Tumor Exosomal ENPP1 Hydrolyzes cGAMP to Inhibit cGAS-STING Signaling.

To evade immune surveillance, tumor cells express ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) on the surface of their membrane, which degrades extracellular cyclic GMP-AMP (cGAMP), thereby inhibiting the cyclic GMP-AMP synthase (cGAS) stimulator of interferon gene (STING) DNA-sensing pathway. To fully understand this tumor stealth mechanism, it is essential to determine whether other forms of ENPP1 with hydrolytic cGAMP activity also are present in the tumor microenvironment to regulate this innate immune pathway. Herein, it is reported that various tumor-derived exosomes carry ENPP1, and can hydrolyze synthetic 2'3'-cGAMP and endogenous 2'3'-cGAMP produced by cells to inhibit cGAS-STING pathway in immune cells. Moreover, tumor exosomal ENPP1 also can hydrolyze 2'3'-cGAMP bound to LL-37 (an effective transporter of 2'3'-cGAMP) to inhibit STING signaling. Furthermore, high expression of ENPP1 in exosomes is observed isolated from human breast and lung cancer tissue, and tumor exosomal ENPP1 inhibited the immune infiltration of CD8+ T cells and CD4+ T cells. The results elucidate the essential function of tumor exosomal ENPP1 in the cGAS-STING pathway, furthering understanding of the crosstalk between the tumor cells and immune system.

Clostridium lamae sp. nov., a novel bacterium isolated from the fresh feces of alpaca.

A novel Gram-positive, anaerobic, nonspore-forming, rod-shaped bacterium, designated strain NGMCC 1.200840 T, was isolated from the alpacas fresh feces. The taxonomic position of the novel strain was determined using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences revealed strain NGMCC 1.200840 T was a member of the genus Clostridium and closely related to Clostridium tertium DSM 2485 T (98.16% sequence similarity). Between strains NGMCC 1.200840 T and C. tertium DSM 2485 T, the average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) were 79.91% and 23.50%, respectively. Genomic DNA G + C content is 28.44 mol%. The strain can utilise D-glucose, D-mannitol, D-lactose, D-saccharose, D-maltose, D-xylose, L-arabinose, D-cellobiose, D-mannose, D-melezitose, D-raffinose, D-sorbitol, L-rhamnose, D-trehalose, D-galactose and Arbutin to produce acid. The optimal growth pH was 7, the temperature was 37 °C, and the salt concentration was 0-0.5% (w/v). The major cellular fatty acids (> 10%) included iso-C15:0, anteiso-C15:0 and iso-C17:0 3-OH. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three unidentified phospholipids and two unidentified aminolipids. Based on phenotypic, phylogenetic and chemotaxonomic characteristics, NGMCC 1.200840 T represents a novel species within the genus Clostridium, for which the named Clostridium lamae sp. nov. is proposed. The type strain is NGMCC 1.200840 T (= CGMCC 1.18014 T = JCM 35704 T).

An Integrative Nomogram for Identifying Cognitive Impairment Using Seizure Type and Cerebral Small Vessel Disease Neuroimaging Markers in Patients with Late-Onset Epilepsy of Unknown Origin.

INTRODUCTION: Cognitive impairment (CI) is a common comorbidity in patients with late-onset epilepsy of unknown origin (LOEU). However, limited data are available on effective screening methods for CI at an early stage. We aimed to develop and internally validate a nomogram for identifying patients with LOEU at risk of CI and investigate the potential moderating effect of education on the relationship between periventricular white matter hyperintensities (PVHs) and cognitive function. METHODS: We retrospectively reviewed the clinical data of 61 patients aged ≥ 55 years diagnosed with LOEU. The main outcome was CI, reflected as an adjusted Montreal Cognition Assessment score of < 26 points. A nomogram based on a multivariable logistic regression model was constructed. Its discriminative ability, calibration, and clinical applicability were tested using calibration plots, the area under the curve (AUC), and decision curves. Internal model validation was conducted using the bootstrap method. The moderating effect of education on the relationship between PVH and cognitive function was examined using hierarchical linear regression. RESULTS: Forty-four of 61 (72.1%) patients had CI. A nomogram incorporating seizure type, total cerebral small vessel disease burden score, and PVH score was built to identify the risk factors for CI. The AUC of the model was 0.881 (95% confidence interval: 0.771-0.994) and 0.78 (95% confidence interval: 0.75-0.8) after internal validation. Higher educational levels blunted the negative impact of PVH on cognitive function. CONCLUSION: Our nomogram provides a convenient tool for identifying patients with LOEU who are at risk of CI. Moreover, our findings demonstrate the importance of education for these patients.

