy. Prompt treatments after rapid clinical recognition is important to improve the prognosis of patients.

In-depth comparative analysis of malaria parasite genomes reveals protein-coding genes linked to human disease in Plasmodium falciparum genome.

BACKGROUND: Plasmodium falciparum is the most virulent malaria parasite capable of parasitizing human erythrocytes. The identification of genes related to this capability can enhance our understanding of the molecular mechanisms underlying human malaria and lead to the development of new therapeutic strategies for malaria control. With the availability of several malaria parasite genome sequences, performing computational analysis is now a practical strategy to identify genes contributing to this disease. RESULTS: Here, we developed and used a virtual genome method to assign 33,314 genes from three human malaria parasites, namely, P. falciparum, P. knowlesi and P. vivax, and three rodent malaria parasites, namely, P. berghei, P. chabaudi and P. yoelii, to 4605 clusters. Each cluster consisted of genes whose protein sequences were significantly similar and was considered as a virtual gene. Comparing the enriched values of all clusters in human malaria parasites with those in rodent malaria parasites revealed 115 P. falciparum genes putatively responsible for parasitizing human erythrocytes. These genes are mainly located in the chromosome internal regions and participate in many biological processes, including membrane protein trafficking and thiamine biosynthesis. Meanwhile, 289 P. berghei genes were included in the rodent parasite-enriched clusters. Most are located in subtelomeric regions and encode erythrocyte surface proteins. Comparing cluster values in P. falciparum with those in P. vivax and P. knowlesi revealed 493 candidate genes linked to virulence. Some of them encode proteins present on the erythrocyte surface and participate in cytoadhesion, virulence factor trafficking, or erythrocyte invasion, but many genes with unknown function were also identified. Cerebral malaria is characterized by accumulation of infected erythrocytes at trophozoite stage in brain microvascular. To discover cerebral malaria-related genes, fast Fourier transformation (FFT) was introduced to extract genes highly transcribed at the trophozoite stage. Finally, 55 candidate genes were identified. Considering that parasite-infected erythrocyte surface protein 2 (PIESP2) contains gap-junction-related Neuromodulin_N domain and that anti-PIESP2 might provide protection against malaria, we chose PIESP2 for further experimental study. CONCLUSIONS: Our analysis revealed a limited number of genes linked to human disease in P. falciparum genome. These genes could be interesting targets for further functional characterization.

Spectrophotometric Determination of Carbonate Ion Concentrations: Elimination of Instrument-Dependent Offsets and Calculation of In Situ Saturation States.

This work describes an improved algorithm for spectrophotometric determinations of seawater carbonate ion concentrations ([CO32-]spec) derived from observations of ultraviolet absorbance spectra in lead-enriched seawater. Quality-control assessments of [CO32-]spec data obtained on two NOAA research cruises (2012 and 2016) revealed a substantial intercruise difference in average Δ[CO32-] (the difference between a sample's [CO32-]spec value and the corresponding [CO32-] value calculated from paired measurements of pH and dissolved inorganic carbon). Follow-up investigation determined that this discordance was due to the use of two different spectrophotometers, even though both had been properly calibrated. Here we present an essential methodological refinement to correct [CO32-]spec absorbance data for small but significant instrumental differences. After applying the correction (which, notably, is not necessary for pH determinations from sulfonephthalein dye absorbances) to the shipboard absorbance data, we fit the combined-cruise data set to produce empirically updated parameters for use in processing future (and historical) [CO32-]spec absorbance measurements. With the new procedure, the average Δ[CO32-] offset between the two aforementioned cruises was reduced from 3.7 µmol kg-1 to 0.7 µmol kg-1, which is well within the standard deviation of the measurements (1.9 µmol kg-1). We also introduce an empirical model to calculate in situ carbonate ion concentrations from [CO32-]spec. We demonstrate that these in situ values can be used to determine calcium carbonate saturation states that are in good agreement with those determined by more laborious and expensive conventional methods.

Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling.

We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knockdown of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential.

Enzyme-responsive multistage vector for drug delivery to tumor tissue.

Various nanodelivery systems have been designed to release therapeutic agents upon contact with specific enzymes. However, enzyme-triggered release typically takes place in the tissue interstitium, thereby resulting in the extracellular delivery of drugs. Here, we have designed an enzyme-stimulated multistage vector (ESMSV), which enables stimulus-triggered release of drug-encapsulated nanoparticles from a microparticle. Specifically, polymeric nanoparticles with a surface matrix metalloproteinase-2 (MMP2) peptide substrate were conjugated to the surface of porous silicon microparticles. In the presence of MMP2, the polymeric nanoparticles were released into the tumor interstitium. This platform can be used to attain triggered drug release, while simultaneously facilitating the cellular internalization of drugs. The results indicate that nanoparticle release was MMP2-specific and resulted in improved intracellular uptake of hydrophobic agents in the presence of MMP2. Furthermore, in a mouse model of melanoma lung metastasis, systemic delivery of ESMSVs caused a substantial increase in intracellular accumulation of agents in cancer cells in comparison to delivery with non-stimulus-responsive particles.

A pyruvate decarboxylase-mediated therapeutic strategy for mimicking yeast metabolism in cancer cells.

Cancer cells have high rates of glycolysis and lactic acid fermentation in order to fuel accelerated rates of cell division (Warburg effect). Here, we present a strategy for merging cancer and yeast metabolism to remove pyruvate, a key intermediate of cancer cell metabolism, and produce the toxic compound acetaldehyde. This approach was achieved by administering the yeast enzyme pyruvate decarboxylase to triple negative breast cancer cells. To overcome the challenges of protein delivery, a nanoparticle-based system consisting of cationic lipids and porous silicon were employed to obtain efficient intracellular uptake. The results demonstrate that the enzyme therapy decreases cancer cell viability through production of acetaldehyde and reduction of lactic acid fermentation.