Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity.

Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long-chain (LCFA) and very-long-chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA-GM3 increase significantly in metabolic disorders, while LCFA-GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA-GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4-mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA-GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA-GM3 and unsaturated VLCFA-GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand-molecular docking analysis supports that VLCFA-GM3 and LCFA-GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA-GM3 is a risk factor for TLR4-mediated disease progression.

Neuroport® makes brain biopsy less invasive and easy even in eloquent areas.

Tissue diagnosis of brain tumours in eloquent is often done via needle biopsy but this method yields small samples that may not be representative of the whole tumour. The Neuroport® system enables a larger tumour biopsy to be taken via a burr hole. We report our experience on 5 cases October 2017 and June 2018. Brainlab® navigation was used. The diagnosis in all patients was made without worsening of their modified Rankin scale scores.

[Surgical Anatomy of the Cavernous Sinus, Parasellar Region, and Orbit].

The cavernous sinus, para-sellar region, and orbit have intricately intertwined cranial nerves, blood vessels, and dura mater. In surgery, anatomical understanding is very important. Recognizing the location(depth)of the cranial nerves running on the lateral and upper wall of the cavernous sinus is vital and is directly linked to postoperative complications. In addition, understanding the dural ring in the clinoid segment of the internal carotid artery is important. The periosteum on the upper surface of the anterior clinoid is the distal dural ring of the internal carotid artery, and the periosteum on the lower surface is the proximal dural ring. The orbit is filled with adipose tissue and is completely different from other intracranial parts. However, understanding the anatomy from the orbital apex to the superior orbital fissure is important in the pterional approach.

Absence of Microbleeds Reduces the Risk for Recurrent Intracerebral Hemorrhage.

BACKGROUND: Many known risk factors, including hypertension and hyperlipidemia cause intracerebral hemorrhage (ICH). Recently, microbleeds have been identified as one of the factors leading to ICH. While some patients have been found to have recurrent ICH, risk factors for recurrent ICH are scarcely reported. We conducted an observational study on the risk-factors of recurrent ICH, comparing stroke patients with a single hemorrhagic episode and those with recurrent ICH. METHODS: A retrospective analysis of a single-center database was performed to analyze the clinical presentation and characteristics of patients with a single and recurrent ICH. From January 2016 to December 2017, a total of 317 patients were analyzed based on suspected factors including patients' sex, age, medical history, antiplatelet therapy use, and presence of microbleeds on images. RESULTS: Of the 317 patients, 36 patients (11.4%) developed a second episode of cerebral hemorrhage. Brain magnetic resonance imaging (MRI) of the patients without microbleeds, predicted reduced risk of recurrence. This is the first report strongly associating the presence of microbleeds with the possibility of a recurrent ICH. Other factors under study did not show an apparent association with recurrent ICH probably because of the high statistical significance obtained with the presence of microbleeds. CONCLUSION: Our findings revealed that the absence of microbleeds on images is a factor that strongly predicts a reduced risk for recurrent ICH and that the detection of microbleeds on MRI performed in patients with a single hemorrhagic episode, is useful in defining further therapeutic management. These findings may benefit physicians treating stroke patients.

Strategy for Designing Selective Lysosomal Acid α-Glucosidase Inhibitors: Binding Orientation and Influence on Selectivity.

Deoxynojirimycin (DNJ) is the archetypal iminosugar, in which the configuration of the hydroxyl groups in the piperidine ring truly mimic those of d-glucopyranose; DNJ and derivatives have beneficial effects as therapeutic agents, such as anti-diabetic and antiviral agents, and pharmacological chaperones for genetic disorders, because they have been shown to inhibit α-glucosidases from various sources. However, attempts to design a better molecule based solely on structural similarity cannot produce selectivity between α-glucosidases that are localized in multiple organs and tissues, because the differences of each sugar-recognition site are very subtle. In this study, we provide the first example of a design strategy for selective lysosomal acid α-glucosidase (GAA) inhibitors focusing on the alkyl chain storage site. Our design of α-1-C-heptyl-1,4-dideoxy-1,4-imino-l-arabinitol (LAB) produced a potent inhibitor of the GAA, with an IC50 value of 0.44 µM. It displayed a remarkable selectivity toward GAA (selectivity index value of 168.2). A molecular dynamic simulation study revealed that the ligand-binding conformation stability gradually improved with increasing length of the α-1-C-alkyl chain. It is noteworthy that α-1-C-heptyl-LAB formed clearly different interactions from DNJ and had favored hydrophobic interactions with Trp481, Phe525, and Met519 at the alkyl chain storage pocket of GAA. Moreover, a molecular docking study revealed that endoplasmic reticulum (ER) α-glucosidase II does not have enough space to accommodate these alkyl chains. Therefore, the design strategy focusing on the shape and acceptability of long alkyl chain at each α-glucosidase may lead to the creation of more selective and practically useful inhibitors.