Bacteroides rhinocerotis sp. nov., isolated from the fresh feces of rhinoceros in Beijing Zoo.

A Gram-negative strain, anaerobic, non-motile, non-spore-forming, rod-shaped bacterial strain named as NGMCC 1.200684 T was isolated from the fresh feces of rhinoceros in Beijing Zoo. Based on 16S rRNA gene sequences, phylogenetic analysis indicated that strain NGMCC 1.200684 T belonged to the genus Bacteroides and was most strongly related to the type strain of Bacteroides uniformis ATCC 8492 T (96.88%). The G + C content of the genomic DNA was determined to be 46.62%. Between strains NGMCC 1.200684 T and B. uniformis ATCC 8492 T, the average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) were 93.89 and 67.60%, respectively. Strain NGMCC 1.200684 T can produce acid from fermentation of several substrates, including glucose, mannitol, lactose, saccharose, maltose, salicin, xylose, cellobiose, mannose, raffinose, sorbitol, trehalose, D-galactose, and maltotriose. The major cellular fatty acids (> 10%) were identified as anteiso-C15:0, iso-C15:0, iso-C14:0, and iso-C17:0 3-OH. The polar lipid profiles of strain NGMCC 1.200684 T were determined to contain diphosphatidyl glycerol, phosphatidylglycerol, phosphatidylethanolamine, three unknown phospholipids, and two unknown amino-phospholipids. Based on phenotypic, phylogenetic, and chemotaxonomic characteristics, a novel species of the genus Bacteroides, Bacteroides rhinocerotis sp. nov. is proposed. The type strain is NGMCC 1.200684 T (= CGMCC 1.18013 T = JCM 35702 T).

Transcutaneous Auricular Vagus Nerve Stimulation (ta-VNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial.

This study explored the efficacy and safety of transcutaneous auricular vagus nerve stimulation (ta-VNS) in patients with epilepsy. A total of 150 patients were randomly divided into active stimulation group and control group. At baseline and 4, 12, and 20 weeks of stimulation, demographic information, seizure frequency, and adverse events were recorded; at 20 weeks, the patients underwent assessment of quality of life, Hamilton Anxiety and Depression scale, MINI suicide scale, and MoCA scale. Seizure frequency was determined according to the patient's seizure diary. Seizure frequency reduction > 50% was considered effective. During our study, the antiepileptic drugs were maintained at a constant level in all subjects. At 20 weeks, the responder rate was significantly higher in active group than in control group. The relative reduction of seizure frequency in the active group was significantly higher than that in the control group at 20 weeks. Additionally, no significant differences were shown in QOL, HAMA, HAMD, MINI, and MoCA score at 20 weeks. The main adverse events were pain, sleep disturbance, flu-like symptoms, and local skin discomfort. No severe adverse events were reported in active and control group. There were no significant differences in adverse events and severe adverse events between the two groups. The present study showed that ta-VNS is an effective and safe therapy for epilepsy. Furthermore, the benefit in QOL, mood, and cognitive state of ta-VNS needs further validation in the future study although no significant improvement was shown in this study.

Lactococcus intestinalis sp. nov., a new lactic acid bacterium isolated from intestinal contents in Alzheimer's disease mice.

A gram-positive, facultatively anaerobic, and coccoid or ovoid-shaped bacterium designated M2458T was isolated from the intestinal contents of APPswe/PSΔE9 mouse model of Alzheimer's disease. With the polyphasic approach, the taxonomic position of the novel isolate was confirmed. Strain M2458T grew well at 37 °C on YCFA agar. Strain M2458T belongs to the family Streptococcaceae and class Bacilli, and it is closed to Lactococcus formosensis NBRC 109475T (97.59% sequence similarity) according to its 16S rRNA gene sequence. In a comparison of two housekeeping genes, rpoA and rpoB, strain M2458T was found to be well separated from Lactococcus formosensis NBRC 109475T. On the basis of whole genome sequences, the DNA G+C content was 38.29 mol%. The phylogentic analysis of the whole genome showed that a different branch was clearly formed in the phylogenetic tree of strain M2458T compared to other strains in the genus Lactococcus. A total of eight genes in strain M2458T are involved in the 'neurodegenerative disease' pathway, which involves an annotated protein (glyceraldehyde 3-phosphate dehydrogenase) involved in Alzheimer's disease. In terms of average nucleotide identity and digital DNA-DNA hybridization, strain M2458T was identified as a novel species of the genus Lacococcus. The major fatty acids (> 10% of the total fatty acids) were C18:1ω9c (39.68%), C16:0 (13.26%) and C18:1ω7c (11.52%). The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, and an unidentified phospholipid. As a result of its genotypic and phenotypic characteristics, strain M2458T was considered to be a new species within the genus Lactococcus; the name Lactococcus intestinalis sp. nov. has been proposed, with type strain M2458T (=JCM 35706 = CGMCC 1.60066).

