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To date, a neuroscientific investigation of drivers’ steering behavior has never been performed because the reaction forces generated by the mechanical characteristics of a steering wheel have been difficult to assess in a magnetic resonance imaging (MRI) environment. In this study, using our previously developed MRI-compatible unit for steering reaction force generation, we investigated changes in human brain activity induced by varying the viscoelastic characteristics associated with manipulating a car steering wheel. Participants performed a simulated driving task with three levels of stiffness and viscosity. An amplitude effect of reaction forces on the measured brain activity due to varying stiffness was found in the primary motor cortex (M1) associated with hand representation. Conversely, the changes in the brain activity induced by varying viscosity were found more dorsally in the premotor cortex and the M1 than in regions associated with hand representation. These results are the first to demonstrate that various viscoelastic characteristics activate different motor regions; more specifically, stiffness and viscosity of the steering wheel mainly affected the motor control of the distal and proximal muscles, respectively.

Previous studies including ours have shown that a low-protein diet up-regulates insulin signaling in the liver and muscle and induces fatty liver in rats. Adiponectin is known as an insulin-sensitizing adipocytokine. We, therefore, examined the effect of a low-protein diet on the adiponectin levels in rats. The low-protein diet significantly increased serum adiponectin level. However, mRNA and protein levels of adiponectin in white adipose tissue (WAT) were not changed by the low-protein diet. Since it is known that oligomerization is important to control serum adiponectin level, we examined the population of adiponectin oligomeric forms in WAT and found that low-protein diet did not change it. Despite these events, the amount of its secretion was significantly increased in the adipocytes isolated from WAT of low-protein diet-fed rats. These results indicate that a low-protein diet enhances adiponectin secretion, which is not due to the increased intracellular amount and oligomerization of adiponectin.

A major hurdle in the development of automobiles that are easy to operate and pleasant to drive is ignorance of the influence of the characteristics of the steering force on the driver based on an understanding of the brain. To address this problem, it is suitable to measure brain activity by using functional magnetic resonance imaging (fMRI), which can measure activity in the entire brain at a high spatial resolution. In this study, we develop an fMRI-compatible steering force generation unit and verify its performance. To avoid disturbance due to the electromagnetic field of the MRI, the unit was configured as follows: a motor installed outside a scan room generated a reaction force that was transmitted to a steering wheel placed in the hands of a subject using a nonmagnetic transmission unit. To verify the performance of the unit, we measured the brain activity of participants of an experiment by using fMRI while they performed steering operations using their arm/arms under various steering forces. The results were consistent with those for motor-related brain activity obtained in past neuroimaging studies. We conclude that the proposed unit can measure brain activity through fMRI in the presence of a steering reaction force.

Background: Achieving clear visibility through a windshield is one of the crucial factors in manufacturing a safe and comfortable vehicle. The optic flow (OF) through the windshield has been reported to divert attention and could impair visibility. Although a growing number of behavioral and neuroimaging studies have assessed drivers' attention in various driving scenarios, there is still little evidence of a relationship between OF, windshield shape, and driver's attentional efficacy. The purpose of this research was to examine this relationship. Methods: First, we quantified the OF across the windshield in a simulated driving scenario with either of two types of the windshield (a tilted or vertical pillar) at different speeds (60 km/h or 160 km/h) and found more upward OF along the tilted pillar than along the vertical pillar. Therefore, we hypothesized that the predominance of upward OF around the windshield along a tilted pillar could distract a driver and that we could observe the corresponding neural activity. Magnetic resonance scans were then obtained while the subjects performed a visual detection task while watching the driving scene used in the OF analysis. The subjects were required to press a button as rapidly as possible when a target appeared at one of five positions (leftmost, left, center, right, and rightmost). Results: We found that the reaction time (RT) on exposure to a tilted pillar was longer than that on exposure to a vertical pillar in the leftmost and rightmost conditions. Furthermore, there was more brain activity in the precuneus when the pillar was tilted than when it was vertical in the rightmost condition near the pillar. In a separate analysis, activation in the precuneus was found to reflect relative changes in the amount of upward OF when the target was at the rightmost position. Conclusions: Overall, these observations suggest that activation in the precuneus may reflect extraneous cognitive load driven by upward OF along the pillar and could distract visual attention. The findings of this study highlight the value of a cognitive neuroscientific approach to research and development in the motor vehicle manufacturing industry.

