Discovery of a quinoline-containing compound JT21-25 as a potent and selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1).

ASK1 kinase inhibition has become a promising strategy for treating inflammatory diseases, such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we reported the discovery of a promising compound 9h (JT21-25) containing quinoline structures as a potent small molecule inhibitor of ASK1. The compound JT21-25 was selective against MAP3K kinases TAK1 (>1960.8-fold), and much higher than the selectivity of GS-4997 for TAK1 (312.3-fold). In addition, different concentrations of JT21-25 did not show significant toxicity in normal LO2 liver cells, and the cell survival rate was greater than 80 %. The Oil Red O staining experiment showed that at the 4 µM and 8 µM concentrations of JT21-25, only slight cytoplasmic fat droplets were observed in LO2 cells, and there was no significant fusion between fat droplets. In the biochemical analysis experiment, JT21-25 significantly reduced the content of CHOL, LDL, TG, ALT, and AST. In summary, these findings suggested that compound JT21-25 might be valuable for further investigation as a potential candidate in the treatment of associated diseases.

Exploring novel indazole derivatives as ASK1 inhibitors: Design, synthesis, biological evaluation and docking studies.

Apoptosis signal regulated kinase 1 (ASK1, MAP3K5) is a member of the mitogen activated protein kinase (MAPK) signaling pathway, involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has become a promising strategy for the treatment of Non-alcoholic steatohepatitis (NASH) disease. A series of novel ASK1 inhibitors with indazole scaffolds were designed and synthesized, and their ASK1 kinase activities were evaluated. The System Structure Activity Relationship (SAR) study discovered a promising compound 33c, which has a strong inhibitory effect on ASK1. Noteworthy observations included a discernible reduction in lipid droplets within LO2 cells stained with Oil Red O, coupled with a decrease in LDL, CHO, and TG content within the NASH model cell group. Mechanistic inquiries revealed that compound 33c could inhibit the protein expression levels of the upregulated ASK1-p38/JNK signaling pathway in TNF-α treated HGC-27 cells and regulate apoptotic proteins. In summary, these findings suggest that compound 33c may be valuable for further research as a potential candidate compound against NASH.

Perforating cutaneous vessels: A key feature of acupoints - Anatomical evidence from five-Shu acupoints in the upper limbs.

Acupuncture has been proven an effective clinical treatment for numerous pathological conditions and malfunctions. However, substantial anatomical evidence for acupuncture points (APs) and meridians is still lacking, so the location of APs is relatively subjective and understanding of the biological mechanisms of acupuncture is limited. All these problems hinder the clinical applications and worldwide acceptance of acupuncture. Our long-term microsurgery experience has indicated that Perforating Cutaneous Vessels (PCVs) are highly relevant to APs but the anatomical evidence is insufficient. To address this lack, two specimens of fresh adult human upper limbs were dissected using an advanced vascular perfusion-fixation method and then examined. The results show that all 30 five-Shu APs in the upper limbs have corresponding PCVs. Both specimens showed a 100% coincidence rate between APs and PCVs, indicating that PCVs could be critical anatomical features of APs. This study also provides an anatomical basis for locating APs objectively via preliminary detection of PCVs. The findings could lead to a better theoretical understanding of mechanisms of acupuncture and the essence of meridians.

Amyloid-Beta Peptides 40 and 42 Employ Distinct Molecular Pathways for Cell Entry and Intracellular Transit at the Blood-Brain Barrier Endothelium.