Dynamic Changes in Fermentation Quality and Structure and Function of the Microbiome during Mixed Silage of Sesbania cannabina and Sweet Sorghum Grown on Saline-Alkaline Land.

Protein-rich Sesbania cannabina and sugar-rich sweet sorghum [Sorghum dochna (Forssk.) Snowden] are characterized by their higher tolerance to saline-alkaline stresses and simultaneous harvests. They could be utilized for coensiling because of their nutritional advantages, which are crucial to compensate protein-rich forage in saline-alkaline regions. The current study investigated the fermentation quality, microbial community succession, and predicted microbial functions of Sesbania cannabina and sweet sorghum in mixed silage during the fermentation process. Before ensiling, the mixtures were treated with compound lactic acid bacteria (LAB) inoculants followed by 3, 7, 14, 30, and 60 days of fermentation. The results revealed that the inoculated homofermentative species Lactobacillus plantarum and Lactobacillus farciminis dominated the early phase of fermentation, and these shifted to the heterofermentative species Lactobacillus buchneri and Lactobacillus hilgardii in the later phase of fermentation. As a result, the pH of the mixed silages decreased significantly, accompanied by the growth of acid-producing microorganisms, especially L. buchneri and L. hilgardii, which actively influenced the bacterial community structure and metabolic pathways. Moreover, the contents of lactic acid, acetic acid, 1,2-propanediol, and water-soluble carbohydrates increased, while the contents of ammonia-N and fiber were decreased, with increasing ratios of sweet sorghum in the mixed silage. Overall, coensiling Sesbania cannabina with >30% sweet sorghum is feasible to attain high-quality silage, and the relay action between homofermentative and heterofermentative LAB species could enhance fermentation quality and conserve the nutrients of the mixed silage. IMPORTANCE The coensiling of Sesbania cannabina and sweet sorghum is of great practical importance in order to alleviate the protein-rich forage deficiency in saline-alkaline regions. Furthermore, understanding the microbial community's dynamic changes, interactions, and metabolic pathways during ensiling will provide the theoretical basis to effectively regulate silage fermentation. Here, we established that coensiling Sesbania cannabina with >30% sweet sorghum was effective at ensuring better fermentation quality and preservation of nutrients. Moreover, the different fermentation types of LAB strains played a relay role during the fermentation process. The homofermentative species L. plantarum and L. farciminis dominated in the early phase of fermentation, while the heterofermentative species L. buchneri and L. hilgardii dominated in the later phase of fermentation. Their relay action in Sesbania cannabina-sweet sorghum mixed silage may help to improve fermentation quality and nutrient preservation.

Comparative Metagenomics and Metabolomes Reveals Abnormal Metabolism Activity Is Associated with Gut Microbiota in Alzheimer's Disease Mice.