The short-term efficacy and safety of insulin degludec U100 (IDeg) in patients with type 2 diabetes have not been reported widely. We compared insulin IDeg and insulin glargine U100 (IGla) for glycemic control and glucose variability in hospitalized patients with type 2 diabetes. In an open-label, multicenter, randomized controlled trial, 74 patients were randomly assigned to either the IDeg (36 patients) or IGla (38 patients) group and were administered with basal-bolus therapy during hospitalization. Following the start of the treatment, on day 11, glucose variability was assessed by continuous glucose monitoring. A fasting blood glucose level of 110 mg/dL and 2-hour postprandial blood glucose level of 180 mg/dL throughout at least one day during the observation period were achieved in 31.3% (10/32) and 30.6% (11/36) of the patients in the IDeg and IGla groups, respectively. The 6-point self-monitoring of blood glucose profiles showed a significant difference between the two groups. On day 7, the intra-day variation was larger in the IDeg group than in the IGla group. The incidence of hypoglycemia or glucose variability was comparable in the two groups. This study suggests that short-term efficacy and safety of IDeg and IGla in patients with type 2 diabetes during the initial phase of basal-bolus therapy were comparable, and these results can help in deciding which treatment to opt for.

In this paper, we report a novel approach to automobile development based on the understanding of the brain mechanism. We aim to realize fun to drive applying the neuroscientific findings of affective states. There are few studies about it, therefore using newly developed experimental unit, we are examining participants' brain activity affected by the load of steering operation task in the MRI scanner. We focused on the brain activity while waiting to steer, assuming that it reflects participants' affective state in preparation of the upcoming steering task. We observed activations in the anterior cingulate and insular cortices comprising the salience network, which is one of the intrinsic brain networks and involved in preparation for an upcoming task. Intriguingly, when waiting for the steering task having larger reaction force, the anterior cingulate cortex, known to be related to anxiety, was more active. Moreover, waiting for the condition in which the steering had to be operated with only the non-dominant arm, the amygdala, known to be associated with negative emotion, was significantly activated. Thus, our results newly show that the steering reaction force and the hand used for steering operation may influence brain activity while waiting for the upcoming steering task.

Recently, patients with oral allergy syndrome (OAS) to fruits or vegetables caused by pollenfood allergy syndrome (PFAS) have increased nationwide. We examined effectiveness of SCIT using birch pollen extract for PFAS.A total of 19 patients (9 male and 10 female) underwent SCIT with birch pollen extract from August 2011 to August 2016. Rush schedule was used for the initial updosing for SCIT in a hospital setting. In maintenance phase, SCIT was administered every 4-8 weeks on an outpatient basis. According to the situation of sensitization, patients underwent SCIT with other extracts at the same time. Oral food challenge (OFC) with fruits and vegetables was performed at baseline and after rush phase. We also investigated about OAS symptoms in maintenance phase.SCIT was remarkably effective in five patients for OAS symptoms just after rush phase, and effective in nine patients. And it was not effective in two patients, and not determined in three patients, but it was confirmed to be effective in four out of these five patients in maintenance phase. There were relapse of OAS symptoms in three patients, then SCIT was remarkably effective or effective in 15 patients (79%) in maintenance phase. No patients dropped off the SCIT protocol.Generally, PFAS can't be expected to remit naturally. SCIT with birch pollen extract effectively reduces OAS symptoms, and it can be expected as a radical therapy for PFAS.

Patients with adult growth hormone deficiency exhibit visceral fat accumulation, which gives rise to a cluster of metabolic disorders such as impaired glucose tolerance and dyslipidemia. Plasma growth hormone levels are lower in obese patients with metabolic syndrome than in healthy subjects. Here we examined the hypothesis that exogenous growth hormone administration regulates function of adipose tissue to improve glucose tolerance in diet-induced obese mice. Twelve-week-old obese male C57BL/6 J mice received bovine growth hormone daily for 6 weeks. In epididymal fat, growth hormone treatment antagonized diet-induced changes in the gene expression of adiponectin, leptin, and monocyte chemoattractant protein-1, and significantly increased the gene expression of interleukin-10 and CD206. Growth hormone also suppressed the accumulation of oxidative stress marker, thiobarbituric acid-reactive substances, in the epididymal fat and enhanced the gene expression of anti-oxidant enzymes. Moreover, growth hormone significantly restored glucose tolerance in obese mice. In cultured 3T3-L1 adipocytes, growth hormone prevented the decline in adiponectin gene expression in the presence of hydrogen peroxide. These results suggest that growth hormone administration ameliorates glucose intolerance in obese mice presumably by decreasing adipose mass, oxidative stress, and chronic inflammation in the visceral fat.

