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A 79-year-old woman presented at our hospital with sudden headache and vomiting. Computed tomography revealed diffuse subarachnoid hemorrhage. Although digital subtraction angiography (DSA) performed on admission and on the following day revealed no vascular abnormalities, DSA on Day 22 revealed microaneurysmal changes in the dorsal basilar artery. However, the aneurysmal changes gradually became smaller during follow-up, and DSA on Day 73 revealed complete disappearance. A 53-year-old man also presented to our hospital with sudden headache and vomiting. Computed tomography revealed perimesencephalic subarachnoid hemorrhage. DSA on Days 9 and 16 revealed microaneurysmal changes in the dorsal basilar artery. Conservative treatment was continued, and DSA on Day 42 revealed spontaneous disappearance of the lesion. It has been reported that basilar artery perforating aneurysms cause angiogram-negative subarachnoid hemorrhage, which disappears spontaneously. The fact that lesions previously reported as basilar artery perforating aneurysms may include cases of acute dissection of the main trunk or perforating branches of the basilar artery implies that surgical or endovascular treatment may worsen the condition. Therefore, conservative treatment may be an important option., Competing Interests: The authors declare no conflicts of interests., (© 2024 The Japan Neurosurgical Society.)

Background: Ewing sarcoma is a malignant bone tumor; however, its prognosis has improved since the development of modern chemotherapy. Although Ewing sarcoma outcomes have improved, issues related to late complications, secondary malignant neoplasms, and late recurrence or metastasis have emerged., Case Presentation: We report a case of Ewing sarcoma that recurred in the occipital bone 21 years after primary tumor treatment. A 45-year-old Japanese woman with a history of Ewing sarcoma 21 years prior, was referred to our hospital due to a severe headache. A tumor was detected in the left occipital bone, and the biopsy revealed Ewing sarcoma. Metastasis was suspected because the patient had been treated for Ewing sarcoma of the left clavicle 21 years prior. There have been several cases of local recurrence or metastasis, occurring 15-20 years after the onset of the initial disease. To our knowledge, very late metastasis of Ewing sarcoma in the skull has not been reported., Conclusion: We report a rare case of very late metastasis of Ewing sarcoma in the skull with a review of the literature. Delayed metastasis secondary to Ewing sarcoma can occur in the lung, which is the most common site for metastasis, as well as other regions of the body, such as the cranium., (© 2022. The Author(s).)

The diazo group is an important functional group that can confer biological activity to natural products owing to its high reactivity. Recent studies have revealed that diazo groups are synthesized from amino groups using nitrous acid in secondary metabolites of actinomycetes. However, genome database analysis indicated that there are still many diazo group-biosynthesizing enzymes for unknown biosynthetic pathways. Here, we discovered an avenalumic acid biosynthesis gene cluster in Streptomyces sp. RI-77 by genome mining of enzymes involved in diazo group formation. Through heterologous expression, the gene cluster was revealed to direct avenalumic acid (AVA) biosynthesis via 3-aminoavenalumic acid (3-AAA). In vitro enzyme assays showed that AvaA6 and AvaA7 catalyzed the diazotization of 3-AAA using nitrous acid and substitution of the diazo group for hydride to synthesize AVA, respectively. This study revealed an unprecedented pathway for amino group removal via diazotization., (© 2022 Wiley-VCH GmbH.)