The blood-brain barrier (BBB) plays a critical role in maintaining the equilibrium between amyloid beta (Aß) levels in blood and the brain by regulating Aß transport. Our previous publications demonstrated that BBB trafficking of Aß42 and Aß40 is distinct and is disrupted under various pathophysiological conditions. However, the intracellular mechanisms that allow BBB endothelium to differentially handle Aß40 and Aß42 have not been clearly elucidated. In this study, we identified mechanisms of Aß endocytosis in polarized human cerebral microvascular endothelial cell monolayers. Our studies demonstrated that Aß peptides with fluorescent label (F-Aß) were internalized by BBB endothelial cells via energy, dynamin, and actin-dependent endocytosis. Interestingly, endocytosis of F-Aß40 but not F-Aß42 was substantially reduced by clathrin inhibition, whereas F-Aß42 but not F-Aß40 endocytosis was reduced by half after inhibiting the caveolae-mediated pathway. Following endocytosis, both isoforms were sorted by the endo-lysosomal system. Although Aß42 was shown to accumulate more in the lysosomes, which could lead to its higher degradation and/or aggregation at lower lysosomal pH, Aß40 demonstrated robust accumulation in recycling endosomes, which may facilitate its exocytosis by the endothelial cells. These results provide a mechanistic insight into the selective ability of BBB endothelium to transport Aß40 versus Aß42. This knowledge contributes to the understanding of molecular pathways underlying Aß accumulation in the BBB endothelium and associated BBB dysfunction. Moreover, it allows us to establish mechanistic rationale for altered Aß40:Aß42 ratios and anomalous amyloid deposition in the cerebral vasculature as well as brain parenchyma during Alzheimer's disease progression. SIGNIFICANCE STATEMENT: Differential interaction of Aß40 and Aß42 isoforms with the blood-brain barrier (BBB) endothelium may contribute to perturbation in Aß42:Aß40 ratio, which is associated with Alzheimer's disease (AD) progression and severity. The current study identified distinct molecular pathways by which Aß40 and Aß42 are trafficked at the BBB, which regulates equilibrium between blood and brain Aß levels. These findings provide molecular insights into mechanisms that engender BBB dysfunction and promote Aß accumulation in AD brain.

Deconvolution of Plasma Pharmacokinetics from Dynamic Heart Imaging Data Obtained by Single Positron Emission Computed Tomography/Computed Tomography Imaging.

Plasma pharmacokinetic (PK) data are required as an input function for graphical analysis of single positron emission computed tomography/computed tomography (SPECT/CT) and positron emission tomography/CT (PET/CT) data to evaluate tissue influx rate of radiotracers. Dynamic heart imaging data are often used as a surrogate of plasma PK. However, accumulation of radiolabel in the heart tissue may cause overprediction of plasma PK. Therefore, we developed a compartmental model, which involves forcing functions to describe intact and degraded radiolabeled proteins in plasma and their accumulation in heart tissue, to deconvolve plasma PK of 125I-amyloid beta 40 (125I-Aß 40) and 125I-insulin from their dynamic heart imaging data. The three-compartment model was shown to adequately describe the plasma concentration-time profile of intact/degraded proteins and the heart radioactivity time data obtained from SPECT/CT imaging for both tracers. The model was successfully applied to deconvolve the plasma PK of both tracers from their naïve datasets of dynamic heart imaging. In agreement with our previous observations made by conventional serial plasma sampling, the deconvolved plasma PK of 125I-Aß 40 and 125I-insulin in young mice exhibited lower area under the curve than aged mice. Further, Patlak plot parameters extracted using deconvolved plasma PK as input function successfully recapitulated age-dependent plasma-to-brain influx kinetics changes. Therefore, the compartment model developed in this study provides a novel approach to deconvolve plasma PK of radiotracers from their noninvasive dynamic heart imaging. This method facilitates the application of preclinical SPECT/PET imaging data to characterize distribution kinetics of tracers where simultaneous plasma sampling is not feasible. SIGNIFICANCE STATEMENT: Knowledge of plasma pharmacokinetics (PK) of a radiotracer is necessary to accurately estimate its plasma-to-brain influx. However, simultaneous plasma sampling during dynamic imaging procedures is not always feasible. In the current study, we developed approaches to deconvolve plasma PK from dynamic heart imaging data of two model radiotracers, 125I-amyloid beta 40 (125I-Aß 40) and 125I-insulin. This novel method is expected to minimize the need for conducting additional plasma PK studies and allow for accurate estimation of the brain influx rate.

The role of ultrasonography in diagnosis of neuralgic amyotrophy.