Background: The aim was to study the clinical efficacy and safety of rush oral immunotherapy (OIT) for severe peanut-allergic children and to measure the antibody responses. Methods: Eighteen Japanese children were enrolled after a positive double-blind, placebo-controlled food challenge (DBPCFC). The patients ingested peanuts up to 3-5 times a day every 30 min, increasing the dose by 20% every time. The goal dose was 3.5-7 g. IgE, IgG, and IgG4 antibody levels to peanut, and peanut allergen components were measured during up to 3 yr of maintenance treatment. Results: Two children dropped out due to side effects. Sixteen patients (14 boys and two girls, median: 9 yr range: 5-14 yr) achieved the goal dose after a median of 11 days (range: 4-19 days). Their median threshold dose at DBPCFC was 0.20 g (range: 0.015-1.0 g). All were sensitized to Ara h 2. Fourteen of them had a history of previous anaphylaxis. In total, 173 adverse events were observed during the treatment (27% of the total ingestions) of which 74 needed medications. The median IgE, IgG, and IgG4 antibody levels to peanut increased during rush OIT. The IgG4 levels were high during the whole maintenance phase. IgE and IgG4 antibodies to Ara h 2 dominated the serological response during the treatment. Conclusions: The present rush OIT protocol for children with severe peanut allergy was effective and relatively safe. A sustained Ara h 2-specific IgG4 antibody response characterized the treatment.

Inflammation drives the formation, progression, and rupture of atherosclerotic plaques. Experimental studies have demonstrated that an inflammatory subset of monocytes/macrophages preferentially accumulate in atherosclerotic plaque and produce proinflammatory cytokines. T lymphocytes can contribute to inflammatory processes that promote thrombosis by stimulating production of collagen-degrading proteinases and the potent procoagulant tissue factor. Recent data link obesity, inflammation, and modifiers of atherosclerotic events, a nexus of growing clinical concern given the worldwide increase in the prevalence of obesity. Modulators of inflammation derived from visceral adipose tissue evoke production of acute phase reactants in the liver, implicated in thrombogenesis and clot stability. Additionally, C-reactive protein levels rise with increasing levels of visceral adipose tissue. Adipose tissue in obese mice contains increased numbers of macrophages and T lymphocytes, increased T lymphocyte activation, and increased interferon-gamma (IFN-gamma) expression. IFN-gamma deficiency in mice reduces production of inflammatory cytokines and inflammatory cell accumulation in adipose tissue. Another series of in vitro and in vivo mouse experiments affirmed that adiponectin, an adipocytokine, the plasma levels of which drop with obesity, acts as an endogenous antiinflammatory modulator of both innate and adaptive immunity in atherogenesis. Thus, accumulating experimental evidence supports a key role for inflammation as a link between risk factors for atherosclerosis and the biology that underlies the complications of this disease. The recent JUPITER trial supports the clinical utility of an assessment of inflammatory status in guiding intervention to limit cardiovascular events. Inflammation is thus moving from a theoretical concept to a tool that provides practical clinical utility in risk assessment and targeting of therapy.

Fused tetracycles, 6-alkyl-3-alkoxy-2-cyano-4,5,6a,11-tetraazabenzo[a]fluorene derivatives (5a,b,c,d,e,f), are synthesized from 2-alkoxy-5-(benzimidazol-2-ylidene)-3-cyano-6-imino-5,6-dihydro-pyridines (4b,c), and when refluxed in ethyl orthoacetate or ethyl orthopropionate, the elecrophilic aromatic substitution occurs at the ortho position of the cyanopyridine ring in the fused tetracycles (5b,c,e,f) to afford 6-alkyl-3-alkoxy-2-cyano-1-ethyl-4,5,6a,11-tetraazabenzo[a]fluorenes(6b,c,e,f).

Macrophage activation participates pivotally in the pathophysiology of chronic inflammatory diseases, including atherosclerosis. Through the receptor EP4, prostaglandin E(2) (PGE(2)) exerts an anti-inflammatory action in macrophages, suppressing stimulus-induced expression of certain proinflammatory genes, including chemokines. We recently identified a novel EP4 receptor-associated protein (EPRAP), whose function in PGE(2)-mediated anti-inflammation remains undefined. Here we demonstrate that PGE(2) pretreatment selectively inhibits lipopolysaccharide (LPS)-induced nuclear factor kappaB1 (NF-kappaB1) p105 phosphorylation and degradation in mouse bone marrow-derived macrophages through EP4-dependent mechanisms. Similarly, directed EPRAP expression in RAW264.7 cells suppresses LPS-induced p105 phosphorylation and degradation, and subsequent activation of mitogen-activated protein kinase kinase 1/2. Forced expression of EPRAP also inhibits NF-kappaB activation induced by various proinflammatory stimuli in a concentration-dependent manner. In co-transfected cells, EPRAP, which contains multiple ankyrin repeat motifs, directly interacts with NF-kappaB1 p105/p50 and forms a complex with EP4. In EP4-overexpressing cells, PGE(2) enhances the protective action of EPRAP against stimulus-induced p105 phosphorylation, whereas EPRAP silencing in RAW264.7 cells impairs the inhibitory effect of PGE(2)-EP4 signaling on LPS-induced p105 phosphorylation. Additionally, EPRAP knockdown as well as deficiency of NF-kappaB1 in macrophages attenuates the inhibitory effect of PGE(2) on LPS-induced MIP-1beta production. Thus, PGE(2)-EP4 signaling augments NF-kappaB1 p105 protein stability through EPRAP after proinflammatory stimulation, limiting macrophage activation.