Objective: To examine the effect of multimodal intraoperative neuromonitoring on the long-term outcome of motor function after microsurgical resection for spinal cord tumors., Materials and Methods: Consecutive fourteen patients with spinal tumors who were surgically treated at the University of Fukui Hospital between 2009 and 2020 [M:F = 10:4, ages ranging from 22 to 83 years (mean ± SD = 58 ± 21 years)] were included in this study. There were eight intra-axial tumors and six extra-axial tumors. There were four patients with hypertension, two patients with diabetes mellitus, and four patients with hyperlipidemia. Three patients were under antithrombotic medication, two were under steroid medication, four were current smokers, and four were current drinkers. Manual muscle test (MMT) of the upper and lower extremities of the patients was examined before surgery, 2 weeks after surgery, and at the final follow-up. The mean follow-up period was 38 ± 37 months. McCormick scores were examined before surgery and at the final follow-up. Microsurgical resection of the tumor was underwent through the posterior approach under transcranial motor-evoked potential (TcMEP) monitoring. The MEP of 46 extremities was recorded during the surgery. Gross total resection was achieved in 13 of 14 surgeries. Spinal cord-evoked potential (Sp-SCEP) monitoring was performed in eight of 14 patients., Results: The length of peritumoral edema was significantly longer in patients with deterioration of McCormick scores than in patients with preservation of McCormick scores ( p = 0.0274). Sp-SCEP could not predict the deterioration. The ratio of MEP at the beginning of the surgery to that at the end of the surgery was the only significant negative factor that predicts deterioration of motor function of the extremity at the final follow-up ( p = 0.0374, odds ratio [OR] 1.02E-05, 95% CI 9.13E+01-7.15E+18). A receiver operating characteristic (ROC) analysis revealed that the cutoff value of the ratio of MEP to predict the deterioration at the final follow-up was 0.23 (specificity 100%, specificity 88%, positive predictive value 100%, and negative predictive value 88%) to predict deterioration at the final follow-up., Conclusions: Ratio MEP was the most significant negative factor to predict the deterioration of motor weakness at spinal tumor surgery. The setting of the cutoff value should be more strict as compared to the brain surgery and might be different depending on the institutions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yamada, Kawajiri, Arishma, Isozaki, Yamauchi, Akazawa, Kidoguchi, Kodera, Shibaike, Umeda, Tsukinowa, Hagihara and Kikuta.)

l-Theanine is a nonproteinogenic amino acid present almost exclusively in tea plants and is beneficial for human health. For industrial production, l-theanine is enzymatically or chemically synthesized from glutamine/glutamate (or a glutamine/glutamate derivative) and ethylamine. Ethylamine is extremely flammable and toxic, which complicates and increases the cost of operational procedures. To solve these problems, we developed an artificial biosynthetic pathway to produce l-theanine in the absence of supplemental ethylamine. For this purpose, we identified and selected a novel transaminase (NCBI:protein accession number AAN70747) from Pseudomonas putida KT2440, which catalyzes the transamination of acetaldehyde to produce ethylamine, as well as γ-glutamylmethylamide synthetase (NCBI:protein accession number AAY37316) from Pseudomonas syringae pv. syringae B728a, which catalyzes the condensation of l-glutamate and ethylamine to produce l-theanine. Expressing these genes in Escherichia coli W3110S3GK and enhancing the production capacity of acetaldehyde and l-alanine achieved successful production of l-theanine without ethylamine supplementation. Furthermore, the deletion of ggt , which encodes γ-glutamyltranspeptidase (EC 2.3.2.2), achieved large-scale production of l-theanine by attenuating its decomposition. We show that an alanine decarboxylase-utilizing pathway represents a promising route for the fermentative production of l-theanine. Our study reports efficient methods to produce l-theanine in the absence of supplemental ethylamine. IMPORTANCE l-Theanine is widely used in food additives and dietary supplements. Industrial production of l-theanine uses the toxic and highly flammable precursor ethylamine, raising production costs. In this study, we used Escherichia coli to engineer two biosynthetic pathways that produce l-theanine from glucose and ammonia in the absence of supplemental ethylamine. This study establishes a foundation for safely and economically producing l-theanine., (Copyright © 2021 American Society for Microbiology.)

DON (6-diazo-5-oxo-l-norleucine), a diazo-containing amino acid, has been studied for more than 60 years as a potent antitumor agent, but its biosynthesis has not been elucidated. Here we reveal the complete biosynthetic pathway of alazopeptin, the tripeptide Ala-DON-DON, which has antitumor activity, by gene inactivation and in vitro analysis of recombinant enzymes. We also established heterologous production of N-acetyl-DON in Streptomyces albus. DON is synthesized from lysine by three enzymes and converted to alazopeptin by five enzymes and one carrier protein. Most interestingly, transmembrane protein AzpL was indicated to catalyze diazotization using 5-oxolysine and nitrous acid as substrates. Site-directed mutagenesis of AzpL indicated that the hydroxy group of Tyr-93 is important for the diazotization. These findings expand our knowledge of the enzymology of N-N bond formation., (© 2021 Wiley-VCH GmbH.)

