Differentiation Between Internal Carotid Artery Hypoplasia and Acquired Narrowing by Neurovascular Ultrasound: Case Series and Literature Review.

Uniformly narrowed internal carotid artery (ICA) without proximal steno-occlusion or parietal anomalies is often subject to misdiagnosis due to lack of awareness. We combined our experiences of 4 cases with 29 previously published cases to form a retrospective series including 18 cases of ICA hypoplasia and 15 cases of ICA acquired narrowing. The ultrasonic manifestations of ICA acquired narrowing and ICA hypoplasia are extremely similar, but narrowed ICA without intracranial occlusion or bottle-neck-sign highly indicates ICA hypoplasia, whereas moyamoya vessels favor ICA acquired narrowing, thus promoting the understanding of and discriminability between the two on neurovascular ultrasound.

P300-dependent acetylation of histone H3 is required for epidermal growth factor receptor-mediated high-mobility group protein A2 transcription in hepatocellular carcinoma.

High-mobility group protein A2 (HMGA2) is highly expressed in hepatocellular carcinoma (HCC) cells and contributes to tumor metastasis and poor patient survival. However, the molecular mechanism through which HMGA2 is transcriptionally regulated in HCC cells remains largely unclear. Here, we showed that the expression HMGA2 was upregulated in HCC, and that elevated HMGA2 could promote tumor metastasis. Incubation of HCC cells with epidermal growth factor (EGF) could promote the expression of HMGA2 mRNA and protein. Mechanistic studies suggested that EGF can phosphorylate p300 at Ser1834 residue through the PI3K/Akt signaling pathway in HCC cells. Knockdown of p300 can reverse EGF-induced HMGA2 expression and histone H3-K9 acetylation, whereas a phosphorylation-mimic p300 S1834D mutant can stimulate HMGA2 expression as well as H3-K9 acetylation in HCC cells. Furthermore, we identified that p300-mediated H3-K9 acetylation participates in EGF-induced HMGA2 expression in HCC. In addition, the levels of H3-K9 acetylation positively correlated with the expression levels of HMGA2 in a chemically induced HCC model in rats and human HCC specimens.

Complete resection of the gastric antrum decreased incidence and severity of delayed gastric emptying after pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is the main complication after pancreaticoduodenectomy (PD), but the mechanism is still unclear. The aim of this study was to elucidate the role of complete resection of the gastric antrum in decreasing incidence and severity of DGE after PD. METHODS: Sprague-Dawley rats were divided into three groups: expanded resection (ER group), complete resection (CR group), and incomplete resection (IR group) of the gastric antrum. The tension (g) of remnant stomach contraction was observed. We analyzed the histological morphology of the gastric wall by different excisional methods after distal gastrectomy. Moreover, patients underwent PD at our department between January 2012 and May 2016 were included in the study. These cases were divided into IR group and CR group of the gastric antrum, and the clinical data were retrospectively analyzed. RESULTS: The ex vivo remnant stomachs of CR group exhibited much greater contraction tension than others (P < 0.05). The contraction tension of the remnant stomach increased with increasing acetylcholine concentration, while remained stable at the concentration of 10 × 10-5 mol/L. Furthermore, 174 consecutive patients were included and retrospectively analyzed in the study. The incidence of DGE was significantly lower (3.5% vs. 21.3%, P < 0.01) in CR group than in IR group. In addition, hematoxylin-eosin staining analyses of the gastric wall confirmed that the number of transected circular smooth muscle bundles were higher in IR group than in CR group (8.24 ± 0.65 vs. 3.76 ± 0.70, P < 0.05). CONCLUSIONS: The complete resection of the gastric antrum is associated with decreased incidence and severity of DGE after PD. Gastric electrophysiological and physiopathological disorders caused by damage to gastric smooth muscles might be the mechanism underlying DGE.

PLD1 promotes dendritic spine morphogenesis via activating PKD1.

Dendritic spines on the dendrites of pyramidal neurons are one of the most important components for excitatory synapses, where excitatory information exchanges and integrates. The defects of dendritic spine development have been closely connected with many nervous system diseases including autism, intellectual disability and so forth. Based on our previous studies, we here report a new functional signaling link between phospholipase D1 (PLD1) and protein kinase D1 (PKD1) in dendritic spine morphogenesis. Coimmunoprecipitation assays showed that PLD1 associates with PKD1. A series of knocking down and rescuing experiments demonstrated that PLD1 acts upstream of PKD1 in positively regulating dendritic spine morphogenesis. Using PLD1 inhibitor, we found that PLD1 activates PKD1 to promote dendritic spine morphogenesis. Thus, we further reveal the roles of the two different enzymes in neuronal development.