Obese individuals often have low plasma adiponectin and concomitant chronic inflammation with a predisposition to metabolic and cardiovascular diseases. The present study reports a novel antiinflammatory action of adiponectin in human monocyte-derived macrophages (MΦ) suppressing T-lymphocyte accumulation in atherogenesis. RNA profiling of lipopolysaccharide-stimulated human MΦ identified CXC chemokine ligands (CXCLs), such as IP-10 (interferon [IFN]-inducible protein 10) (CXCL10), I-TAC (IFN-inducible T-cell α chemoattractant) (CXCL11), and Mig (monokine induced by IFN-γ) (CXCL9), T-lymphocyte chemoattractants associated with atherogenesis, among the top 14 transcripts suppressed by adiponectin. Real-time quantitative RT-PCR and ELISA verified that adiponectin inhibited expression of these chemokines at both the mRNA and protein levels in a concentration-dependent manner. Adiponectin reduced the release by lipopolysaccharide-stimulated MΦ of chemoattractant activity for CXC chemokine receptor 3–transfected (receptor for IP-10, Mig, and I-TAC) lymphocytes. Adiponectin decreased lipopolysaccharide-inducible IP-10 promoter activity in promoter-transfected THP-1 MΦ but did not change IP-10 mRNA stability. In lipopolysaccharide-stimulated MΦ, reduction of IFN-β by adiponectin preceded inhibition of IP-10 mRNA expression. Immunoblot and chromatin immunoprecipitation analyses demonstrated that adiponectin attenuated activation of the transcription factor IFN regulatory factor 3, involved in the MyD88-independent pathway of Toll-like receptor 4 signaling, and subsequent IFN regulatory factor 3 binding to IFN-β promoter. In vivo studies further demonstrated that apolipoprotein E/adiponectin double-deficient (apoE −/− APN −/− ) mice had increased plasma IP-10 levels, accelerated T-lymphocyte accumulation in atheromata, and augmented atherogenesis compared with apoE single-deficient (apoE −/− APN +/+ ) mice. This study establishes that low levels of adiponectin associated with obesity, the metabolic syndrome, and diabetes favor T-lymphocyte recruitment and contribute to adaptive immune response during atherogenesis.

The reaction of 7-chloro-1-methylpyridazino[3,4-b]quinoxalin-4(1H)-ones 3a-5a with sodium methylthiolate gave 1-methyl-7-methylsulfanylpyridazino[3,4-b]quinoxalin-4(1H)-ones 8a-c, whose reaction with m-chloroperbenzoic acid afforded the 7-methanesulfonyl-1-methylpyridazino[3,4-b]-quinoxalin-4(1H)-ones 9a-c, respectively. The above substituent change at the 7-position resulted in the activity alteration to microorganisms.

The metabolic syndrome, a cluster of metabolic disorders often associated with visceral obesity, increases cardiovascular mortality and morbidity. As the body's largest endocrine organ, adipose tissue not only stores excess body energy, but also secretes a variety of bioactive adipocytokines. Obese patients, particularly those with visceral fat accumulation, have reduced plasma levels of adiponectin, the most abundant and adipose-specific adipocytokine. Although the association of adiponectin with several diseases remains controversial, many clinical studies have demonstrated that low plasma concentrations of adiponectin (hypoadiponectinaemia) associate closely with obesity-related diseases, including atherosclerotic cardiovascular diseases, Type II diabetes mellitus, hypertension and dyslipidaemia. Accumulating experimental evidence indicates that adiponectin possesses anti-atherogenic, anti-inflammatory and anti-diabetic properties and may also participate importantly in the mechanism of metabolic syndrome and other diseases. Despite these associations, further clinical and experimental investigations will be needed to illuminate the in vivo pathophysiological significance of this protein. Although evaluation of adiponectin as a novel therapy will ultimately require clinical intervention studies, this mediator may represent a novel target for the prevention and treatment of visceral obesity metabolic syndrome.

