Severity of hot flushes is inversely associated with dietary intake of vitamin B6 and oily fish.

Objectives: This study investigated the links between the severity of vasomotor symptoms (VMS) and the dietary consumption of a variety of nutrients. Method: A cross-sectional analysis of the first-visit records of 262 women aged 40-65 years was conducted. The severity of their hot flushes (HF) and night sweats (NS) and their dietary consumption of nutrients were evaluated using the Menopausal Health-Related Quality of Life Questionnaire and the brief-type self-administered Diet History Questionnaire, respectively. The relationships between severity of HF/NS and dietary intake were analyzed separately for 43 major nutrients. We then evaluated different food items as sources of the nutrients. Results: After adjustment for age, body mass index, menopausal status, and background factors significantly related to VMS, only vitamin B6 (VB6) was significantly related to severity of HF (adjusted odds ratio per 10 µg/MJ in VB6 intake, 0.92; 95% confidence interval, 0.86-0.97). Moreover, a significant inverse relationship was found between the consumption of oily fish as a source of VB6 and the severity of HF. Conclusions: VB6 and oily fish intake is inversely associated with the severity of HF in middle-aged women. Therefore, increased intake of VB6 could help attenuate HF.

Feelings of unattractiveness in peri- and postmenopausal women are associated with depressed mood, poor memory and unsatisfactory sexual relationships.

OBJECTIVES: This study aimed to investigate the prevalence of, and risk factors associated with, the feeling of unattractiveness in peri- and postmenopausal women. METHODS: The records of 351 women aged 40-76 who enrolled in a health and nutrition education program at a menopause clinic were analyzed in a cross-sectional manner. Perceptions of unattractiveness were estimated according to responses for the item 'feeling less attractive than before' on the Menopausal Health-Related Quality of Life Questionnaire. Age, menopausal status, body composition, cardiovascular parameters, physical fitness, and genitourinary, physical, and psychological symptoms of menopause were assessed for associations with feeling unattractive. RESULTS: The percentage of women who felt they were less attractive than before for more than half of the previous week was 33.6%. Multivariate logistic regression analysis revealed that independent risk factors for feeling unattractive included depression (adjusted odds ratio (OR) 1.35; 95% confidence interval (CI) 1.24-1.47), dissatisfaction with sexual relationship (adjusted OR 1.74; 95% CI 1.21-2.57), and poor memory (adjusted OR 1.89; 95% CI 1.46-2.49). CONCLUSIONS: Feelings of unattractiveness are highly prevalent in peri- and postmenopausal women. Such feelings are associated with depressed moods, poor memory, and unsatisfactory sexual relationships, rather than with age or body composition.

Subjective insomnia is associated with low sleep efficiency and fatigue in middle-aged women.

OBJECTIVES: Many middle-aged women are affected by sleep disturbance. We investigated how subjective insomnia is associated with objective sleep parameters and other background characteristics. METHODS: This cross-sectional study used baseline data obtained from 95 women aged 40-59 years who participated in another study assessing the effects of a dietary supplement. Participants wore an actigraph unit for 3 days to collect information concerning physical activities and objective sleep parameters and were then evaluated for body composition, cardiovascular parameters, and menopausal symptoms including insomnia and fatigue, and lifestyle factors. Stratifying Athens Insomnia Scale scores as low (0-5 points, control group) and high (≥ 6 points, subjective insomnia group), we sought to identify the parameters that are independently associated with subjective insomnia. RESULTS: Women with subjective insomnia (n = 30) had lower sleep efficiency than did the controls. They were also older; had more live births, lower height, higher body mass index, lower ankle brachial index, and more severe menopausal symptoms including fatigue; took more naps; smoked more cigarettes; and more of them were full-time workers. Multivariate logistic regression analysis revealed that low sleep efficiency (adjusted odds ratio, 1.44 per 1% decrease in sleep efficiency; 95% confidence interval 1.06-2.05) and fatigue assessed with Brief Fatigue Inventory (BFI) (adjusted odds ratio, 1.57 per 1-point increase in BFI score; 95% confidence interval 1.19-2.13) were independent contributors to subjective insomnia. CONCLUSIONS: Low sleep efficiency and feeling of fatigue were found to be independently associated with subjective insomnia in middle-aged women.

Insomnia in Japanese peri- and postmenopausal women.