Emissive push-pull-type bisnaphthyridylamine derivatives (BNA-X: X=Me, Et, Bzl, Ph, BuBr, and BuTEMPO) aggregate in aqueous methanol. Furthermore, a two-step emission and aggregation process is controllable by varying the methanol-to-water ratio. At 2:3 MeOH/H 2 O, crystallization-induced emission enhancement (CIEE) occurs via formation of an emissive crystal phase, whereas, at 1:9 MeOH/H 2 O, aggregation-induced emission enhancement (AIEE) occurs, induced by emissive supramolecular nanoparticles (NPs). For BNA-Ph, the emission quantum yield was 25 times higher in aqueous methanol than that in pure methanol. Despite the high hydrophobicity of BNA-X (C log P=6.1-8.0), the spherical NPs were monodisperse (polydispersity indices <0.2). Moreover, the emissive NPs exhibited fluorescence resonance energy transfer (FRET) with pyrene; however, for BNA-X bearing the TEMPO radical (BNA-BuTEMPO), no FRET was observed because of quenching. In particular, the BNA-BuTEMPO NPs have a slow rotational correlation time (1.3 ns), suggesting applications as magnetic resonance imaging contrast agents with large relaxivity., (© 2020 Wiley-VCH GmbH.)

Push-pull type fluorescent amino-quinoline derivatives (TFMAQ) bearing phenyl aromatic groups in the 8-position (TFMAQ-8Ar series) were synthesized via palladium-catalyzed C-H activation reaction in short steps. The N-arylation or C-H activation reactions were selectively controlled with high yield by combinations of palladium and phosphine ligands. The TFMAQ-8Ar analogues exhibited fluorescent solvatochromism in non-polar and polar solvents. In non-polar solvent, the absolute fluorescence quantum yield was high, wheareas the fluorescence was almost quenched in polar solvent. The TFMAQ-8Ar derivatives also showed high fluorescence emission at solid state owing to the planar structure between the quinoline ring and phenyl ring at the 7-amino group, as demonstrated by X-ray crystal structure analysis. The fluorescence imaging of 3T3-L1 cell using TFMAQ-8Ar derivatives was performed by confocal laser microscopy. Strong and specific emissions at lipid droplets were observed owing to the accumulation of TFMAQ-8Ar derivatives. Therefore, we propose that the TFMAQ-8Ar derivatives should become a versatile fluorescence probe for the live imaging of lipid droplets.

Water-soluble donor-acceptor-type fluorophore 15Nap-Cl having two trifluoromethyl groups and a Cl group on a 1,5-aminonaphthyridine framework was prepared. Fluorophore 15Nap-Cl showed strong solvatochromic fluorescence, and, as the solvent polarity increased, a bathochromic shift was observed accompanied by an increase in the fluorescence quantum yield. In addition, in the presence of amines such as ethylamine, diethylamine, and aniline, further considerable bathochromic shifts in the fluorescence were observed. Density functional calculations identified the source of the fluorescence behavior as exciplex formation between 15-Nap-Cl and the corresponding amine. The fluorescence behavior was exploited to fabricate a sensor that can identify various primary, secondary, and tertiary amines., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

New data are reported from analyses of stomach contents from 114 long-finned pilot whales mass-stranded at four locations around Tasmania, Australia from 1992-2006. Identifiable prey remains were recovered from 84 (74%) individuals, with 30 (26%) individuals (17 females and 13 males) having empty stomachs. Prey remains comprised 966 identifiable lower beaks and 1244 upper beaks, belonging to 17 families (26 species) of cephalopods. Ommastrephidae spp. were the most important cephalopod prey accounting for 16.9% by number and 45.6% by reconstructed mass. Lycoteuthis lorigera was the next most important, followed by Ancistrocheirus lesueurii. Multivariate statistics identified significant differences in diet among the four stranding locations. Long-finned pilot whales foraging off Southern Australia appear to be targeting a diverse assemblage of prey (≥10 species dominated by cephalopods). This is compared to other similar studies from New Zealand and some locations in the Northern Hemisphere, where the diet has been reported to be primarily restricted to ≤3 species dominated by cephalopods. This study emphasises the importance of cephalopods as primary prey for Southern long-finned pilot whales and other marine vertebrates, and has increased our understanding of long-finned pilot whale diet in Southern Ocean waters., Competing Interests: The authors have declared that no competing interests exist.