A common symptom in Alzheimer's disease (AD) is cognitive decline, of which the potential pathogenesis remains unclear. In order to understand the mechanism of gut microbiota in AD, it is necessary to clarify the relationship between gut microbiota and metabolites. Behavioral tests, pathological examination, metagenomics, and metabolomics were applied to analyze the difference of gut microbiota and metabolome between APPswe/PS1ΔE9 (PAP) mice with cognitive decline and age-matched controls, and their possible correlations. Our results showed that PAP mice and health mice had different structures of the bacterial communities in the gut. The abundances and diversities of the bacterial communities in health mice were higher than in PAP mice by metagenomics analysis. The abundances of Libanicoccus massiliensis, Paraprevotella clara, and Lactobacillus amylovorus were significantly increased in PAP mice, while the abundances of Turicibacter sanguinis, Dubosiella newyorkensis, and Prevotella oris were greatly reduced. Furthermore, PAP mice possessed peculiar metabolic phenotypes in stool, serum, and hippocampus relative to WT mice, as is demonstrated by alterations in neurotransmitters metabolism, lipid metabolism, aromatic amino acids metabolism, energy metabolism, vitamin digestion and absorption, and bile metabolism. Microbiota-host metabolic correlation analysis suggests that abnormal metabolism in stool, serum, and hippocampus of PAP mice may be modulated by the gut microbiota, especially T. sanguinis, D. newyorkensis, and P. oris. Therefore, abnormal metabolism activity is associated with gut microbiota in Alzheimer's disease mice. Our results imply that modifying host metabolism through targeting gut microbiota may be a novel and viable strategy for the prevention and treatment of AD in the future.

Whole-brain metabolic pattern analysis in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.

BACKGROUND AND PURPOSE: Faciobrachial dystonic seizures (FBDS) and hyponatremia are the distinct clinical features of autoimmune encephalitis (AE) caused by antibodies against leucine-rich glioma-inactivated 1 (LGI1). The present study aims to explore the pathophysiological patterns and neural mechanisms underlying these symptoms. METHODS: We included 30 patients with anti-LGI1 AE and 30 controls from a retrospective observational cohort. Whole-brain metabolic pattern analysis was performed to assess the pathological network of anti-LGI1 AE, as well as the symptom networks associated with FBDS. Logistic regression was applied to explore independent predictors of FBDS. Finally, we used a multiple regression model to investigate the hyponatremia-associated brain network and its effect on serum sodium levels. RESULTS: The pathological network of anti-LGI1 AE involved hypermetabolism in the cerebellum, subcortical structures and Rolandic area, as well as hypometabolism in the medial prefrontal cortex. The symptom network of FBDS included hypometabolism in the cerebellum and Rolandic area (pFDR <0.05). Hypometabolism in the cerebellum was an independent predictor of FBDS (p < 0.001). Hyponatremia-associated network highlighted a negative effect on the caudate nucleus, frontal and temporal white matter. The metabolism of the hypothalamus was negatively associated with (Pearson's R = -0.180, p = 0.342), while not the independent predictor for serum sodium level (path c' = -7.238, 95% confidence interval = -30.947 to 16.472). CONCLUSIONS: Our results provide insights into the whole-brain metabolic patterns of patients with anti-LGI1 AE, including the symptom network associated with FBDS and the hyponatremia-associated brain network. The findings help us to understand the neural mechanisms underlying anti-LGI1 AE and to evaluate the progress of this disease.

Modulation of Fermentation Quality and Metabolome in Co-ensiling of Sesbania cannabina and Sweet Sorghum by Lactic Acid Bacterial Inoculants.

Sesbania cannabina (SC) is a protein-rich roughage that thrives under moderate-severe saline-alkali (MSSA) soils with the potential to relieve the shortage of high nutritive forage. Sweet sorghum (SS) also tolerates MSSA soils and contains rich fermentable carbohydrates which could improve the fermentation quality in mixed silage. The present study investigated the silage quality, bacterial community, and metabolome in the mixed silage of SC and SS (SC-SS) with or without lactic acid bacterial (LAB) inoculants. Four ratios (10:0, 7:3, 5:5, and 3:7) of SC and SS were treated with sterile water or LAB inoculants (homofermentative Companilactobacillus farciminis and Lactiplantibacillus plantarum, and heterofermentative Lentilactobacillus buchneri and Lentilactobacillus hilgardii), which were analyzed after 60 days of ensiling. Results revealed that LAB inoculation improved the fermentation quality by increasing the lactic acid content and decreasing the ammonia nitrogen and butyric acid contents compared with the untreated group. LAB inoculation also raised the relative feed value by reducing indigestible fibers [e.g., neutral detergent fiber (NDF), acid detergent fiber, and hemicellulose]. Microbial and metabolomic analysis indicated that LAB inoculants could modify the bacterial community and metabolome of SC-SS silage. In co-ensiling samples except for SC alone silage, L. buchneri and L. hilgardii were the dominant species. Metabolites with bioactivities like anti-inflammatory, antioxidant, antimicrobial, and anti-tumor were upregulated with LAB inoculation. Furthermore, correlation analysis demonstrated that active metabolites (e.g., glycitin, glabrene, alnustone, etc.) were positively correlated with L. buchneri, while tripeptides (e.g., SPK, LLK, LPH, etc.) were positively correlated with L. hilgardii. Adequately describing the SC-SS silage by multi-omics approach might deepen our understanding of complicated biological processes underlying feature silages fermentation. Moreover, it may also contribute to screening of targeted functional strains for MSSA-tolerating forage to improve silage quality and promote livestock production.