OBJECTIVE: To investigate the value of high frequency ultrasound in diagnosis of neuralgic amyotrophy. MATERIALS AND METHODS: From January 2010 to December 2020, the ultrasonographic images of 117 patients with neuralgic amyotrophy diagnosed by the Department of Neurology and hand & foot surgery of Shandong Provincial Hospital Affiliated to Shandong First Medical University were retrospectively analyzed. The ultrasonographic features were summarized. RESULTS: High frequency ultrasound could clearly show the degree of the affected nerves: No ultrasonic findings were found in 12 cases (10%). The affected nerves were thickening and hypoechogenicity with loss of normal fascicular definition in 28 cases (24%). The affected nerves showed hourglass-like changes, including constriction and torsion in 77 cases (66%). In addition, ultrasound can determine the extent of the lesion, and microvascular imaging can display small blood flow signal within the nerve. There was a significant statistical difference between the diameter of the thickened nerve fascicle and the diameter of the nerve fascicle at the corresponding site of the contralateral normal limb. CONCLUSIONS: High frequency ultrasound is a valuable imaging method for diagnosis of neuralgic amyotrophy.

Soluble ST2 predicts continuous renal replacement therapy in patients receiving venoarterial extracorporeal membrane oxygenation.

OBJECTIVE: This study aimed to evaluate the relationship between plasma soluble ST2 (sST2) levels 24 h after extracorporeal membrane oxygenation (ECMO) initiation and continuous renal replacement therapy (CRRT) in patients receiving venoarterial ECMO (V-A ECMO) support. METHODS AND RESULTS: Data of patients who received ECMO support for postcardiotomy cardiogenic shock between January 2017 and July 2019 were retrospectively collected from Beijing Anzhen Hospital, Capital Medical University. Ultimately, 116 patients were included in the present study for analysis. The concentration of sST2 was determined by enzyme-linked immunosorbent assay (ELISA). The log10 sST2 levels were higher in patients undergoing CRRT than those who did not (6.06 vs. 6.22, p = 0.019). Patients undergoing CRRT had a lower survival rate than those who did not (32.8% vs. 67.3%, p < 0.001). In the univariate logistic regression analysis, sST2, HCO3-, lactate, and creatinine levels 24 h after ECMO initiation were related to CRRT (p < 0.05). In the multivariate logistic regression analysis, HCO3- and sST2 were identified as independent risk factors for CRRT use in patients undergoing ECMO (p < 0.05). The area under receiver operator characteristic curve (AUC) for sST2 and HCO3- together was 0.72 (95% confidence interval (CI), 0.79-0.91), which was better than those of sST2 or HCO3- alone (0.63 vs. 0.67). CONCLUSIONS: sST2 and HCO3-levels at 24 h after ECMO initiation were associated with CRRT and could predict CRRT use in postcardiotomy cardiogenic shock patients undergoing ECMO.

Design, Synthesis and In Vivo Fluorescence Imaging Study of a Cytochrome P450 1B1 Targeted NIR Probe Containing a Chelator Moiety.

Cytochrome P450 (CYP) 1B1 has been found to be overexpressed specifically in tumor tissues at an early stage, which makes it a potential cancer biomarker for molecular imaging. Multimodal imaging combines different imaging modalities and offers more comprehensive information. Thus, imaging probes bearing more than one kind of signal fragment have been extensively explored and display great promise. Herein, we developed a near infrared (NIR) probe with a chelator moiety targeting CYP1B1 by conjugating α-naphthoflavone (ANF) derivatives with both an NIR dye and a chelator for potential application in bimodal imaging. Enzymatic inhibitory studies demonstrated inhibitory activity against CYP1B1 and selectivity among CYP1 were successfully retained after chemical modification. Cell-based saturation studies indicated nanomolar range binding affinity between the probe and CYP1B1 overexpressed cancer cells. In vitro competitive binding assays monitored by confocal microscopy revealed that the probe could specifically accumulate in tumor cells. In vivo and ex vivo imaging studies demonstrated that the probe could effectively light-up the tumor tissues as early as 2 hours post-injection. In addition, the fluorescence was significantly blocked by co-injection of CYP1B1 inhibitor, which indicated the probe accumulation in tumor sites was due to specific binding to CYP1B1.