PKD1 Promotes Functional Synapse Formation Coordinated with N-Cadherin in Hippocampus.

Functional synapse formation is critical for the wiring of neural circuits in the developing brain. The cell adhesion molecule N-cadherin plays important roles in target recognition and synaptogenesis. However, the molecular mechanisms that regulate the localization of N-cadherin and the subsequent effects remain poorly understood. Here, we show that protein kinase D1 (PKD1) directly binds to N-cadherin at amino acid residues 836-871 and phosphorylates it at Ser 869, 871, and 872, thereby increasing the surface localization of N-cadherin and promoting functional synapse formation in primary cultured hippocampal neurons obtained from embryonic day 18 rat embryos of either sex. Intriguingly, neuronal activity enhances the interactions between N-cadherin and PKD1, which are critical for the activity-dependent growth of dendritic spines. Accordingly, either disruption the binding between N-cadherin and PKD1 or preventing the phosphorylation of N-cadherin by PKD1 in the hippocampal CA1 region of male rat leads to the reduction in synapse number and impairment of LTP. Together, this study demonstrates a novel mechanism of PKD1 regulating the surface localization of N-cadherin and suggests that the PKD1-N-cadherin interaction is critical for synapse formation and function.SIGNIFICANCE STATEMENT Defects in synapse formation and function lead to various neurological diseases, although the mechanisms underlying the regulation of synapse development are far from clear. Our results suggest that protein kinase D1 (PKD1) functions upstream of N-cadherin, a classical synaptic adhesion molecule, to promote functional synapse formation. Notably, we identified a crucial binding fragment to PKD1 at C terminus of N-cadherin, and this fragment also contains PKD1 phosphorylation sites. Through this interaction, PKD1 enhances the stability of N-cadherin on cell membrane and promotes synapse morphogenesis and synaptic plasticity in an activity-dependent manner. Our study reveals the role of PKD1 and the potential downstream mechanism in synapse development, and contributes to the research for neurodevelopment and the therapy for neurological diseases.

Construction and Photoluminescent Properties of Schiff-Base Macrocyclic Mono-/Di-/Trinuclear ZnII Complexes with the Common 2-Ethylthiophene Pendant Arm.

A new flexible 2-ethylthiophene pendant-armed dialdehyde (H2tdd) was reacted with 1,3-propanediamine, [( S, S),( R, R),(±)]-1,2-diaminocyclohexane, and 1,2-bis(2-aminoethoxy)ethane, giving birth to 36-membered [2 + 2] Schiff-base macrocyclic trinuclear ZnII complex 1, 18-membered [1 + 1] mononuclear ZnII macrocycles 2-4, chiral/racemic 34-membered [2 + 2] dinuclear ZnII complexes 5-9, and 46-membered [2 + 2] dinuclear ZnII macrocycles 10-12 via ZnII ion template-assisted Schiff-base condensation. It is worth mentioning that the secondary template effects for nitrate and halide counterions have been observed in the 1,3-propanediamine involved imine condensation. In all [2 + 2] ZnII macrocycles, dinuclear complexes 5-9 display a full-folded molecular conformation, while trinuclear complex 1 and dinuclear complexes 10-12 exhibit distinct half-folded structures in the presence or absence of intramolecular π-π stacking interactions between two phenolic rings of the dialdehyde component. Interestingly, a solvent-induced single-crystal-to-single-crystal transformation was first achieved for two types of solvated mononuclear macrocycles 3a and 3b (H2O vs CH3CN) with folded and unfolded ligand conformations. In addition, the photoluminescent properties were studied for this family of Schiff-base macrocyclic ZnII complexes as well as the dialdehyde precursor H2tdd.

Genome-wide characterization and expression analysis enables identification of abiotic stress-responsive MYB transcription factors in cassava (Manihot esculenta).