Recently, a novel nitrous acid biosynthetic pathway composed of two enzymes was discovered to be involved in the biosynthesis of cremeomycin for the formation of its diazo group. In this pathway, CreE oxidizes L-aspartic acid to nitrosuccinic acid and CreD liberates nitrous acid from nitrosuccinic acid. Bioinformatic analysis showed that various actinobacteria have putative secondary metabolite biosynthesis gene clusters containing creE and creD homologs, suggesting that this pathway is widely used for the biosynthesis of various natural products. Here, we focused on creE and creD homologs (BN159&#95;4422 and BN159&#95;4421) in Streptomyces davawensis. In vitro analysis of recombinant BN159&#95;4422 and BN159&#95;4421 proteins showed that these enzymes synthesized nitrous acid from L-aspartic acid. Secondary metabolites produced by this gene cluster were investigated by comparing the metabolic profiles of the wild-type and ΔBN159&#95;4422 strains. When these strains were co-cultured with Tsukamurella pulmonis TP-B0596, three compounds were specifically produced by the wild-type strain. These compounds were identified as novel desferrioxamine derivatives containing either of two unique five-membered heterocyclic ring structures and shown to have iron-binding properties. A putative desferrioxamine biosynthetic gene cluster was found in the S. davawensis genome, and inactivation of a desD homolog (BN159&#95;5485) also abolished the production of these compounds. We propose that these compounds should be synthesized by the modification of desferrioxamine B and a shorter chain analog using nitrous acid produced by the CreE and CreD homologs. This study provides an important insight into the diverse usage of the secondary metabolism-specific nitrous acid biosynthetic pathway in actinomycetes.

π-Conjugated helicenes containing heteroatoms have attracted significant attention due to their diverse chemical and electronic structures, as well as tunable physical properties. It was rationally anticipated that the self-assembly of coumarin-fused helicenes would be controlled by the effects of a substituent on the internal edge of the helix. Here, this work reports the efficient syntheses of coumarin-fused helicenes 1 a,b (R=Ph, Me), and the enantioselective synthesis of 1 a (R=Ph) by chiral Au I -catalyzed hydroarylation. The helical structure of 1 was unambiguously determined by X-ray crystallography. Of particular note, the enantiomerically pure crystal of 1 a adopted a one-dimensional columnar structure based on π-π stacking interactions, as expected. Furthermore, a significant difference between the fluorescence quantum yields of the enantiomerically pure form and racemate of 1 a was observed., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The probability of an aquatic animal being available for detection is typically <1. Accounting for covariates that reduce the probability of detection is important for obtaining robust estimates of the population abundance and determining its status and trends. The dugong (Dugong dugon) is a bottom-feeding marine mammal and a seagrass community specialist. We hypothesized that the probability of a dugong being available for detection is dependent on water depth and that dugongs spend more time underwater in deep-water seagrass habitats than in shallow-water seagrass habitats. We tested this hypothesis by quantifying the depth use of 28 wild dugongs fitted with GPS satellite transmitters and time-depth recorders (TDRs) at three sites with distinct seagrass depth distributions: 1) open waters supporting extensive seagrass meadows to 40 m deep (Torres Strait, 6 dugongs, 2015); 2) a protected bay (average water depth 6.8 m) with extensive shallow seagrass beds (Moreton Bay, 13 dugongs, 2011 and 2012); and 3) a mixture of lagoon, coral and seagrass habitats to 60 m deep (New Caledonia, 9 dugongs, 2013). The fitted instruments were used to measure the times the dugongs spent in the experimentally determined detection zones under various environmental conditions. The estimated probability of detection was applied to aerial survey data previously collected at each location. In general, dugongs were least available for detection in Torres Strait, and the population estimates increased 6-7 fold using depth-specific availability correction factors compared with earlier estimates that assumed homogeneous detection probability across water depth and location. Detection probabilities were higher in Moreton Bay and New Caledonia than Torres Strait because the water transparency in these two locations was much greater than in Torres Strait and the effect of correcting for depth-specific detection probability much less. The methodology has application to visual survey of coastal megafauna including surveys using Unmanned Aerial Vehicles.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids. Because pravastatin is a water-soluble organic anion, it cannot easily penetrate the lipid bilayer of the cell membrane. As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified, we examined the roles of the organic anion transporter family on pravastatin-treated islet and adipocyte functions. Rat oatp1/slco1a1, oatp2/slco1a4 and oatp3/slco1a5 were expressed in the pancreas, and rat oatp3/slco1a5 was also detected in rat insulinoma cell line INS-1e. Pravastatin was transported not only by oatp1/slco1a1 and oatp2/slco1a4, but also by rat oatp3/slco1a5. Pravastatin uptake into INS-1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin, both of which are known to inhibit oatp family-mediated uptake. In addition, pravastatin enhanced the glucose-stimulated insulin secretion from INS-1e cells. When fat-loaded db/db mice were treated with pravastatin, glucose intolerance and insulin resistance were prevented. In addition, insulin secretion from isolated islets was enhanced by pravastatin. These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat/glucose conditions.