Design, Synthesis, and Preliminary Evaluation of [68Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer's Disease Mouse Model.

Aberrant insulin signaling has been considered one of the risk factors for the development of Alzheimer's disease (AD) and has drawn considerable attention from the research community to further study its role in AD pathophysiology. Herein, we describe the development of an insulin-based novel positron emission tomography (PET) probe, [68Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [68Ga]Ga-NOTA-insulin showed a significantly higher uptake (0.396 ± 0.055 SUV) in the AD mouse brain compared to the normal (0.140 ± 0.027 SUV) mouse brain at 5 min post injection and also showed a similar trend at 10, 15, and 20 min post injection. In addition, [68Ga]Ga-NOTA-insulin was found to have a differential uptake in various brain regions at 30 min post injection. Among the brain regions, the cortex, thalamus, brain stem, and cerebellum showed a significantly higher standard uptake value (SUV) of [68Ga]Ga-NOTA-insulin in AD mice as compared to normal mice. The inhibition of the insulin receptor (IR) with an insulin receptor antagonist peptide (S961) in normal mice showed a similar brain uptake profile of [68Ga]Ga-NOTA-insulin as it was observed in the AD case, suggesting nonfunctional IR in AD and the presence of an alternative insulin uptake route in the absence of a functional IR. The Gjedde-Patlak graphical analysis was also performed to predict the input rate of [68Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [68Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [18F]AV1451 and [11C]PIB to noninvasively study the role of insulin in AD pathophysiology.

Phenotypic and functional alterations of monocyte subsets with aging.

BACKGROUND: It has been widely accepted that monocytes are one of the central mediators contributing to inflammaging. However, it remains unclear whether aged monocytes, similar to aged T cells, have characteristics of hyperactivation and increased expression of co-inhibitory molecules. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from young (21-40 years old), middle-aged (41-60 years old), and older human subjects (> 60 years old). Flow cytometry was used to monitor changes in the expression of surface molecules of monocyte subsets and cytokine-producing capacity. RESULTS: We observed increased tumor necrosis factor-α: TNF-α and decreased interleukin-6 (IL-6) production in monocytes from older adults compared with young and middle-aged adults. Older adults had a greater percentage of intermediate and non-classical monocyte subsets, along with increased levels of the immune activation markers human leukocyte antigen-DR (HLA-DR), and adhesion molecules cluster of differentiation molecule 11b (CD11b) and L-selectin (CD62L). Furthermore, we observed increased C-C motif chemokine receptor 2 (CCR2) expression on classical monocytes and decreased C-X3-C motif chemokine receptor 1 (CX3CR1) expression on non-classical monocytes in older adult subjects. The expression of co-inhibitory receptors was reduced on monocyte subsets in older adults. CONCLUSIONS: Circulating monocytes in older adults exhibit increased expression of activation, adhesion, and migration markers, but decreased expression of co-inhibitory molecules.

The role of ultrasonography in diagnosing hourglass-like fascicular constriction(s) of the anterior interosseous nerve.

BACKGROUND: In the past, the diagnosis of hourglass-like fascicular constriction(s) of the anterior interosseous nerve mostly depended on electrophysiological examination, by which the location could not be diagnosed. There are few studies on the evaluation of hourglass-like fascicular constriction(s) by ultrasonography. PURPOSE: To evaluate the role of ultrasonography in the diagnosis of hourglass-like fascicular constriction(s) of the anterior interosseous nerve. MATERIAL AND METHODS: A retrospective analysis of 12 patients with hourglass-like fascicular constriction(s) of the anterior interosseous nerve was carried out, and the characteristics of the high-frequency ultrasonographic images were summarized and compared with surgical exploration. RESULTS: The 12 cases of hourglass-like fascicular constriction(s) of the anterior interosseous nerve were all located in the median nerve of the distal upper arm, including nine cases of single hourglass-like fascicular constriction and three cases of multiple hourglass-like fascicular constrictions. High-frequency ultrasonography can accurately locate the hourglass-like fascicular constriction(s) of the anterior interosseous nerve and the extent of neuropathy. The ultrasonographic images of hourglass-like fascicular constriction(s) of the anterior interosseous nerve showed single or multiple hourglass-like change(s) in the median nerve of the distal upper arm. The nerve fascicles on both sides of the affected nerve with hourglass-like change thickened. CONCLUSIONS: High-frequency ultrasonography could be a reliable, convenient, and non-invasive diagnostic imaging method for hourglass-like fascicular constriction(s) of the anterior interosseous nerve.