The myeloblastosis (MYB) transcription factor superfamily is the largest transcription factor family in plants, playing different roles during stress response. However, abiotic stress-responsive MYB transcription factors have not been systematically studied in cassava (Manihot esculenta), an important tropical tuber root crop. In this study, we used a genome-wide transcriptome analysis to predict 299 putative MeMYB genes in the cassava genome. Under drought and cold stresses, many MeMYB genes exhibited different expression patterns in cassava leaves, indicating that these genes might play a role in abiotic stress responses. We found that several stress-responsive MeMYB genes responded to abscisic acid (ABA) in cassava leaves. We characterize four MeMYBs, namely MeMYB1, MeMYB2, MeMYB4, and MeMYB9, as R2R3-MYB transcription factors. Furthermore, RNAi-driven repression of MeMYB2 resulted in drought and cold tolerance in transgenic cassava. Gene expression assays in wild-type and MeMYB2-RNAi cassava plants revealed that MeMYB2 may affect other MeMYBs as well as MeWRKYs under drought and cold stress, suggesting crosstalk between MYB and WRKY family genes under stress conditions in cassava.

Total closure of pancreatic section for end-to-side pancreaticojejunostomy decreases incidence of pancreatic fistula in pancreaticoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a serious complication and results in prolonged hospitalization and high mortality. The present study aimed to evaluate the safety and effectiveness of total closure of pancreatic section for end-to-side pancreaticojejunostomy in pancreaticoduodenectomy (PD). METHODS: This was a prospective randomized clinical trial comparing the outcomes of PD between patients who underwent total closure of pancreatic section for end-to-side pancreaticojejunostomy (Group A) vs those who underwent conventional pancreaticojejunostomy (Group B). The primary endpoint was the incidence of pancreatic fistula. Secondary endpoints were morbidity and mortality rates. RESULTS: One hundred twenty-three patients were included in this study. The POPF rate was significantly lower in Group A than that in Group B (4.8% vs 16.7%, P<0.05). About 38.3% patients in Group B developed one or more complications; this rate was 14.3% in Group A (P<0.01). The wound/abdominal infection rate was also much higher in Group B than that in Group A (20.0% vs 6.3%, P<0.05). Furthermore, the average hospital stays of the two groups were 18 days in Group A, and 24 days in Group B, respectively (P<0.001). However, there was no difference in the probability of mortality, biliary leakage, delayed gastric emptying, and pulmonary infection between the two groups. CONCLUSION: Total closure of pancreatic section for end-to-side pancreaticojejunostomy is a safe and effective method for pancreaticojejunostomy in PD.

Transcription Factor Egr1 is Involved in High Glucose-Induced Proliferation and Fibrosis in Rat Glomerular Mesangial Cells.

UNLABELLED: Backgroud: Diabetic nephropathy is one of the most frequent causes of end-stage renal disease and is associated with proliferation of glomerular mesangial cells (MCs) and excessive production of the extracellular matrix (ECM). Several studies have shown that early growth response factor 1 (Egr1) plays a key role in renal fibrosis by regulating the expression of genes encoding ECM components. However, whether Egr1 also contributes to diabetic nephropathy is unclear. METHODS: In the present study, we compared the expression of Egr1 in kidneys from OLETF rats with spontaneous type 2 diabetes and healthy LETO rats. We also examined whether high glucose and TGF-ß1 signaling up-regulated Egr1 expression in cultured MCs, and whether Egr1 expression influenced MC proliferation and expression of ECM genes. RESULTS: We found that higher expression of Egr1 and TGF-ß1, at both the mRNA and protein levels, the kidneys from OLETF rats vs. LETO rats. High glucose or TGF-ß1 signaling rapidly up-regulated expression of Egr1 mRNA and protein in cultured MCs. Overexpressing Egr1 in MCs by transfection with M61-Egr1 plasmid or treatment with high glucose up-regulated expression of fibronectin, type IV collagen and TGF-ß1, and promoted MC proliferation. Conversely, siRNA-mediated silencing of Egr1 expression down-regulated these genes and inhibited MC proliferation. Chromatin immunoprecipitation (ChIP) assays revealed that Egr1 bound to the TGF-ß1 promoter. CONCLUSION: Our results provide strong evidence that Egr1 contributes to diabetic nephropathy by enhancing MC proliferation and ECM production, in part by interacting with TGF-ß1.

[Efficacy and Prognosis of Chemotherapy Regimen Containing BTK Inhibitor in Treatment of Recurrent/Refractory Mantle Cell Lymphoma].