[Two Case Reports of Paroxysmal Sympathetic Hyperactivity Following Craniotomy for Cerebral Hemorrhages].

Paroxysmal sympathetic hyperactivity(PSH)is a clinical condition characterized by abnormal paroxysmal surges in sympathetic nervous system activity. PSH is well known to happen after severe head injury and hypoxic encephalopathy. There are reports of cases of PSH developing after stroke, but PSH is not well recognized in the stroke field in Japan. Case 1 is a 79-year-old woman who became unconscious and suffered a large left mixed-type hemorrhage. Emergency craniotomy was performed. Two months postoperatively, she developed a high fever, tachycardia, tachypnea, and decerebrate posture. After taking clonazepam, her symptoms improved, and she was transferred to another hospital. Case 2 is a 67-year-old man with right hemiplegia, a history of thrombectomy for left M1, occlusion and left carotid artery stenting for asymptomatic left severe carotid artery stenosis performed one year previously. Five hours after right corotid artery stenting, he became restless and hemiplegic on his left side. His computed tomography showed extensive cerebral hemorrhage in the right hemisphere necessitating emergency craniotomy. About a month after surgery, he had a high fever, tachypnea, tachycardia, and decerebrate posture. Taking gabapentin improved his symptoms. Prolonged PSH may be a factor greatly impairing activities of daily living in stroke patients. It is important to diagnose and treat PSH early.

A chemically contiguous hapten approach for a heroin-fentanyl vaccine.

Background: Increased death due to the opioid epidemic in the United States has necessitated the development of new strategies to treat addiction. Monoclonal antibodies and antidrug vaccines provide a tool that both aids addiction management and reduces the potential for overdose. Dual drug vaccines formulated by successive conjugation or by mixture have certain drawbacks. The current study examines an approach for combatting the dangers of fentanyl-laced heroin, by using a hapten with one epitope that has domains for both fentanyl and heroin. Results: We evaluated a series of nine vaccines developed from chemically contiguous haptens composed of both heroin- and fentanyl-like domains. Analysis of the results obtained by SPR and ELISA revealed trends in antibody affinity and titers for heroin and fentanyl based on epitope size and linker location. In antinociception studies, the best performing vaccines offered comparable protection against heroin as our benchmark heroin vaccine, but exhibited attenuated protection against fentanyl compared to our fentanyl vaccine. Conclusion: After thorough investigation of this strategy, we have identified key considerations for the development of a chemically contiguous heroin-fentanyl vaccine. Importantly, this is the first report of such a strategy in the opioid-drug-vaccine field.

Synthesis of 4'-Thionucleosides as Antitumor and Antiviral Agents.

Many attempts have been made to synthesize structurally novel nucleoside derivatives in order to identify effective compounds for the treatment of tumors and virus-caused disease. At our laboratories, as part of our efforts to synthesize 4'-thionucleosides, we have identified and characterized biologically active nucleosides. During the course of our synthetic study, we developed the Pummerer-type thioglycosylation reaction. As a result, we synthesized a potent antineoplastic nucleoside, 1-(2-deoxy-2-fluoro-ß-D-4-thio-arabino-furanosyl)cytosine (4'-thioFAC), and several novel 4'-thionucleosides that possess antiherpes virus activities.

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates.

To synthesize nucleoside and oligosaccharide derivatives, we often use a glycosylation reaction to form a glycoside bond. Coupling reactions between a nucleobase and a sugar donor in the former case, and the reaction between an acceptor and a sugar donor of in the latter are carried out in the presence of an appropriate activator. As an activator of the glycosylation, a combination of a Lewis acid catalyst and a hypervalent iodine was developed for synthesizing 4'-thionucleosides, which could be applied for the synthesis of 4'-selenonucleosides as well. The extension of hypervalent iodine-mediated glycosylation allowed us to couple a nucleobase with cyclic allylsilanes and glycal derivatives to yield carbocyclic nucleosides and 2',3'-unsaturated nucleosides, respectively. In addition, the combination of hypervalent iodine and Lewis acid could be used for the glycosylation of glycals and thioglycosides to produce disaccharides. In this paper, we review the use of hypervalent iodine-mediated glycosylation reactions for the synthesis of nucleosides and oligosaccharide derivatives.

Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease.