Full color 3D printing of anatomical models.

We propose an effective method for manufacturing human anatomical specimens in response to the shortage of cadaver specimens and the poor simulation results of anatomical specimen substitutes. Digital human data with high precision were used to create digital models and corresponding mapped textures. Different materials were chosen to print the digital models with full-color and multimaterial 3D-printing technology based on the histological characteristics of the anatomical structures. Anatomy experts and surgeons were then invited to compare the 3D printed models with authentic anatomical specimens in terms of morphological appearance, anatomical detail, and textural properties. The skull, brain, hand muscles, blood vessels and nerves of the hand, and the deep structure of the head and face were printed. The skull model used hard material, and the brain and hand muscles models used flexible and hard materials combined. The blood vessels, nerves of the hand, and the superficial and deep structure of the head and face used transparent materials, revealing the small vessels and nerves in the interior. In all the models, there were no significant differences from anatomical specimens in morphological appearance and anatomical detail. They also affected vision and touch in the same way as authentic specimens in the textural properties of color, roughness, smoothness, and fineness. Full-color and multi-material 3D printed anatomical models have the same visual and tactile properties as anatomical specimens and could serve to complement or supplement them in anatomy teaching to compensate for the shortage of cadavers.

Semimechanistic Population Pharmacokinetic Modeling to Investigate Amyloid Beta Trafficking and Accumulation at the BBB Endothelium.

Elevated exposure to toxic amyloid beta (Aß) peptides and consequent blood-brain barrier (BBB) dysfunction are believed to promote vasculopathy in Alzheimer's disease (AD). However, the accumulation kinetics of different Aß isoforms within the BBB endothelium and how it drives BBB dysfunction are not clearly characterized. Using single positron emission computed tomography (SPECT)-computed tomography (CT) dynamic imaging coupled with population pharmacokinetic modeling, we investigated the accumulation kinetics of Aß40 and Aß42 in the BBB endothelium. Brain clearance was quantified after intracerebral administration of 125I-Aß, and BBB-mediated transport was shown to account for 54% of 125I-Aß40 total clearance. A brain influx study demonstrated lower values of both maximal rate (Vmax) and Michaelis constant (Km) for 125I-Aß42 compared to 125I-Aß40. Validated by a transcytosis study in polarized human BBB endothelial cell (hCMEC/D3) monolayers, model simulations demonstrated impaired exocytosis was responsible for inefficient permeability and enhanced accumulation of Aß42 in the BBB endothelium. Further, both isoforms were shown to disrupt the exocytosis machinery of BBB endothelial cells so that a vicious cycle could be generated. The validated model was able to capture changes in Aß steady-state levels in plasma as well as the brain during AD progression and allowed us to predict the kinetics of Aß accumulation in the BBB endothelium.

Anatomical and Clinical Comparison of Small Free Flaps for Repairing Finger Skin Defects.