The 3-amino-1-methylpyridazino[3,4-b]quinoxalin-4(1H)-one 6 and N-(1,4-dihydro-1-methyl-4-oxopyridazino[3,4-b]quinoxalin-3-yl)carbamates 17a,b were synthesized from the 1,4-dihydro-1-methyl-4-oxopyridazino[3,4-b]quinoxa-line-3-carboxylate 1b via the 1,5-dihydro-4-hydroxy-1-methylpyridazino[3,4-b]quinoxaline-3-carbohydrazide 13b and then 1,4-dihydro-1-methyl-4-oxopyridazino[3,4-b]quinoxaline-3-carboxazide 8. Heating of compound 13b and arylalde-hydes afforded the 1,4-dihydro-1-methyl-4-oxopyridazino[3,4-b]quinoxaline-3-carbo(2-arylmethylene)hydrazides 14a-d.

The 3-heteroaryl-1-methylpyridazino[3,4-b]quinoxalin-4(1H)-ones 6a-e were synthesized by the oxidative-hydrolytic ring transformation of the 3-heteroaryl-1,2-diazepino[3,4-b]]quinoxaline-5-carbonitriles 9a-c, which were obtained by the 1,3-dipolar cycloaddition reaction of the 2-(2-heteroarylmethylene-1-methylhydrazino)quinoxaline 4-oxides with 2-chloroacrylonitrile. The assignment of the thiophene and furan ring protons was carried out through the data of the NOE, decoupling, and coupling constants.

The reaction of the quinoxaline N-oxides 7a,b with diethyl ethoxymethylenemalonate gave the 1-methylpyridazino[3,4-b]quinoxaline-4,4-dicarboxylates 8a,b, whose reaction with N-bromosuccinimide or N-chlorosuccinimide afforded the 3-halogeno-1-methylpyridazino[3,4-b]quinoxaline-4,4-dicarboxylates 9a-d. The reaction of compounds 9a-d with hydrazine hydrate resulted in hydrolysis and decarboxylation to provide the 3-halogeno-1-methylpyridazino[3,4-b]quinoxaline-4-carboxylates 10a-d, whose reaction with nitrous acid effected oxidation to furnish the 3-halogeno-4-hydroxy-1-methylpyridazino[3,4-b]quinoxaline-4-carboxylates 11a-d, respectively. The reaction of compounds 11a-d with hydrazine hydrate afforded the 3-halogeno-1-methylpyridazino[3,4-b]quinoxalin-4-ols 12a-d, whose oxidation provided the 3-halogeno-1-methylpyridazino[3,4-b]quinoxalin-4(1H)-ones 6a-d, respectively. Compounds 6a-d had antifungal activities in vitro.

To obtain fundamental design data on bearing/seal parts made of PEEK and stainless steel, friction characteristics were tested by a pin-on-disc machine. The test parameters were mean load pressure, sliding speed, water temperature, water properties, and surface roughness. Based on the test results, a mixed lubrication model, which is applicable to rubbing parts in hydraulic equipment, was proposed.

Background— Dysregulation of adipocyte-derived bioactive molecules plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the injured artery from the plasma and suppressed endothelial inflammatory response and vascular smooth muscle cell proliferation, as well as macrophage-to-foam cell transformation in vitro. The current study investigated whether the increased plasma adiponectin could actually reduce atherosclerosis in vivo. Methods and Results— Apolipoprotein E-deficient mice were treated with recombinant adenovirus expressing human adiponectin (Ad-APN) or β-galactosidase (Ad-βgal). The plasma adiponectin levels in Ad-APN–treated mice increased 48 times as much as those in Ad-βgal treated mice. On the 14th day after injection, the lesion formation in aortic sinus was inhibited in Ad-APN–treated mice by 30% compared with Ad-βgal–treated mice ( P P Conclusions— These findings documented for the first time that elevated plasma adiponectin suppresses the development of atherosclerosis in vivo.

Obesity is more linked to vascular disease, including atherosclerosis and restenotic change, after balloon angioplasty. The precise mechanism linking obesity and vascular disease is still unclear. Previously we have demonstrated that the plasma levels of adiponectin, an adipose-derived hormone, decreases in obese subjects, and that hypoadiponectinemia is associated to ischemic heart disease. In current the study, we investigated the in vivorole of adiponectin on the neointimal thickening after artery injury using adiponectin-deficient mice and adiponectin-producing adenovirus. Adiponectin-deficient mice showed severe neointimal thickening and increased proliferation of vascular smooth muscle cells in mechanically injured arteries. Adenovirus-mediated supplement of adiponectin attenuated neointimal proliferation. In cultured smooth muscle cells, adiponectin attenuated DNA synthesis induced by growth factors including platelet-derived growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), basic fibroblast growth factor, and EGF and cell proliferation and migration induced by HB-EGF. In cultured endothelial cells, adiponectin attenuated HB-EGF expression stimulated by tumor necrosis factor α. The current study suggests an adipo-vascular axis, a direct link between fat and artery. A therapeutic strategy to increase plasma adiponectin should be useful in preventing vascular restenosis after angioplasty.