We report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human ß-glucocerebrosidase but showed moderate intestinal α-glucosidase inhibition; in contrast, extension of α-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the ß-glucocerebrosidase. Our design of α-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the ß-glucocerebrosidase, with IC50 value of 0.77 µM. A molecular docking study revealed that the α-1-C-tridecyl group has a favorable interaction with the hydrophobic pocket and the sugar analogue part (DAB) interacted with essential hydrogen bonds formed to Asp127, Glu235 and Glu340. Furthermore, α-1-C-tridecyl-DAB (5j) displayed enhancement of activity at an effective concentration 10-times lower than isofagomine. α-1-C-Tridecyl-DAB therefore provides the first example of a pyrrolidine iminosugar as a new class of promising pharmacological chaperones with the potential for treatment of Gaucher disease.

Synthesis and biological evaluation of α-1-C-4'-arylbutyl-L-arabinoiminofuranoses, a new class of α-glucosidase inhibitors.

A series of α-1-C-4'-arylbutyl-L-arabinoiminofuranoses 3 with functional groups attached to the phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by using a Negishi cross-coupling reaction as the key reaction. Arylbutyl derivatives 3a-e showed potent inhibitory activities against intestinal maltase. Among them, difluorophenylbutyl derivative 3e showed good inhibition activities against intestinal isomaltase and sucrase as compared to those of 1 and commercial drugs.

Asymmetric synthesis of 2,5-disubstituted 3-hydroxypyrrolidines based on stereodivergent intramolecular iridium-catalyzed allylic aminations.

Intramolecular iridium-catalyzed allylic aminations of homochiral (E)-6-N-nosylaminohept-2-en-1-yl methyl carbonates were investigated. The relative position of the 2,5-substituents of the resulting pyrrolidines was found to be controlled by using both enantiomers (4 and 5) of the appropriate chiral ligand, demonstrating a simple and highly stereodivergent synthetic protocol. Selected trans- and cis-2,5-disubstituted 3-hydroxypyrrolidines (2a and 18a) were converted to (+)-bulgecinine (6) and (+)-preussin (7), respectively.

A novel three-dimensional and high-definition flexible scope.

PURPOSE: Recent high-tech innovations in digital surgical technology have led to advances in three-dimensional (3D) and high-definition (HD) operating scopes. We introduce a novel 3D-HD flexible surgical scope called "3D-Eye-Flex" and evaluate its utility as an alternative to the operating microscope. METHODS: The 3D-Eye-Flex has a 15 mm long 3D-HD scope-head with a 15 mm outer diameter, a focus distance of 18-100 mm and 80° angle of view. Attached to a 615-mm-long flexible bellows, 3D-Eye-Flex can be easily fixed to the operating table. Microsurgical dissection of wet brain tissue and drilling a skull base model were performed under the scope while using the 3D-HD video monitor. RESULTS: This scope system provided excellent illumination and image quality during the procedures. A large depth of field with stereoscopic vision had a greater advantage over using an operating microscope. 3D-Eye-Flex was easy to manipulate and provided an abundance of space above the operative field. Surgeons felt comfortable while working and could easily shift the position of the scope. CONCLUSION: This novel 3D-HD flexible scope is an effective alternative to the operating microscope as a new surgeon's eye and will be suitable for digital image-based surgery with further refinement.

Evaluation of misdiagnosed cases of subarachnoid hemorrhage and causal factors for misdiagnosis.

BACKGROUND: Diagnosis has a major impact on the outcome of subarachnoid hemorrhage (SAH). We studied patients with SAH who were admitted to our hospital in an effort to identify ways to prevent misdiagnosis. METHODS: A total of 494 patients with SAH were admitted to the Department of Neurosurgery from 2003 through 2010. Misdiagnosis occurred in 30 patients (6.1%). We studied the symptoms and the types of misdiagnoses in these 30 patients. RESULTS: Misdiagnosis occurred 37 times in the 30 patients (6 patients were given more than 1 misdiagnosis). There were 3 types of misdiagnoses. Type 1 cases were misdiagnosed as a common cold, type 2 cases were misdiagnosed as circulatory organ disease, and type 3 cases were misdiagnosed as digestive organ disease. CONCLUSIONS: Type 1 cases were mild, and diagnosis required detailed medical history analyses. Type 2 cases were severe and were diagnosed based on electrocardiographic and echocardiographic changes characteristic of SAH. Symptoms of type 3 cases included vomiting, and diagnosis required recognition of meningeal irritation syndrome and detailed medical history analyses.

An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity that Reverses Carfentanil-Induced Respiratory Depression.

The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored for synthetic opioids and that can help prevent post-treatment renarcotization. The ultrapotent analog carfentanil, is especially concerning due to its unique pharmacological properties. With this in mind, we generated a fully human antibody through a drug-specific B cell sorting strategy with a combination of carfentanil and fentanyl probes. The resulting pan-specific antibody was further optimized through scFv phage display. This antibody, C10-S66K, displays high affinity to carfentanil, fentanyl, and other analogs, and reversed carfentanil-induced respiratory depression. Additionally, x-ray crystal structures with carfentanil and fentanyl bound provided structural insight into key drug:antibody interactions.