Effects of Lactobacillus hilgardii 60TS-2, with or without homofermentative Lactobacillus plantarum B90, on the aerobic stability, fermentation quality and microbial community dynamics in sugarcane top silage.

This study investigated the effects of Lactobacillus hilgardii (LH), alone or in combination with Lactobacillus plantarum (LP), on the aerobic stability, fermentation quality and dynamics of the bacterial and fungal communities of sugarcane top silage. Results demonstrated that LH and LHLP (LH combined with LP) improved the aerobic stability of sugarcane top silages. As the exposure time increased, the pH values and the contents of lactic acid, acetic acid, as well as propionic acid remained stable in silage treated with LH and LHLP. The abundance of L. hilgardii was enriched and the undesirable microorganisms, such as Acetobacter pasteurianus, Paenibacillus amylolyticus and yeasts like Kazachstania humilis, were suppressed in silages treated with LH and LHLP. In conclusion, LH-treated silage, whether with LP or not, positively impacted the fungal and bacterial microbes. This improved the quality of fermentation, the aerobic stability, and reduced aerobic spoilage in sugarcane top silage.

The Clinical Value of 18 F-FDG-PET in Autoimmune Encephalitis Associated With LGI1 Antibody.

Purpose: The metabolic patterns of 18F-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG-PET) in autoimmune encephalitis associated with leucine-rich glioma-inactivated 1 antibody (LGI1 AE) are still unclear. We performed a cohort study to investigate the clinical metabolic characteristics and diagnostic value based on 18F-FDG-PET in patients with LGI1 AE. Materials and Methods: A total of 34 patients including 18 patients (53%) in the acute phase and 16 patients (47%) in the chronic phase who were diagnosed with LGI1 AE were retrospectively analyzed from October 2014 to June 2018 at the Department of Neurology in Beijing Tiantan Hospital, the Capital Medical University. The clinical data were collected by searching through electronic medical records. Results: The initial 18F-FDG-PET scan indicated a significant abnormal metabolic pattern in 31 LGI1 AE patients (91%), whereas only 20 patients (59%) showed an abnormal MRI signal (P < 0.05). The 18F-FDG-PET metabolic pattern was reversible after treatment; most of the patients showed an almost normal uptake of 18F-FDG-PET after discharge. Regarding the spatial distribution, the abnormal metabolic pattern in LGI1 AE subjects exhibiting hypermetabolism was specifically located in the basal ganglia (BG) and medial temporal lobe (MTL). BG hypermetabolism was observed in 28 subjects (82%), and 68% of patients showed MTL hypermetabolism. A total of 17 patients (50%) exhibited faciobrachial dystonic seizures (FBDS), and the remaining subjects showed non-FBDS symptoms (50 and 50%). BG-only hypermetabolism was detected in seven subjects in the FBDS subgroup (7/16) but in only one subject in the non-FBDS subgroup (1/15) (44 vs. 7%, P < 0.05). Conclusion: 18F-FDG-PET imaging was more sensitive than MRI in the diagnosis of LGI1 AE. Isolated BG hypermetabolism was more frequently observed in subjects with FBDS, suggesting the potential involvement of the BG.

Effects of ferulic acid esterase-producing Lactobacillus fermentum and cellulase additives on the fermentation quality and microbial community of alfalfa silage.

