Spirotoamides A and B, novel 6,6-spiroacetal polyketides isolated from a microbial metabolite fraction library

Two new 6,6-spiroacetal polyketides, spirotoamides A (1) and B (2), were isolated from a microbial metabolite fraction library of Streptomyces griseochromogenes JC82-1223 by screening of structurally unique compounds based on a search of spectral database. The fraction library was constructed using a systematic separation method to efficiently discover new metabolites from microbial sources such as actinomycetes and fungi. The structures of 1 and 2 were elucidated by 2D-NMR and mass spectrometric measurements. They belong to a class of polyketides, and contain a 6,6-spiroacetal core structure and a carboxamide group. The biosynthetic pathway of 1 and 2 is discussed in the text.     

Apolipoprotein E accelerates the efflux of cholesterol from macrophages: mechanism of xanthoma formation in apolipoprotein E deficiency

A patient with congenitally deficient apolipoprotein (apo) E showed numerous tuberoerutive, tendon xanthomas and severe atherosclerosis, despite a low LDL concentration. In order to study the mechanism of xanthoma formation observed in apo E deficient patients, we evaluated the effect of VLDL and HDL from the patient on cholesterol ester (CE) accumulation in macrophages. The results showed that there was no difference in CE formation in macrophages among normal VLDL, the patient's VLDL and apo E containing VLDL, which was prepared by incubation of the patient's VLDL with recombinant apo E. On the other hand, apo E containing HDL, which was prepared by incubation of the patient's HDL with recombinant apo E, accelerated cholesterol efflux more effectively than did the patient's HDL and decreased intracellular CE content. Moreover, free apo E accelerated cholesterol efflux from lipid loaded macrophages. These results suggest that macrophages are prevented from transforming into foam cells by their secretion of apo E. This may also explain the marked atherosclerosis and xanthomatosis observed in the patient with apo E-deficiency.     

Mondini dysplasia with recurrent bacterial meningitis caused by three different pathogens

Mondini dysplasia is rare, but has an important association with recurrent bacterial meningitis. We herein describe the case of a 3‐year‐old girl with unilateral sensorineural hearing loss who presented with three independent episodes of bacterial meningitis within 8 months. Temporal bone computed tomography indicated the characteristic features of Mondini dysplasia in the right inner ear. This was treated by surgical closure of the inner ear defect via oval window and additional vaccination was administered. Appropriate vaccination might prevent the recurrent bacterial meningitis associated with Mondini dysplasia.     

CETP is a determinant of serum LDL-cholesterol but not HDL-cholesterol in healthy Japanese

Cholesteryl ester transfer protein (CETP) is one of the factors that regulate plasma levels of HDL-cholesterol. To identify the factors that may regulate CETP activity, and to determine to what extent CETP is correlated with physiologic concentrations of lipoprotein, we performed an epidemiologic study in 586 healthy volunteers (317 males and 269 females, mean age 52.2 ± 10.9 years). CETP activity in these subjects was 192.96 ± 48.73 (mean ± S.D.) nmol/ml/h and distributed to a wide range (60–450 nmol/ml/h). Using multiple regression analysis, we found significant positive correlations between CETP activity and LDL-cholesterol (P < 0.03), apolipoprotein (apo) E (P < 0.005) and LCAT activity (P < 0.001). CETP activities showed significant negative correlation with apo A-I (P < 0.03). However, CETP activity showed no significant correlation either with HDL cholesterol or with apo B. One-way layout analysis of variance showed that alcohol drinking and cigarette smoking significantly reduced CETP activity, but there was no significant association between CETP activity and body mass index. Although CETP activities were significantly higher in females than in males (P < 0.001), multiple regression analysis showed no correlation between CETP activity and age in either the males or the females. Our results suggest that CETP activity regulates the concentration of apo A-I and LDL-cholesterol, and that such activity may be influenced by gender, alcohol consumption and cigarette smoking.     

Pharmacological Profile of U‐37883A,a Channel Blocker of Smooth Muscle‐Type ATP‐Sensitive K+ Channels

U‐37883A (PNU‐37883A, guanidine; 4‐morpholinecarboximidine‐N‐1‐adamantyl‐N′‐cyclohexyl hydrochloride) was originally developed as a potential diuretic with specific binding in kidney and vascular smooth muscle rather than in brain or pancreatic β cells. U‐37883A inhibits ATP‐sensitive K⁺ channels (K_ATP channels) in vascular smooth muscle at submicromolar concentrations whilst even at high concentrations (≥10 μM) it has no inhibitory effect at pancreatic, cardiac or skeletal K_ATP channels. Thus, it is generally thought that U‐37883A is a selective inhibitor of vascular smooth muscle K_ATP channels. Approximately one decade ago, K_ATP channels were cloned and found to consist of at least two subunits: an inwardly‐rectifying K⁺ channel six family (K_ir6.x; K_ir6.1 and K_ir6.2) which forms the ion conducting pore and a modulatory sulphonylurea receptor (SUR.x; SUR1, SUR2A, and SUR2B) that accounts for several pharmacological properties. It is generally believed that different combinations of K_ir6.x and SUR.x determine the molecular properties of K_ATP channels. Thus, K_ir6.2/SUR1 channel represents the pancreatic β‐cell K_ATP channel, K_ir6.2/SUR2A channel is thought to represent the cardiac K_ATP channel, whereas K_ir6.1/SUR2B channel is likely to represent the vascular smooth muscle K_ATP channel. Recent molecular studies have shown that U‐37883A selectively suppresses the activity of recombinant K_ATP channels which contain K_ir6.1 subunits in the channel pore unit. It was thus thought that U‐37883A was a selective pharmacological tool which could be used to investigate the activity of vascular smooth muscle K_ATP channels. However, due to its multiple pharmacological actions on several ion channels and poor tissue selectivity, U‐37883A should not be viewed as a selective blocker of smooth muscle K_ATP channels.     