An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity That Reverses Carfentanil-Induced Respiratory Depression.

The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short-acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored to synthetic opioids and help prevent post-treatment renarcotization. The ultrapotent analog carfentanil is especially concerning due to its unique pharmacological properties. With this in mind, we generated a fully human antibody through a drug-specific B cell sorting strategy with a combination of carfentanil and fentanyl probes. The resulting pan-specific antibody was further optimized through scFv phage display, producing C10-S66K. This monoclonal antibody displays high affinity to carfentanil, fentanyl, and other analogs and reversed carfentanil-induced respiratory depression. Additionally, X-ray crystal structures with carfentanil and fentanyl bound provided structural insight into key drug:antibody interactions.

Synthesis of 5-thiodidehydropyranylcytosine derivatives as potential anti-HIV agents.

As a part of our ongoing efforts to identify new anti-HIV agents, a 5'-thiopyrano-nucleoside derivative 4, designed based on 4'-thioD4C 1 and cyclohexenylnucleoside 3, was synthesized. The dihydrothiopyran skeleton of 4 was constructed by the ring closing metathesis of 21 which was synthesized from but-2-yne-1,4-diol. After converting the protecting group from MOM to TBS followed by oxidation, a Pummerer-type thioglycosylation reaction of 24 with persilylated uracil gave the desired 5-thiodihydrothiopyranyluracils 25 and 26 as a mixture of anomers. The conversion of 25 to a cytosine derivative and subsequent deprotection gave a 5-thiodidehydropyranosylcytosine derivative 4 in good yield. The anti-HIV activity of 4 was also evaluated.

The synthesis and biological evaluation of 1-C-alkyl-L-arabinoiminofuranoses, a novel class of α-glucosidase inhibitors.

The asymmetric synthesis of 1-C-alkyl-l-arabinoiminofuranoses 1 was achieved by asymmetric allylic alkylation (AAA), ring closing metathesis (RCM), and Negishi cross coupling as key reactions. Some of the prepared compounds showed potent inhibitory activities towards intestinal maltase, with IC(50) values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity (IC(50)=0.032µM) towards intestinal sucrase of 1c was quite strong compared to the above commercial drugs.

Feasibility of intraoperative motor-evoked potential monitoring for skull base tumors with a high risk of postoperative motor deterioration.

OBJECTIVE: To establish the validity and utility of motor-evoked potential (MEPs) monitoring for skull base tumor resection, we explored the relationship between MEP monitoring results and postoperative motor function. METHODS: MEPs were successfully monitored during 76 operations in 68 patients with a high risk of motor morbidity. MEP monitoring data were correlated with perioperative clinical motor function. RESULTS: MEPs remained stable in 56 operations (73.7%), and no postoperative motor deterioration was observed. Transient or permanent deterioration of MEPs (<50% of the initial amplitude before surgery) occurred in 20 operations (26.3%). This deterioration was reversible after intervention in seven cases (9.2%). Irreversible deterioration in MEPs was seen in 13 cases (17.1%). In five cases, the final amplitude was greater than 10%. Two of these patients experienced transient loss of MEPs and moderate to severe hemiparesis. Both patients showed full recovery within 6 months after the operation. The other three patients experienced no postoperative worsening of motor function. The final MEP amplitude was less than 10% in the other eight patients, including five with permanent MEP loss. All of these patients experienced severe postoperative motor dysfunction. Recovery of motor function was worse in most participants in this group compared with those in the other groups. CONCLUSION: Intraoperative MEP monitoring is a valid indicator of pyramidal tract pathway function for skull base tumor surgery.

[Coil embolization of a ruptured posterior cerebral artery aneurysm via the internal carotid artery and a posterior communicating artery: a case report].

A posterior cerebral artery aneurysm is a rare condition. Various surgical approaches have to be considered for operating on these aneurysms because the position of the aneurysm and the surrounding structures restrict the operative field and render the operation difficult. Recently, endovascular treatments for posterior cerebral artery aneurysms have been reported to provide a good outcome. We present a case of a ruptured posterior cerebral artery aneurysm treated with coil embolization. We adopted endovascular treatment because a large vein of Labbé was expected to restrict the operative field. The internal carotid artery and a fetal-type posterior communicating artery (PCoA) were chosen as the access route because of P1 hypoplasty, and a coaxial guiding system was used because of the tortuous access route. The aneurysm was suitably embolized using Guglielmi detachable coils (GDCs). In a case of posterior cerebral artery aneurysm, we report the usefulness of endovascular treatment performed through the internal carotid artery and a fetal-type PCoA.