BACKGROUND: Alfalfa (Medicago sativa) is an important forage material widely used for animal feed production. Ensiling is an effective method for preserving alfalfa, but it has shown some limitations in the production of high-quality alfalfa silage due to its low water soluble carbohydrates (WSC) content and high buffering capacity. Lactic acid bacteria (LAB) and cellulase are often used as silage additives to promote the ensiling process and enhance fermentation quality. METHODS: Experiments were conducted to investigate the effects of ferulic acid esterase (FAE)-producing Lactobacillus fermentum 17SD-2 (LF) and cellulase (CE) on the fermentation quality and microbial community of alfalfa silage. After 60 days of ensiling, analysis of fermentation quality and bacterial diversity in alfalfa silages were conducted using high-performance liquid chromatography and high-throughput sequencing methods. RESULTS: Alfalfa was ensiled with additives (LF, CE, and LF+CE) or without additives for 60 days. All additives increased lactic acid and decreased pH values and ammonia-N contents compared to control. Among all treatments, the combined addition of LF and CE showed lowest pH (4.66) and ammonia-N (NH3-N, 0.57% DM) content, highest contents of lactic acid (LA, 10.51% DM), dry matter (DM, 22.54%) and crude protein (CP, 24.60% DM). Combined addition of LF and CE performed better in reducing neutral detergent fiber (NDF, 29.76% DM) and acid detergent fiber (ADF, 22.86% DM) contents than the addition of LF (33.71, 27.39% DM) or CE (32.07, 25.45% DM) alone. Moreover, the microbial analysis indicated that LF+CE treatments increased the abundance of desirable Lactobacillus and inhibited the growth of detrimental Enterobacter and Clostridia in alfalfa silage. DISCUSSION: Combined addition of FAE-producing LF and CE is more effective than treatments of LF or CE alone in improving fermentation quality and nutrition values of alfalfa silage. This is likely due to a synergistic effect of CE and FAE produced by LF on plant cell wall degradation, indicating that these additives promote each other to improve fiber degradation and silage fermentation. In conclusion, combined addition of FAE-producing LF and CE could be a feasible way to improve alfalfa silage quality.

Quinolone derivatives: Potential anti-HIV agent-development and application.

Acquired immune deficiency syndrome (AIDS)/human immunodeficiency virus (HIV) is one of the largest and most devastating public health pandemics throughout the world. The global pandemic of drug-sensitive HIV and the increasing threat from drug-resistant HIV result in an urgent need to develop more effective anti-HIV candidates. Quinolone represents a significant class of privileged heterocycles, and its derivatives possess promising in vitro and in vivo anti-HIV properties. The 4-quinolone elvitegravir has already been approved for the treatment of HIV; thus, quinolone derivatives might be promising candidates with anti-HIV activity. This review emphasizes quinolone derivatives with potential anti-HIV activity, covering articles published between 1992 and 2019. The structure-activity relationship is also discussed to provide insights for further development of more active quinolone derivatives.

Lactobacillus plantarum PFM 105 Promotes Intestinal Development Through Modulation of Gut Microbiota in Weaning Piglets.

Lactobacillus plantarum is a widespread bacterial species and is commonly used as a probiotic. L. plantarum PFM105 was isolated from the rectum of a healthy sow. Here we found that L. plantarum PFM105 showed probiotic effect on weaning piglets in which intestinal inflammation and unbalanced gut microbiota happened frequently. L. plantarum PFM105 was identified to improve the growth of weaning piglet and promote the development of small intestinal villi. Antibiotics are often used in weaning piglet to prevent intestinal infection and promote the growth of animal. We found that weaning piglets feeding with L. plantarum PFM105 showed similar growth promotion but decreased diarrhea incidence compared with those feeding with antibiotics. High-throughput sequencing was used to analyze the gut microbiota in weaning piglets treated with L. plantarum PFM105 or antibiotics. The relative abundance of beneficial microbes Prevotellaceae and Bifidobacteriaceae were increased in colon of weaning piglet feeding L. plantarum PFM105, while antibiotics increased the relative abundance of bacteria associated with pathogenicity, such as Spirochaeta and Campylobacteraceae. L. plantarum PFM 105 increased indicators of intestinal health including serum levels of IgM, IL-10, and TGF-ß, and colonic levels of SCFAs. We found strong correlations between the alterations in gut microbiota composition caused by feeding antibiotics and probiotics and the measured growth and health parameters in weaning piglets. The addition of L. plantarum PFM105 could significantly increase the relative abundance of metabolic genes which may important to intestinal microbiota maturation. Altogether, we demonstrated here that L. plantarum PFM 105 could promote intestinal development through modulation of gut microbiota in weaning piglets.

The efficacy and safety of nimodipine in acute ischemic stroke patients with mild cognitive impairment: a double-blind, randomized, placebo-controlled trial.