OBJECTIVE: To determine the prevalence and to identify the correlates of insomnia in Japanese peri- and postmenopausal women. METHOD: We retrospectively analyzed the records of 1451 peri- and postmenopausal women enrolled in the Systematic Health and Nutrition Education Program, conducted at the Menopause Clinic of the Tokyo Medical and Dental University Hospital, between 1995 and 2009. RESULTS: The prevalence of insomnia was 50.8%. The severity of insomnia correlated negatively with health-related quality of life (HR-QOL) scores on all the four domains assessed: physical health, mental health, life satisfaction and social involvement. With regard to other menopausal symptoms, insomnia correlated more strongly with depressed mood than with vasomotor symptoms, and one-third of insomniac women were seriously depressed. On categorizing the participants into four groups--not insomniac or depressed, N; insomniac but not depressed, I; not insomniac but depressed, D; insomniac and depressed, ID--the HR-QOL scores were observed to worsen in order N > I > D > ID. No significant difference was detected between groups I and ID with regard to their sleep quality measures. The number of heavy smokers was high in groups I and ID. With regard to the effect of the combination of medication and health/nutrition education, hormone therapy and nightly hypnotics significantly improved the insomnia symptoms, but hypnotics administered 'as needed' did not. CONCLUSIONS: Insomnia in Japanese peri- and postmenopausal women correlates more strongly with depressed mood than with vasomotor symptoms. Cessation of smoking may improve the women's sleep quality, and hormone therapy and nightly hypnotics are both effective treatments.

Celecoxib inhibits production of MMP and NO via down-regulation of NF-kappaB and JNK in a PGE2 independent manner in human articular chondrocytes.

The purpose of this study was to examine the effects of celecoxib on matrix metalloproteinases (MMP-1 and MMP-3), nitric oxide (NO), and the phosphorylation of nuclear factor-kappaB (NF-kappaB) and three mitogen-activated protein kinases (MAPKs), (p38, JNK and ERK) in human articular chondrocytes from normal, osteoarthritis, and rheumatoid arthritis cartilages. Celecoxib at 100 nM reduced the IL-1beta-induced productions of MMP-1, MMP-3, iNOS, and NO, whereas indomethacin at 100 nM showed no effect. The additional stimulation of prostaglandin E2 (PGE2) failed to restore those productions, while the production of PGE2 were reduced by 1 and 10 microM but not 100 nM of celecoxib. The inhibitors of NF-kappaB, JNK and p38, but not ERK, decreased IL-1beta-enhanced MMP-1, MMP-3 and NO production, respectively, and 100 nM celecoxib down-regulated the phosphorylation of NF-kappaB and JNK but has no effect on either p38 or ERK. Celecoxib has inhibitory effects on MMP-1, MMP-3 and NO productions, suggesting the protective roles directly on articular chondrocytes. Despite the COX-2 selectivity, celecoxib affects those productions via not PGE2 but NF-kappaB and JNK MAPK.

Intercellular adhesion molecule-1 mediates the inhibitory effects of hyaluronan on interleukin-1beta-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts via down-regulation of NF-kappaB and p38.