The reconstruction of finger defects requires improved functional outcomes and acceptable esthetic outcomes, and small free flaps present a good alternative technique for repairing finger skin defects. From January 2006 to December 2018, we investigated the number and diameter of proximal digital artery perforators, medial plantar artery perforators, and peroneal proper plantar digital arteries of the hallux by dissection and then transplanted free digital arterial perforator flaps, free medial plantar flaps, and free peroneal flaps from the hallux to repair small finger skin defects. The number (SD) of perforators from the medial plantar artery was approximately 2.2 (0.5), and these perforators measured 0.53 (0.20) mm in diameter. The diameter (SD) of the first metatarsal dorsal artery was approximately 1.16 (0.30) mm. A total of 25 patients were included in this study. The transplantation times (SD) for free digital arterial perforator flaps, free medial plantar flaps, and free peroneal flaps from the hallux were 3.5 (0.5) hours, 3.2 (0.7) hours, and 2.0 (0.4) hours, respectively. The follow-up period ranged from 8 to 15 months. All flaps survived and were appropriately shaped. The donor site was either covered with a free flap or directly sutured. Among these 3 types of small flaps, the free peroneal flap from the hallux can be recommended for clinical use because of the large diameter of the contributing vessels, the short operative time, the ease of access, and the improved appearance of the donor site.

Distal Finger Reconstruction by Bilateral Lateral Hallux Osteo-onychocutaneous Free Flap.

OBJECTIVE: In this report, we present our experience on the use of bilateral lateral hallux osteo-onychocutaneous free flaps for reconstruction of distal finger and the aesthetic and functional results of this technique in a series of cases. PATIENTS AND METHODS: From February 2005 to May 2015, 7 patients underwent finger reconstruction distal to the distal interphalangeal joint using the bilateral lateral hallux osteo-onychocutaneous free flaps. The mean age was 29.3 years (range, 24-33 years). The lateral hallux osteo-onychocutaneous flaps were harvested from bilateral donor sites. The size of each flap was designed based on the size of half distal finger defect. The lateral hallux osteo-onychocutaneous free flaps from both donor sites were combined to reconstruct the distal finger. More than 50% of hallux nail was preserved in each of donor sites, which was covered with a local flap. RESULTS: All flaps used for reconstruction survived without complications after surgery. The average length of follow-up was 93.4 months (range, 16-163 months). All reconstructed distal fingers showed good aesthetic appearance, except one that underwent a secondary debulking procedure. The average total active motion of the finger was 215.7 degrees (range, 200-230 degrees). Neither pain nor numbness sensation in the reconstructed fingers was complained by the patients. The donor site morbidity was minimal. All patients had pain-free and good function outcome in both feet. CONCLUSIONS: The use of the bilateral lateral hallux osteo-onychocutaneous free flaps may provide an option for distal finger reconstruction with satisfactory function and anesthetic outcomes with minimal hallux donor site morbidity.

Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4-triazolone moiety.

A novel series of benzoxazole derivatives containing 1,2,4-triazolone (5a-m) was designed. These compounds were synthesized in order to screen their anticonvulsant activities by the maximal electroshock seizure (MES) model and the subcutaneous pentylenetetrazole (sc-PTZ) seizure model in mice. The rotarod test was used to evaluate their neurotoxicities. Most of the compounds showed anti-MES activities at 100 and 300 mg/kg. Compound 5f, which showed potential anticonvulsant activity in the MES model with ED50 values of 22.0 mg/kg, was considered as the most promising one in this study. It exhibited greater safety than that of carbamazepine and valproate regarding neurotoxicity. The efficacy of compound 5f in inhibiting the tonic seizures and death induced by the convulsants 3-mercaptopropionic acid and BIC was also verified. In an enzyme-linked immunosorbent assay, compound 5f and the positive drug phenytoin significantly increased the γ-aminobutyric acid (GABA) level in the mouse brain. Further, pretreatment with an inhibitor of the GABA synthesizing enzyme dramatically raised the ED50 value of 5f in the MES model. These results confirmed that the compound 5f plays its anticonvulsive action via regulating the GABA function in the brain. Also, a docking study of the compound 5f in the benzodiazepine (BZD) binding site of the GABAA receptor confirmed possible binding of the compound 5f with BZD receptors.

Impact of Social Media on Current Medical Conferences.