Hepatic uptake and biliary excretion of olmesartan, a new angiotensin II blocker, were investigated in vitro using human hepatocytes, cells expressing uptake transporters and canalicular membrane vesicles, and in vivo using Eisai hyperbilirubinemic rats (EHBR), inherited multidrug resistance-associated protein (mrp2)-deficient rats. The uptake by human hepatocytes reached saturation with a Michaelis constant (K(m)) of 29.3 +/- 9.9 microM. Both Na(+)-dependent and Na(+)-independent uptake of olmesartan by human hepatocytes were observed. The uptake by Na(+)-independent human liver-specific organic anion transporters OATP1B1 and OATP1B3 expressed in Xenopus laevis oocytes was also saturable, with K(m) values of 42.6 +/- 28.6 and 71.8 +/- 21.6 microM, respectively. The Na(+)-dependent taurocholate-cotransporting polypeptide expressed in HEK 293 cells did not transport olmesartan. The cumulative biliary excretion in EHBR was one-sixth compared with that in Sprague-Dawley rats. ATP-dependent uptake of olmesartan was observed in both human canalicular membrane vesicles (hCMVs) and MRP2-expressing vesicles. An MRP inhibitor, MK-571 ([[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid) completely inhibited the uptake of olmesartan by hCMVs. In conclusion, the hepatic uptake and biliary excretion of olmesartan are mediated by transporters in humans. OATP1B1 and OATP1B3 are involved in hepatic uptake, at least in part, and MRP2 plays a dominant role in the biliary excretion.

We report a case of effective treatment with clonidine ointment for herpetic neuralgia in a child. Clonidine hydrochloride is an alpha 2-agonist. It is generally administered intravenously, intramuscularly, intrathecally and orally. However, there have been only a few reports on transdermal usage. In our department, we have investigated the analgesic effect of topical application of clonidine in adults, and we have obtained sufficient evidence on the effects of clonidine. Therefore, we decided to use clonidine to a child. A 9-year-old child who had undergone BMT and developed herpes zoster was experiencing severe pain, itch, and insomnia. Many drugs were ineffective in relieving the pain, itch, and insomnia. To remove the symptoms, we tried clonidine ointment. Immediate improvement was observed in all the symptoms. Therefore, clonidine ointment was thought to be effective and we decided to prescribe clonidine ointment and amitriptyline hydrochloride. The application of clonidine showed no side effects such as bradycardia and low blood pressure. We conclude that clonidine can be administered to children without causing side effects.