Background — Vascular smooth muscle cell proliferation plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the human injured artery and suppressed endothelial inflammatory response as well as macrophage-to-foam cell transformation. The present study investigated the effects of adiponectin on proliferation and migration of human aortic smooth muscle cells (HASMCs). Methods and Results — HASMC proliferation was estimated by [ 3 H] thymidine uptake and cell number. Cell migration assay was performed using a Boyden chamber. Physiological concentrations of adiponectin significantly suppressed both proliferation and migration of HASMCs stimulated with platelet-derived growth factor (PDGF)-BB. Adiponectin specifically bound to 125 I-PDGF-BB and significantly inhibited the association of 125 I-PDGF-BB with HASMCs, but no effects were observed on the binding of 125 I-PDGF-AA or 125 I-heparin–binding epidermal growth factor (EGF)–like growth factor (HB-EGF) to HASMCs. Adiponectin strongly and dose-dependently suppressed PDGF-BB–induced p42/44 extracellular signal–related kinase (ERK) phosphorylation and PDGF β-receptor autophosphorylation analyzed by immunoblot. Adiponectin also reduced PDGF-AA–stimulated or HB-EGF–stimulated ERK phosphorylation in a dose-dependent manner without affecting autophosphorylation of PDGF α-receptor or EGF receptor. Conclusions — The adipocyte-derived plasma protein adiponectin strongly suppressed HASMC proliferation and migration through direct binding with PDGF-BB and generally inhibited growth factor–stimulated ERK signal in HASMCs, suggesting that adiponectin acts as a modulator for vascular remodeling.

Reaction of 2-(aminomethyl)pyridine with selenium dioxide leads to the formation of imidazo[1,5-a]pyridine (2-azaindolizine) skeleton in a single step. The major products of the reactions are 3-(2-...

Rush oral immunotherapy was provided to a 9 year old boy suffering from egg allergy. The patient reached the goal of one boiled egg daily on day 22 of treatment. He was discharged from the hospital the following day, with the maintenance dose of one whole egg to be taken daily. However, the patient began to experience abdominal pain and vomiting after ingestion of egg approximately one day after discharge. Blood tests revealed a remarkable increase in eosinophils in peripheral blood, and we reduced the patient's intake of egg. The patient's condition did not improve, and he gradually started to lose weight. Maintenance dosing was stopped completely on day 38. An endoscopic biopsy of the mucosa lining from the esophagus to the duodenum was performed on day 45. The results confirmed prominent diffuse eosinophilic infiltration of the entire upper gastrointestinal tract. The patient was finally diagnosed with eosinophil esophagogastroenteritis. While this condition is rare, it should be considered in future cases of persistent gastrointestinal symptoms during food allergy immunotherapy.

Background —Excessive lipid accumulation in macrophages plays an important role in the development of atherosclerosis. Recently, we discovered an adipocyte-specific plasma protein, adiponectin, that is decreased in patients with coronary artery disease. We previously demonstrated that adiponectin acts as a modulator for proinflammatory stimuli and inhibits monocyte adhesion to endothelial cells. The present study investigated the effects of adiponectin on lipid accumulation in human monocyte-derived macrophages. Methods and Results —Human monocytes were differentiated into macrophages by incubation in human type AB serum for 7 days, and the effects of adiponectin were investigated at different time intervals. Treatment with physiological concentrations of adiponectin reduced intracellular cholesteryl ester content, as determined using the enzymatic, fluorometric method. The adiponectin-treated macrophages contained fewer lipid droplets stained by oil red O. Adiponectin suppressed the expression of the class A macrophage scavenger receptor (MSR) at both mRNA and protein levels by Northern and immunoblot analyses, respectively, without affecting the expression of CD36, which was quantified by flow cytometry. Adiponectin reduced the class A MSR promoter activity, as measured by luciferase reporter assay. Adiponectin treatment dose-dependently decreased class A MSR ligand binding and uptake activities. The mRNA level of lipoprotein lipase as a marker of macrophage differentiation was decreased by adiponectin treatment, but that of apolipoprotein E was not altered. Adiponectin was detected around macrophages in the human injured aorta by immunohistochemistry. Conclusions —The adipocyte-derived plasma protein adiponectin suppressed macrophage-to-foam cell transformation, suggesting that adiponectin may act as a modulator for macrophage-to-foam cell transformation.