Exploration of immobilization conditions of cellulosic lyotropic liquid crystals in monomeric solvents by in situ polymerization and achievement of dual mechanochromism at room temperature

We investigated conditions to prepare cellulosic cholesteric liquid crystalline (ChLC) films in order to accomplish dual mechanochromism, i.e., colour control and circular dichroic inversion upon mechanical stimulus, at room temperature. Flexible propionylated hydroxypropyl cellulose (PHPC) was prepared by a simple reaction and found to be capable of forming lyotropic ChLC in various monomeric solvents. The ChLC solutions were subjected to in situ polymerization to obtain PHPC/synthetic polymer composite films incorporating the ChLC structure. However, the immobilization behaviour depended on the type of original monomers. Differential scanning calorimetry and solid-state NMR measurement revealed that the ChLC structure was more highly fixed when the compatibility between PHPC and the coexisting polymers was lower. Eventually, thus obtained ChLC composite films exhibited dual mechanochromism under ambient temperature.

We obtained cellulosic/synthetic polymer composites incorporating a cholesteric liquid crystalline structure by in situ polymerization and accomplished dual mechanochromism at room temperature.     

Effect of pitch–space correspondence on sound-induced visual motion perception

The brain tends to associate specific features of stimuli across sensory modalities. The pitch of a sound is for example associated with spatial elevation such that higher-pitched sounds are felt as being “up” in space and lower-pitched sounds as being “down.” Here we investigated whether changes in the pitch of sounds could be effective for visual motion perception similar to those in the location of sounds. We demonstrated that only sounds that alternate in up/down location induced illusory vertical motion of a static visual stimulus, while sounds that alternate in higher/lower pitch did not induce this illusion. The pitch of a sound did not even modulate the visual motion perception induced by sounds alternating in up/down location. Interestingly, though, sounds alternating in higher/lower pitch could become a driver for visual motion if they were paired in a previous exposure phase with vertical visual apparent motion. Thus, only after prolonged exposure, the pitch of a sound became an inducer for upper/lower visual motion. This occurred even if during exposure the pitch and location of the sounds were paired in an incongruent fashion. These findings indicate that pitch–space correspondence is not so strong to drive or modulate visual motion perception. However, associative exposure could increase the saliency of pitch–space relationships and then the pitch could induce visual motion perception by itself.     

In Vitro Analysis of the Functional Effects of an NLRP3 G809S Variant with the co-Existence of MEFV Haplotype Variants in Atypical Autoinflammatory Syndrome

Purpose

Hereditary periodic fever syndromes have been considered monogenic diseases. However, some recent reports have described patients with co-existence of recurrent fever responsible genes. This study assessed whether a rare variant, found in Japanese children showing atypical autoinflammatory syndrome, located in the leucine-rich repeat domain of Nod-like receptor family, pyrin domain containing 3 (NLRP3) with co-existence of Mediterranean fever (MEFV) haplotype variants may contribute to a proinflammatory phenotype using a systematic approach.

Methods

Cytokine production in serum or from peripheral blood monocytes was measured by ELISA. DNA sequence analysis of genes including NLRP3, MEFV, mevalonate kinase (MVK), and tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) were performed on patient samples. In vitro functional assays determined the effects of the NLRP3 variants and pyrin using NF-κB activation and speck formation assays.

Results

A heterozygous genetic variant of NLRP3, G809S, was found in samples from both patients. Additionally the previously reported heterozygous MEFV variants (P369S-R408Q or E148Q-P369S-R408Q) were also detected in both patients. Serum IL-1ra and sTNFR1 levels increased in the attack phase of the disease in both patients. The production levels of IL-1β from monocytes isolated from both cases were elevated following LPS and IFN-γ stimulation. The NLRP3 G809S variant demonstrated no increase of NF-κB activity following monosodium urate stimulation, whereas it significantly increased speck formation by interacting with apoptosis-associated speck-like protein with caspase recruitment domain.

Conclusions

The phenotype of atypical autoinflammatory disease in patients could be modified by a synergistic effect with two other variants of autoinflammatory-associated genes.     

Varicose bleeding after liver transplantation in a patient with severe portosystemic shunts

Recipients for liver transplantation often have portosystemic shunts due to portal hypertension. It is an important problem whether such shunts should be ligated during operations. Ligating the shunts seems of benefit for increasing portal blood flow to the liver, but it is sometimes difficult technically, and it is invasive to the patient. We experienced a recipient with huge portosystemic shunts and no esophageal varices before living-related liver transplantation. Some shunts were ligated during operation to increase portal blood flow to the graft. Unfortunately, the patient suffered severe bleeding from esophagogastric varices after he underwent retransplantation owing to accidental liver failure. Based on our experience, extreme care should be exercised to avoid varicose bleeding after ligating the portosystemic shunts of liver transplantation patients.