OBJECTIVE: To investigate the efficacy and prognosis of chemotherapy regimen containing Bruton's tyrosine kinase (BTK) inhibitor in the treatment of relapsed/refractory mantle cell lymphoma (R/R MCL). METHODS: The clinical data of 134 patients with R/R MCL were collected and analyzed retrospectively. The clinical characteristics of patients and effect of chemotherapy regimen on efficacy, overall survival (OS) and progression-free survival (PFS) were observed. RESULTS: The median age of the patients was 58(56-61) years old, and male to female ratio was about 2.9∶1. Patients with Ann Arbor stage III-IV accounted for 77.6%, extranodal involvement > 2 for 43.3%, bone marrow involvement for 60.4%, gastrointestinal involvement for 24.6%, and hepatosplenomegaly for 38.1%. The median follow-up time was 30 (2-103) months, overall response rate (ORR) was 41.8%, 3-year PFS was not reached, and 3-year and 5-year OS rate was 62.7% and 53.8%, respectively. The ORR of BTK inhibitor group was 56.9%, which was higher than 32.5% of non-BTK inhibitor group (P =0.006). The difference was statistically significant in PFS between the two groups (P =0.002), but was not in OS (P>0.05). The difference was statistically significant in OS between classical and special morphology (P < 0.001), but was not in PFS (P >0.05). Ki-67 was an influencing factor for OS and PFS. Multivariate analysis showed that Ki-67, B symptoms, MIPI score, and Ann Arbor stage were independent prognostic factors affecting patients' OS. The second-line treatment regimen was an independent prognostic factor affecting patients' PFS. CONCLUSIONS: The chemotherapy regimen containing BTK inhibitors can effectively improve the efficacy and prolong the PFS of R/R MCL patients. Ki-67, B symptoms, MIPI score, and Ann Arbor stage are independent prognostic factors for R/R MCL patients.

Discovery of N-benzyl-6-methylpicolinamide as a potential scaffold for bleaching herbicides.

BACKGROUND: In pesticide research, bleaching herbicides have always been a hot topic. Our previous research showed that N-(4-fluorobenzyl)-2-methoxybenzamide is an innovative lead compound for bleaching herbicides. RESULTS: A total of 40 derivatives of picolinamides were prepared and evaluated for their herbicidal activity by Petri dish tests and postemergence trials. The structure-activity relationship (SAR) revealed that introducing electron-withdrawing groups at the 3- or 4-positions of the benzyl significantly enhances herbicidal activity. Furthermore, ZI-04 induced similar symptoms such as bleaching effect in treated weeds and accumulation of biosynthetic precursors for carotenoids as observed with diflufenican. ZI-04 also exhibited significant cross-resistance to diflufenican and had a lower resistance risk than diflufenican. CONCLUSION: N-benzyl-6-methylpicolinamides were discovered as a novel scaffold for bleaching herbicides. The accumulation of phytoene, phytofluene and ζ-Carotene in radish cotyledons, and cross-resistance observed with diflufenican, showed that title compounds can interfere with carotenoid biosynthesis. © 2024 Society of Chemical Industry.

[Changes in Soil Nitrogen Components and Their Relationship with Environmental Factors with Different Tea Plantation Ages].

Changes in soil nitrogen components in tea gardens affect the soil nitrogen supply capacity and nitrogen cycle. In this study, soil samples were collected from forest land, cultivated land, and tea gardens with different plantation ages (30, 50, and 70 years) to explore the changes in soil nitrogen components and their relationship with physicochemical properties and enzyme activities. The results showed that:① with the increase in tea plantation age, the silt, total phosphorus, and urease and catalase activities gradually increased, whereas the sand, clay, pH, electrical conductivity, soil organic carbon, and the activities of invertase gradually decreased. The alkaline phosphatase activity increased first and then decreased with the increase in tea plantation age, and no significant differences were observed in soil water content and acid phosphatase activity. ② With the increase in tea plantation age, the contents of acid ammonia nitrogen, amino acid nitrogen, and nitrate nitrogen (NO3--N) increased significantly, and the contents of total nitrogen, acid ammonia nitrogen, hydrolyzable unknown nitrogen, and non-hydrolyzable nitrogen in tea gardens were significantly higher than those in forest land. ③ The total phosphorus, alkaline phosphatase, and urease were the main factors affecting soil nitrogen components. Among them, organic nitrogen components were significantly correlated with total phosphorus and alkaline phosphatase, and inorganic nitrogen components were significantly correlated with alkaline phosphatase, whereas total nitrogen had significant correlations with sand, silt, total phosphorus, urease, and alkaline phosphatase.