We present a case of a 27-year-old man with gunshot injury in the neck and the chest. On admission, he had an entry wound in the neck and his chest radiograph showed left hemopneumothorax. Nasal endotracheal intubation and chest drainage were immediately performed. Angiography revealed pseudoaneurysm of the left carotid artery and fistula between the artery and the innominate vein. The patient showed progressive severe facial edema due to the fistula. Anesthesia was induced and maintained with fentanyl and sevoflurane. The carotid artery was repaired with an autologous saphenous vein graft. Although one lung ventilation (OLV) was requested for partial resection of the left lung, replacing the endotracheal tube was impossible due to severe facial edema. OLV was successfully performed by blocking the left main trunchus with a 7 Fr Fogarty catheter placed under fiberscopic monitoring. The patient recovered without any serious complications. Prompt and proper airway management is required in gun shot injury of the neck and chest.

Implications: Transesophageal echocardiography was used to identify and guide management of reversible tricuspid valve obstruction by a tumor mass during surgical removal of a renal cell carcinoma.

Lecithin: cholesterol acyltransferase (LCAT) is an enzyme that catalyzes the esterifying reaction of cholesterol in plasma high density lipoprotein (HDL). Deficiency of LCAT is a rare hereditary disease characterized by several clinical symptoms such as proteinuria, corneal opacity, and anemia due to a shortened life span of erythrocytes. In this communication, we report a case of 40 year-old female patient of LCAT deficiency. She visited a hospital for work-up of proteinuria, corneal opacity and anemia. Activity of her serum LCAT was found to be extremely low, and characteristic changes in plasma lipids due to deficiency of LCAT was observed: those were marked decreases in HDL-cholesterol, degree of esterification in serum cholesterol, and apoprotein A-I, A-II, B and C-II levels. The diagnosis of LCAT deficiency was finally made. We studied about histopathological changes in the patient's kidney, and erythrocyte membrane lipid composition and fluidity. Histopathological findings in renal biopsy were follows: a) Light microscopy showed spherical deposits stained with periodic acid-Schiff in mesangial matrix and adjacent capillary loops, and hyaline deposits in arterioles, b) Electron microscopy showed vacuoles in mesangial matrix and along the glomerular basement membranes. In erythrocyte membrane lipids, increase of cholesterol to phospholipid molar ratio was evident, being accompanied by changes in phospholipid fractions: increase of phosphatidylcholine, and decreases of phosphatidylethanolamine, sphingomyelin and lysophosphatidylcholine. In phospholipid acyl chains, increase of C18:2 and decreased of C18:1 were evident in the patient. Erythrocyte membrane fluidity was found to be decreased in the patient in a measurement by pyrene, probably being related to the changes in membrane lipid composition.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic nerve dysfunction in patients with chronic renal failure has of late become an issue to be investigated. R-R intervals in resting electrocardiograms were measured to evaluate activities of the cardiac parasympathetic nerve system. A total of 140 patients with chronic renal failure were studied to be compared with 20 normal controls (cont.) and 39 with diabetes mellitus (DM). Of these patients 15 were subjected to conservative treatment (CRF), while 125 patients were undergoing hemodialysis due to chronic renal failure-100 of them derived from chronic glomerulonephritis (HD) and 25 from diabetes mellitus (DM.HD). The variation coefficient of the R-R interval (CVRR) was measured after the subject patients had rested for over 15 minutes before a dialysis session. The mean CVRR were 2.15 +/- 1.25% in CRF group, 2.36 +/- 1.37% in HD and 1.37 +/- 0.99% in DM.HD. These values were significantly lower than in control group (4.70 +/- 2.64%). On the other hand, the value in DM.HD group, as shown above, was significantly lower than in HD. In CRF group the CVRR values lowered as residual renal functions decreased. No significant correlations between CVRR S and the duration of hemodialysis treatment were noted among the groups. In HD group the CVRR S were significantly lower in patients with hypotensive tendency during hemodialysis than in those who enjoyed good control of blood pressure. These results suggest that the measurement of CVRR S can be of help in evaluating autonomic nerve dysfunction in patients with chronic renal failure.