The reaction of the quinoxaline N-oxide 1 with thiophene-2-carbaldehyde gave 6-chloro-2-[1-methyl-2-(2-thienylmethylene)hydrazino]quinoxaline 4-oxide 5, whose reaction with 2-chloroacrylonitrile afforded 8-chloro-2,3-dihydro-4-hydroxy-1-methyl-3-(2-thienyl)-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6. The reaction of compound 6 with various alcohols in the presence of a base effected alcoholysis to provide the 5-alkoxy-8-chloro-2,3,4,6-tetrahydro-1-methyl-4-oxo-3-(2-thienyl)-1H-1,2-diazepino[3,4-b]-quinoxalines 7a-d. The reaction of compounds 7a and 7b with diethyl azodicarboxylate effected dehydrogenation to give the 5-alkoxy-8-chloro-4,6-dihydro-1-methyl-4-oxo-3-(2-thienyl)-1H-1,2-diazepino[3,4-b]-quinoxalines 8a and 8b, respectively. Compounds 8a and 8b were found to show good algicidal activities against Selenastrum capricornutum and Nitzchia closterium.

The reaction of the 2-(1-alkylhydrazino)-6-chloroquinoxaline 4-oxides 1a,b with diethyl acetone-dicarboxylate or 1,3-cyclohexanedione gave ethyl 1-alkyl-7-chloro-3-ethoxycarbonylmethylene-1,5-dihydropyridazino[3,4-b]quinoxaline-3-carboxylates 5a,b or 6-alkyl-10-chloro-1-oxo-1,2,3,4,6,12-hexahydroquinoxalino[2,3-c]cinnolines 7a,b, respectively. Oxidation of compounds 5a,b with nitrous acid afforded the ethyl 1-alkyl-7-chloro-3-ethoxycarbonylmethylene-4-hydroxy-1,4-dihydropyridazino-[3,4-b]quinoxaline-4-carboxylates 9a,b, whose reaction with base provided the ethyl 2-(1-alkyl-7-chloro-4-oxo-1,4-dihydropyridazino[3,4-b]quinoxalin-3-yl)acetates 6a,b, respectively. On the other hand, oxidation of compounds 7a,b with N-bromosuccinimide/water furnished the 4-(1-alkyl-7-chloro-4-oxo-1,4-dihydropyridazino[3,4-b]quinoxalin-3-yl)butyric acids 8a,b, respectively. The reaction of compound 8a with hydroxylamine gave 4-(7-chloro-4-hydroxyimino-1-methyl-1,4-dihydropyridazino[3,4-b]quinoxalin-3-yl)-butyric acid 12.

The reaction of the alkylhydrazinoquinoxaline N-oxides 2a-d with dimethyl acetylenedicarboxylate gave the dimethyl 1-alkyl-1,5-dihydropyridazino[3,4-b]qumoxaline-3,4-dicarboxylates 3a-d, whose reaction with nitrous acid effected the C4-oxidation to afford the dimethyl 1-alkyl-4-hydroxy-1,4-dihydropyridazino-[3,4-b]quinoxaline-3,4-dicarboxylates 4a-d, respectively. The reaction of compounds 4a-d with 1,8-diazabicyclo[5.4.0]-7-undecene in ethanol provided the ethyl 1-alkyl-4-oxo-1,4-dihydropyridazino[3,4-b]quinoxa-line-3-carboxylates 5a-d, while the reaction of compounds 4a-d with potassium hydroxide furnished the 1-alkyl-4-oxo-1,4-dihydropyridazino[3,4-b]quinoxaline-3-carboxylic acids 6a-d, respectively. Compounds 6c,d were also obtained by the reaction of compounds 5c,d with potassium hydroxide, respectively.

Abstract —Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)–matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6±0.4 versus 7.9±0.5 μg/mL in men, 7.6±0.7 versus 11.7±1.0 μg/mL in women; P P r =−0.18, P r =−0.26, P

Adipose tissue secretes a variety of proteins into the bloodstream. We have previously reported a novel cDNA, apM1 (adipose most abundant gene transcript 1), which is specifically and abundantly expressed in adipose tissue [1]. Primary structure analysis predicted that the apM1 gene product possesses significant homology to collagens VIII, X and complement factor C1q, and we named it adiponectin. In the current study, we analyzed characteristics of adiponectin in vitro and in vivo. Adiponectin protein was proved to be secreted into the medium when the cDNA was transfected to COS cells. Anti-adiponectin cross-reactivities were abundantly detected in the human plasma. In solid-phase binding assays, adiponectin specifically bound to collagen types I, III and V, which are present in vascular intima. Immunohistochemical analysis revealed that adiponectin was detected in the walls of the catheter-injured vessels but not in the intact vascular walls. These data suggest that adiponectin is a plasma protein produced by adipose tissue and accumulates in vascular walls when the endothelial barrier is injured.