A mutation in a coproporphyrinogen III oxidase gene confers growth inhibition, enhanced powdery mildew resistance and powdery mildew-induced cell death in Arabidopsis.

KEY MESSAGE: A gene encoding a coproporphyrinogen III oxidase mediates disease resistance in plants by the salicylic acid pathway. A number of genes that regulate powdery mildew resistance have been identified in Arabidopsis, such as ENHANCED DISEASE RESISTANCE 1 to 3 (EDR1 to 3). To further study the molecular interactions between the powdery mildew pathogen and Arabidopsis, we isolated and characterized a mutant that exhibited enhanced resistance to powdery mildew. The mutant also showed dramatic powdery mildew-induced cell death as well as growth defects and early senescence in the absence of pathogens. We identified the affected gene by map-based cloning and found that the gene encodes a coproporphyrinogen III oxidase, a key enzyme in the tetrapyrrole biosynthesis pathway, previously known as LESION INITIATION 2 (LIN2). Therefore, we designated the mutant lin2-2. Further studies revealed that the lin2-2 mutant also displayed enhanced resistance to Hyaloperonospora arabidopsidis (H.a.) Noco2. Genetic analysis showed that the lin2-2-mediated disease resistance and spontaneous cell death were dependent on PHYTOALEXIN DEFICIENT 4 (PAD4), SALICYLIC ACID INDUCTION-DEFICIENT 2 (SID2), and NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1), which are all involved in salicylic acid signaling. Furthermore, the relative expression levels of defense-related genes were induced after powdery mildew infection in the lin2-2 mutant. These data indicated that LIN2 plays an important role in cell death control and defense responses in plants.

A retrospective cohort study evaluating the improvement of medical records management based on whole-process control.

BACKGROUND: Whole-process management is a novel approach widely applied in industry and commerce; however, it is not widely used in the management of medical records in hospitals. OBJECTIVE: The purpose of this study is to investigate the application of whole-process control in the administration of a hospital's medical records department to achieve refined management of medical records. METHODS: Whole-process control is a management measure that begins with process conception and implementation and includes control over all processes. The control group included medical records that were created prior to the implementation of whole-process control, i.e., those created between June 1 and December 31, 2020. The observation group included medical records that were created after the implementation of whole-process control. The behavior of the medical records staff (in terms of medical record collection, sorting, entry, inquiry, and supply) and the final quality of the medical records (the number of grade-A medical records and their front-page quality) were compared between the two groups, and subjective judgments related to staff satisfaction were reviewed. RESULTS: The implementation of whole-process control improved the behavior of the medical records staff. The final quality of the medical records was also improved, as was the job satisfaction of the medical records staff. CONCLUSION: Implementing whole-process control improved the management of medical records and quality of medical records.

[Effect of Spartina alterniflora Invasion on Soil C:N:P Stoichiometry in Coastal Wetland of Hangzhou Bay].

The invasion of Spartina alterniflora poses a great threat to coastal wetland ecosystems. In this study, the stoichiometric characteristics of soil carbon, nitrogen, and phosphorus under a Spartina alterniflora invasion were explored using ANOVA in a coastal wetland in Hangzhou Bay, and the driving coupling relationship between soil environmental factors and soil C:N:P stoichiometric characteristics of the coastal wetland were further explored based on the redundancy analysis (RDA), boosted regression tree (BRT), and partial least squares-structural equation (PLS-SEM) model. The results showed that:① after the invasion of Spartina alterniflora, soil N:P and total nitrogen (TN) in the wetland increased significantly, and with the increase in invasion time, TN and N:P decreased significantly, whereas soil organic carbon (SOC), C:N, and C:P increased significantly. ② The RDA model revealed that the main factors affecting the stoichiometric characteristics of topsoil C:N:P were SOC>electrical conductivity (EC)>TN in winter and SOC>bulk density (BD)>TN in summer. ③ The BRT model showed that under the invasion of Spartina alterniflora, TN was the key factor affecting soil C:N and N:P, and SOC was the key factor affecting C:P. ④ The PLS-SEM model showed that clay and water content directly affected SOC, thus affecting C:N and C:P; the clay and EC directly affected total phosphorus (TP), thus affecting N:P and C:P; and the EC directly affected TN, thus affecting C:N and N:P. In conclusion, the invasion of Spartina alterniflora had a significant impact on soil C:N:P stoichiometric characteristics in the study area. Soil physical properties and nutrient content directly or indirectly affected soil C:N:P stoichiometric characteristics to varying degrees.