BACKGROUND: Medical conferences are forums for research, continuing medical education, and networking. Social media is increasingly used for communication and networking due to its low cost and ability to overcome large distances. This study investigates the impact that social media brings to the current conference system. METHODS: There are three parts of this study: (1) comparing two similar brachial plexus injuries (BPIs) courses without (2009) and with (2017) social media support, and the participants' feedback; (2) sharing our experiences in the management of the 2018 International Course on SuperMicrosurgery (ICSM) conference; and (3) evaluating the studies from the social media platform International Microsurgery Club (IMC), for the consensus pertaining to social media and conference system. RESULTS: With the help of social media, international attendance increased during the 2017 BPI conference compared with the 2009 BPI course (25 nationalities in 2009 vs. 35 in 2017). At least 23% obtained their meeting information through social media. Live surgery was the overall main attraction (79%). The 2018 ICSM meeting revealed that video posts increased attendance; videos that were the most effective in attracting (viewership) were either short or pertained to surgical procedures. Facebook, Messenger, and WeChat smartphone applications were effective for immediate communication and troubleshooting among the participants. From the IMC polls, 78% believe that the social media and the conference complemented each other. 97% attended the conference to update their skills and knowledge. CONCLUSION: Social media is a quick and economic tool in promoting medical conferences and instant messenger systems offer immediate communication amongst associates. Despite the popularity of social media, the conference still has its irreplaceable role. The combination of the conference and the social media enhances the training and education of microsurgeons.

Design, synthesis, biological evaluation, homology modeling and docking studies of (E)-3-(benzo[d][1,3]dioxol-5-ylmethylene) pyrrolidin-2-one derivatives as potent anticonvulsant agents.

A series of (E)-3-(benzo[d][1,3]dioxol-5-ylmethylene)pyrrolidin-2-one derivatives were designed, synthesized, and evaluated for their anticonvulsant activities. In the preliminary screening, compounds 5, 6a-6f and 6h-6i showed promising anticonvulsant activities in MES model, while 6f and 6g represented protection against seizures at doses of 100 mg/kg and 0.5 h in scPTZ model. The most active compound 6d had a high-degree protection against the MES-induced seizures with ED50 value of 4.3 mg/kg and TD50 value of 160.9 mg/kg after intraperitoneal (i.p.) injection in mice, which provided 6d in a high protective index (TD50/ED50) of 37.4 comparable to the reference drugs. Beyond that, 6d has been selected and evaluated in vitro experiment to estimate the activation impact. Apparently, 6d clearly inhibits the Nav1.1 channel. Our preliminary results provide new insights for the development of small-molecule activators targeting specifically Nav1.1 channels to design potential drugs for treating epilepsy. The computational parameters, such as homology modeling, docking study, and ADME prediction, were made to exploit the results.

Design and Synthesis of 5-Substituted Benzo[d][1,3]dioxole Derivatives as Potent Anticonvulsant Agents.

A series of 5-substituted benzo[d][1,3]dioxole derivatives was designed, synthesized, and tested for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. Neurotoxicity was determined by rotarod test. In the preliminary screening, six compounds, 3a, 3c, 3d, and 4d-f, showed promising anticonvulsant activities in the MES model, and compounds 4c and 4d exhibited full protection against seizures at doses of 300 mg/kg in the scPTZ model. Among the synthesized compounds, 3c as the most active compound showed high protection against the MES-induced seizures with an ED50 value of 9.8 mg/kg and a TD50 value of 229.4 mg/kg after intraperitoneal injection into mice, thus providing compound 3c with a high protective index (TD50 /ED50 ) of 23.4 comparable to those of reference antiepileptic drugs.

Synthesis and Evaluation of 5-(o-Tolyl)-1H-tetrazole Derivatives as Potent Anticonvulsant Agents.

A series of 5-(o-tolyl)-1H-tetrazole derivatives were synthesized and evaluated for their anticonvulsant activities. 1-(2-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed important anticonvulsant activity against the MES-induced seizures, as well as lower neurotoxicity with an ED50 value of 12.7 mg/kg and a TD50 value of over 500 mg/kg after intraperitoneal injection into mice, providing 3h with a high protective index (TD50 /ED50 ) of over 39.4. The achieved results prove that the distinctive compounds could be valuable as a model for future development, adaptation, and investigation to construct more active analogues.