Nimodipine might be effective in subcortical vascular dementia (VaD). Its benefit in preventing further cognitive decline in patients with acute ischemic stroke (AIS) and vascular mild cognitive impairment (VaMCI) remains to be established. In this multicenter, double-blind trial, we randomly assigned 654 eligible patients to nimodipine 30 mg three times a day or placebo. The primary outcome was any cognitive decline defined by the changes on the Mini-Mental State Examination (ΔMMSE ≤ -3) or vascular AD assessment scale cognitive subscale (ΔADAS-cog ≥ 4) at 6 months. Secondary outcomes included any distribution shift of ΔADAS-cog, ΔMMSE or cognitive improvement defined by ΔADAS-cog ≤ -2, or ΔMMSE ≥ 0. The primary outcome in the nimodipine group and placebo group were similar for ΔMMSE ≤ -3 (4.18% and 7.22%, respectively, P = 0.15) and ΔADAS-cog ≥ 4 (8.36% and 8.93% respectively, P = 0.88). The distribution shift of ΔADAS-cog and ΔMMSE differed significantly between the two groups (P = 0.03 and P = 0.05 respectively). Cognitive improvement occurred in 55.4% in the nimodipine group and 43.6% in the placebo group measured by ΔADAS-cog ≤ -2 (Odds Ratio, 1.54; 95% confidence interval [CI] 1.10-2.14, P < 0.01) or 84.0% and 74.6% respectively by ΔMMSE ≥ 0 (Odds Ratio, 1.79; 95% CI 1.18-2.70, P < 0.01). Nimodipine was associated with better cognitive function in the memory domain. The adverse events rate was similar in two groups. This study is registered with ClinicalTrials.gov, NCT01220622. Nimodipine did not show benefit to prevent cognitive decline in AIS patients with VaMCI, but improved cognition moderately, especially measured in the memory domain.

Seizure semiology in leucine-rich glioma-inactivated protein 1 antibody-associated limbic encephalitis.

OBJECTIVE: The objective of this study was to advance the characterization of seizure semiology in leucine-rich glioma-inactivated protein 1 (LGI1) antibody-associated limbic encephalitis (LE). METHODS: Eighteen patients diagnosed with LGI1 LE were identified. Seizure semiology, demographic features, MRI and fluorodeoxyglucose positron emission tomography (FDG-PET), electroencephalograms, and outcomes following immunotherapy were evaluated. RESULTS: Patients were divided into the following groups based on seizure semiology: faciobrachial dystonic seizure only (FBDS-only, n=4), epileptic seizure without FBDS (Non-FBDS, n=6), and FBDS plus epileptic seizure (FBDS+, n=8). In the group with Non-FBDS, the majority of patients (5/6) manifested mesial temporal lobe epilepsy (MTLE) like semiology (i.e., fear, epigastric rising, staring, and automatisms) with a frequency of 7±5 times per day and a duration of 15.3±14.3s. In the group with FBDS+, the distinctive symptom was FBDS followed by epileptic events, especially automatisms (7/8), with a frequency of 16±12 times per day and a duration of 13.0±8.0s. In these cases, 67% and 50% of the patients showed abnormalities on MRI and FDG-PET, respectively, and the mesial temporal lobe structures were most often involved. Ictal discharges were observed in 0/4, 6/6, and 8/8 of the patients in the groups with FBDS only, Non-FBDS, and FBDS+, respectively. The temporal lobe was mainly affected. Immunotherapy had favorable therapeutic effects. SIGNIFICANCE: The LGI1 LE should be considered as one disease syndrome with a series of clinical manifestation. Identifying types of unique semiology features will facilitate the early diagnosis and the timely initiation of immunotherapy.

Clinical analysis of leucine-rich glioma inactivated-1 protein antibody associated with limbic encephalitis onset with seizures.