LncRNA HIF1A-AS2 modulated by HPV16 E6 regulates apoptosis of cervical cancer cells via P53/caspase9/caspase3 axis.

BACKGROUND: Plentiful evidence proves that lncRNAs play a crucial role in tumor development. However, the function and mechanism that were mediated by lncRNA HIF1A-AS2 in cervical cancer remain unclear. METHODS: The lncRNA HIF1A-AS2 was identified via high-throughput microarray analysis of three HPV 16-positive cervical squamous cell carcinoma (CSCC) samples and three HPV-negative normal controls. The expression of HIF1A-AS2 was detected by qRT-PCR in clinical tissues and cancer cells. In vitro and in vivo assays were performed through downregulation or upregulation of HIF1A-AS2. The possible mechanisms of HIF1A-AS2 in cervical cancer cells were explored by western blot, flow cytometric analysis and rescue assays. RESULTS: HIF1A-AS2 was significantly increased in cervical cancer tissue, and in the HPV- positive cervical cancer cells. Further investigation showed that the inhibition of HIF1A-AS2 suppressed cell proliferation, migration, invasion, and induced apoptosis, while up-regulation of HIF1A-AS2 revealed opposite results. In terms of mechanism, we found that HIF1A-AS2 was mediated by HPV16 E6 and regulated cell apoptosis via P53/caspase 9/caspase 3 axis. CONCLUSION: Our findings demonstrate that HIF1A-AS2 functions as a carcinogenic lncRNA that promotes tumor development, and serves as a candidate prognostic factor, which may contribute to the treatment of cervical cancer.

Myo1b promotes tumor progression and angiogenesis by inhibiting autophagic degradation of HIF-1α in colorectal cancer.

Myosin 1b (Myo1b) is an important single-headed membrane-associated motor of class I myosins that participate in many critical physiological and pathological processes. Mounting evidence suggests that the dysregulation of Myo1b expression has been extensively investigated in the development and progression of several tumors. However, the functional mechanism of Myo1b in CRC angiogenesis and autophagy progression remains unclear. Herein, we found that the expression of Myo1b was upregulated in CRC tissues and its high expression was correlated with worse survival. The overexpression of Myo1b promoted the proliferation, migration and invasion of CRC cells. Conversely, silencing of Myo1b suppressed tumor progression both in vitro and in vivo. Further studies indicated that Myo1b inhibited the autophagosome-lysosome fusion and potentiated the VEGF secretion of CRC cells to promote angiogenesis. Mechanistically, Myo1b blocked the autophagic degradation of HIF-1α and then led to the accumulation of HIF-1α, thus enhancing VEGF secretion and then promoting tumor angiogenesis in CRC. Together, our study provided novel insights into the role of Myo1b in CRC progression and revealed that it might be a feasible predictive biomarker and promising therapeutic target for CRC patients.

Hirudin alleviates acute ischemic stroke by inhibiting NLRP3 inflammasome-mediated neuroinflammation: In vivo and in vitro approaches.

Acute ischemic stroke is a severe condition that a vessel supplying blood to the brain is abruptly blocked mostly due to cerebral thrombosis and embolism. There is a dearth of the effective prevention and early intervention strategies. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation plays a crucial role in the pathophysiology of ischemic stroke. Hirudin is a secretion from the salivary glands of the leech Hirudo medicinalis and has a role in regulating inflammation. In this study, hirudin with a dose of 10-40 mg/kg was given to middle cerebral artery occlusion/reperfusion mice. Hirudin markedly constrained cerebral infarct area in a dose-dependent manner, and significantly improved locomotor disability at 40 mg/kg dose. Similar to MCC950, a selective NLRP3 inflammasome inhibitor, hirudin inhibited M1 polarization and promoted M2 polarization. It also strikingly suppressed the ischemia-induced overexpression of NLRP3 and its downstream components, caspase-1, apoptosis-associated speck-like protein (ASC), and interleukin-1ß (IL-1ß). Hirudin and MCC950 equivalently protected viability and death of BV-2 microglia cells against oxygen-glucose deprivation/reperfusion (OGD/R), an in vitro cell model of brain ischemia. Both agents had similar effects in normalizing the OGD/R-evoked aberrant microglial profiles and NLRP3 pathway dysregulation as observed in the mice. These results demonstrated anti-ischemic effects of hirudin and its association with the inhibition of microglial NLRP3 inflammasome-mediated neuroinflammation. Hirudin is a promising agent for the early intervention of acute ischemic stroke.