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 1b with acetylacetone or benzoylacetone gave 6-chloro-2-(3,5-dimethylpyrazol-i-yl)quinoxaline 4-oxide 5a or 6-chloro-2-(3-methyl-5-phenylpyrazol-1-yl)quinoxaline 4-oxide 5b, respXectively. Compound 5a or 5b was converted into the pyrrolo[1,5-a]quinoxaline 6a or 6b, triazolo[4,3-a]quinoxaline 9a or 9b, and tetrazolo[1,5-a]quinoxaline 10.

3-Chloro- and 3-bromo-4-methoxycoumarins 1a,b were readily transformed into 4-halo-5-(2-hydroxyphenyl)-3-oxo-2,3-dihydropyrazoles 2a,b with hydrazines. In the reaction of 1a,b with excess hydrazine and phenylhydrazine in boiling ethanol, unexpected 4-hydrazono-3-(2-hydroxyphenyl)-2-pyrazolin-5-ones 3, 5 were obtained. The structure of 3 was determined by X-ray diffraction analysis.

The reaction of 2-acyiamino-8-chloro-4-methyl-4H-1,3,4-oxadiazino[5,6-b]quinoxalines 2a-d with methyl iodide/base gave the 8-chloro-4,10-dimethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxalin-10-ium-2-acylamidates 4a-d, respectively. Comparison of the nmr spectral data between compounds 2a-d and 4a-d in deuteriodimethyl sulfoxide or in deuteriotrifluoroacetic acid established that compounds 2a-d existed as the zwitterionic tautomers 2′a-d in solution.

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5 with a 2-fold molar amount of ethyl chloroglyoxalate gave ethyl 8-chloro-4-methyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline-2-carboxylate 6, whose reaction with hydrazine hydrate afforded the C2-hydrazinocarbonyl derivative 7. The reaction of compound 7 with nitrous acid provided the C2-acylazide derivative 8, which was converted into the C2-amino 9, C2-carbamate 11a-c, 12a,b, and C2-ureido 13a-c, 14 derivatives. The mass spectral fragmentation patterns were examined for compounds 10–14, wherein the molecular ion peak did not appear in the mass spectra of compounds 10c, 11a-c, 12a,b, 13c, and 14.

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with acetic anhydride resulted in the intramolecular cyclization to give 8-chloro-2,4-dimethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7a, while the reaction of compound 8 with acetic anhydride/pyridine or acetic anhydride/acetic acid afforded 3-(2,2-diacetyl-1-memymydrazmo)-7-chloro-2-oxo-1,2-dihydroquinoxaline 9, effecting no intramolecular cyclization. The reaction of 2-(2-acetyl-1-methylhydrazino)-6-chloroquinoxaline 4-oxide 10a or 6-chloro-2-(1-methyl-2-trifluoroacetylhydrazino)quinoxaline 4-oxide 10b with phosphoryl chloride provided compound 7a or 8-chloro-4-memyl-2-trifluoromethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7b, respectively. The reaction of compound 7b with phosphorus pentasulfide gave 7-chloro-3-(1-methyl-2-trifluoroacetylhydrazino)-2-thioxo-1,2-dihydroquinoxaline 11, whose dehydration with sulfuric acid in acetic acid afforded 8-chloro-4-methyl-2-trifluoromemyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 12.

The reaction of the 6-chloro-2-(1-methyl-2-thiocarbamoylhydrazino)quinoxaline 4-oxides 3a-d with trifluoroacetic anhydride gave the 2-(N-aryl)trifluoroacetamido-8-chloro-4-methyl-4H-1,3,4-thiadiazino-[5,6-b]quinoxalines 7a-d, respectively, while the reflux of compounds 3a-c in N,N-dimethylformamide afforded the mesoionic triazolo[4,3-a]quinoxaline 4. Hydrolysis of compounds 7a-d with triethylamine/water provided the 2-arylamino-8-chloro-4-methyl-4H-1,3,4-thiadiazino[5,6-b)]quinoxalines 8a-d, respectively.

The 13C-nmr study was carried out for the tautomerism of the 3-(arylhydrazono)methyl-2-oxo-1,2-dihy-droquinoxalines 1a-g and 2a-e between the hydrazone imine A and diazenylenamine B forms, providing the carbon chemical shifts for the tautomers A and B of compounds 1a-g and 2a-e. The comparison of the carbon chemical shifts for the tautomer B of compounds 1d, 1f, and 2b in deuteriodimethyl sulfoxide with those in deuteriotrifluoroacetic acid showed that the C4a, C5, and diazenyl carbons were considerably shielded presumably due to the azo N-deuteration in deuteriotrifluoroacetic acid.