We summarized the clinical characteristics of patients presenting with seizures and limbic encephalitis (LE) associated with leucine-rich glioma inactivated-1 protein antibody (LGI1) in order help recognize and treat this condition at its onset.We analyzed clinical, video electroencephalogram (VEEG), magnetic resonance imaging (MRI), and laboratory data of 10 patients who presented with LGI1-LE and followed up their outcomes from 2 to 16 (9.4 ±â€Š4.2) months.All patients presented with seizures onset, including faciobrachial dystonic seizure (FBDS), partial seizure (PS), and generalized tonic-clonic seizure (GTCS). Four patients (Cases 3, 5, 7, and 8) had mild cognitive deficits. Interictal VEEG showed normal patterns, focal slowing, or sharp waves in the temporal or frontotemporal lobes. Ictal VEEG of Cases 4, 5, and 7 showed diffuse voltage depression preceding FBDS, a left frontal/temporal origin, and a bilateral temporal origin, respectively. Ictal foci could not be localized in other cases. MRI scan revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity and evidence of edema in the right medial temporal lobe in Case 3, left hippocampal atrophy in Case 5, hyperintensities in the bilateral medial temporal lobes in Case 7, and hyperintensities in the basal ganglia and frontal cortex in Case 10. All 10 serum samples were positive for LGI1 antibody, but it was only detected in the cerebrospinal fluid (CSF) of 7 patients. Five patients (Cases 2, 4, 6, 7, and 8) presented with hyponatremia. One patient (Case 2) was diagnosed with small cell lung cancer. While responses to antiepileptic drugs (AEDs) were poor, most patients (except Case 2) responded favorably to immunotherapy.LGI1-LE may initially manifest with various types of seizures, particularly FBDS and complex partial seizures (CPS) of mesial temporal origin, and slowly progressive cognitive involvement. Clinical follow-up, VEEG monitoring, and MRI scan are helpful in early diagnosis. Immunotherapy is effective for the treatment of both seizure and LE associated with LGI1 antibody. Although mostly nonparaneoplastic, tumor screening is recommended in some cases.

Rationale and design of a double-blind, placebo-controlled, randomized trial to evaluate the safety and efficacy of nimodipine in preventing cognitive impairment in ischemic cerebrovascular events (NICE).

BACKGROUND: Stroke is the second most common cause of mortality and the leading cause of neurological disability, cognitive impairment and dementia worldwide. Nimodipine is a dihydropyridinic calcium antagonist with a role in neuroprotection, making it a promising therapy for vascular cognitive impairment and dementia. METHODS/DESIGN: The NICE study is a multicenter, randomized, double-blind, placebo-controlled study being carried out in 23 centers in China. The study population includes patients aged 30-80 who have suffered an ischemic stroke (≤7 days). Participants are randomly allocated to nimodipine (90 mg/d) or placebo (90 mg/d). The primary efficacy is to evaluate the level of mild cognitive impairment following treatment of an ischemic stroke with nimodipine or placebo for 6 months. Safety is being assessed by observing side effects of nimodipine. Assuming a relative risk reduction of 22%, at least 656 patients are required in this study to obtain statistical power of 90%. The first patient was recruited in November 2010. DISCUSSION: Previous studies suggested that nimodipine could improve cognitive function in vascular dementia and Alzheimer's disease dementia. It is unclear that at which time-point intervention with nimodipine should occur. Therefore, the NICE study is designed to evaluate the benefits and safety of nimodipine, which was adminstered within seven days, in preventing/treating mild cognitive impairment following ischemic stroke.

Acute stepwise challenge test with levodopa in treated patients with parkinsonism.

OBJECTIVE: The aim of this study was to establish a new stepwise type of acute challenge test with incremental doses of levodopa/benserazide, and verify its predictive value in follow-up diagnoses and outcomes of deep-brain stimulation (DBS) in treated patients with parkinsonism. DESIGN: Prospective cohort study. OUTCOMES: The optimal cutoff points for UPDRS-III improvement in these stepwise levodopa tests. In this study, we established acute challenge tests with incremental doses of levodopa/benserazide (100/25mg, 150/37.5mg, 200/50mg and 300/75 mg) in treated patients with parkinsonism (n=175). The receiver operating characteristic (ROC) curves were plotted to compare peak UPDRS-III improvement of PD patients (n=112) with that of non-PD parkinsonism patients (n=63). The point on the ROC curve with the highest Youden index was defined as the optimal cutoff point in motor improvement for differential diagnoses. The results of the new tests were compared with follow-up diagnoses and the outcomes of DBS. RESULTS: The optimal cutoff points for UPDRS-III improvement with maximal Youden Indices on ROC curves from the tests, with the four incremental doses of levodopa/benserazide, were 12.2% (100/25mg), 22.3% (150/37.5mg), 27.9% (200/50mg) and 33.4% (300/75 mg). The test showed significant correlation with follow-up diagnosis and the outcomes of DBS (P of Kappa <0.01). CONCLUSIONS: The results suggested that the new acute stepwise levodopa challenge test is a useful tool for the diagnosis of PD.