[Impact of metoprolol use in the treatment of patients with electrical-storm after cardioverter defibrillators implantation].

OBJECTIVE: To explore the effectiveness of the metoprolol dosage adjustment on reducing the incidence of electrical-storm (ES) in patients with Implantable Cardioverter Defibrillators (ICDs). METHODS: Data from patients with ICD implantation between Jan, 2003 and Jun, 2006 in our hospital were retrospectively analyzed. ES was defined as either ≥ 3 times of ventricular tachyarrhythmias (VTAs) resulting in ICD therapy or VTAs lasting more than 30 s detected by ICD without any therapy within 24 hours. RESULTS: During a follow-up period of (27.5 ± 21.2) months, ES was recorded in 39 cases [34 males, average age (52.0 ± 13.1) years] out of 119 patients (32.8%) and 9 patients died after ES. During the period of storm attack, ES was successfully controlled in 25/30 patients by various interventions, including predisposing factors corrected in 5 cases, ICD reprogramming and antiarrhythmic drugs therapy optimized in 16 cases (one received intravenous injection of metoprolol), and VTAs eliminated by catheter ablation in 4 cases. ES was spontaneously resolved in the remaining 5 cases. In the chronic phase, 2 patients with Brugada syndrome were treated with Quinidine mono-therapy while the dosage of metoprolol was adjusted in the remaining 23 patients and the dosage of metoprolol was increased gradually from (26.8 ± 13.9) mg/d to (88.9 ± 53.5) mg/d without any adverse effects (9 patients received also oral amiodarone 200 mg/d). Post dosage adjustment, the total VTA episodes [(1.9 ± 1.7) times/month vs. (0.8 ± 0.6) times/month, P = 0.004], incidence of antitachycardia pacing therapies [(4.2 ± 3.8) runs/month vs. (2.3 ± 2.0) runs/month, P = 0.003], as well as electrical cardioversion or defibrillation [(1.1 ± 0.9) times/month vs. (0.4 ± 0.2) times/month, P = 0.001] were significantly decreased. ES was not controlled until a extremely high dosage [225 - 300 (255.3 ± 41.7) mg/d] of metoprolol was reached in the remaining 5 patients. CONCLUSIONS: Metoprolol use is essential and its dosage should be individualized in the majority of ICD recipients with ES. In approximately 1/6 patients, the dosage of metoprolol should be higher than 200 mg/d.

Tortoise Plastron and Deer Antler Gelatin Prevents Against Neuronal Mitochondrial Dysfunction In Vitro: Implication for a Potential Therapy of Alzheimer's Disease.

Mitochondrial dysfunction with oxidative damage plays the fundamental roles in the pathogenesis of Alzheimer's disease. In traditional Chinese medicine (TCM) practice, animal tissue-derived gelatins are often used as nootropic agents to treat cognitive deterioration and senile dementia. Tortoise plastron gelatin (TPG) and deer antler gelatin (DAG) are the two most commonly used gelatins for this purpose. This study sought to examine the effects of the two gelatins in preventing neuronal mitochondria from oxidative damage. PC12 cells, a cell line derived from rat pheochromocytoma, exposed to the neurotoxin Aß25-35 served as an in vitro model of Alzheimer's disease. The cells were separately pre-treated with TPG and DAG at various concentrations ranging from 6.26 µg/ml-200 µg/ml, followed by co-incubation with 20 µM Aß25-35 for different duration. Cell viability, mitochondrial membrane potential (MMP) and ultrastructure, intracellular ATP, reactive oxygen species (ROS) and calcium (Ca2+) level, the expression of mitochondrial dynamic proteins and biomarkers of apoptosis were measured. Pretreatment with TPG and DAG reversed the Aß-induced reduction of cell viability in a dose-dependent manner. Both TPG and DAG significantly increased MMP and ATP, alleviated the accumulation of damaged mitochondrial fragments, and normalized the aberrant expression of multiple mitochondrial dynamic proteins of the Aß-exposed cells. Both gelatins also suppressed intracellular ROS overproduction and Ca2+ overload, overexpression of cytochrome c and pro-apoptosis biomarkers induced by the Aß exposure. These results suggest that TPG and DAG may have the anti-dementia potential by preventing neuronal mitochondria from oxidative damage.