OBJECTIVE: In rheumatoid arthritis (RA), it is well known that rheumatoid synovial fibroblasts (RSF) produce matrix metalloproteinases (MMPs) when stimulated with proinflammatory cytokines such as interleukin-1beta (IL-1beta), which causes joint destruction. We have previously shown that hyaluronan (HA) inhibits IL-1beta actions in RSF via CD44, the principal HA receptor. However, CD44 mediates HA effects only partially, and intracellular events after the HA binding to its receptors remain unclear. We investigated the role of intercellular adhesion molecule-1 (ICAM-1), another cell surface receptor for HA, and the intracellular signalling pathways in the actions of HA. METHODS: RSF were isolated from rheumatoid synovial tissues by enzymatic digestion and cultured in monolayers. The confluent cells were incubated for 48 h with IL-1beta, IL-1beta in the presence of HA, or IL-1beta in the presence of HA with pretreatment with anti-ICAM-1 antibody. Secretion of MMP-1 and MMP-3 was analysed by immunoblotting and immunofluorescence cytochemistry. Immunofluorescence cytochemistry was also performed to evaluate binding of HA to ICAM-1. The phosphorylation of nuclear factor (NF)-kappaB and mitogen-activated protein kinases (MAPKs) was analysed by immunoblotting. RESULTS: Production of MMP-1 and MMP-3 by RSF was stimulated by IL-1beta. HA at > or =2 mg/ml significantly inhibited MMP production induced by IL-1beta in a dose-dependent manner. Moreover, pretreatment with anti-ICAM-1 antibody at 50 mug/ml significantly blocked the effects of HA on the actions of IL-1beta on RSF, as shown by immunoblotting and immunofluorescence cytochemistry. Another immunofluorescence cytochemistry study demonstrated that HA bound RSF via ICAM-1. Inhibition studies revealed the requirement of NF-kappaB, p38 and c-jun NH2-terminal kinase (JNK) for IL-1beta-induced MMP production. IL-1beta activated all three pathways, whereas HA down-regulated their phosphorylation. Pretreatment with anti-ICAM-1 antibody reversed the inhibitory effects of HA on the activation of NF-kappaB and p38 without affecting JNK. CONCLUSION: HA suppresses IL-1beta-enhanced MMP-1 and MMP-3 synthesis in RSF via ICAM-1 through down-regulation of NF-kappaB and p38. Intra-articular injection of HA of high molecular weight may work through such a mechanism in RA joints.

COOH-terminal heparin-binding fibronectin fragment induces nitric oxide production in rheumatoid cartilage through CD44.

OBJECTIVES: To examine the mechanism of nitric oxide (NO) production by a COOH-terminal heparin-binding fibronectin fragment (HBFN-f) in rheumatoid arthritis (RA) cartilage. METHODS: Articular cartilage slices from RA knee joints and normal hip joints were cultured with HBFN-f. Secreted NO levels in conditioned media were determined. Cultures were pretreated with anti-CD44 antibody or HBFN-f-derived synthetic peptide (peptide V; WQPPRARI) to evaluate the role of CD44 in HBFN-f action. Immunofluorescence histochemistry was performed using fluorescein isothiocyanate-conjugated anti-CD44 antibody. RESULTS: HBFN-f stimulated NO production in a dose-dependent manner. Whereas CD44 expression was up-regulated in RA cartilage, anti-CD44 antibody blocked HBFN-f-stimulated NO production. Peptide V with heparin-binding ability significantly reduced NO levels elevated by HBFN-f. Compared with normal cartilage, cartilage response to HBFN-f and the blocking effects of anti-CD44 antibody on HBFN-f action were stronger in RA cartilage. CONCLUSIONS: The present study clearly demonstrated that HBFN-f stimulated NO production through CD44 in RA cartilage. Increased expression of CD44 in RA cartilage may play a pathological role in joint destruction through enhanced NO production by binding to fibronectin fragments such as HBFN-f.

Effect of a new hypoglycemic agent, A-4166 [(-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine], on postprandial blood glucose excursion: comparison with voglibose and glibenclamide.

(-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166) is a new nonsulfonylurea hypoglycemic agent that lowers blood glucose by stimulating insulin release. In the present study, we examined the effects of A-4166, voglibose (an alpha-glucosidase inhibitor), and glibenclamide (a sulfonylurea) on the postprandial glycemic increase in rats with or without diabetes mellitus. Oral administration of A-4166 (25-100 mg/kg) dose-dependently decreased blood glucose with a rapid onset and short duration in normal rats. On the other hand, glibenclamide (1-4 mg/kg) showed a slower onset of its hypoglycemic action, and voglibose (0.2 mg/kg) had no effect. In the case of postprandial glucose excursion, the carbohydrate-induced increase in blood glucose was reduced by oral administration of either A-4166 or voglibose without causing sustained hypoglycemia in both normal and neonatal streptozotocin-induced diabetic rats. However, the efficacy of voglibose varied with the type of carbohydrate load. Glibenclamide produced a prolonged decrease in blood glucose without any appreciable effect on the initial glucose excursion. After sucrose loading, plasma insulin levels during the initial 1 h were significantly higher in A-4166-treated rats than in control rats, while voglibose completely inhibited the insulin response to sucrose. In glibenclamide-treated rats, an augmented insulin response was not seen. In conclusion, unlike other hypoglycemic agents, A-4166 suppresses postprandial glucose excursions by stimulating the early phase of insulin secretion.

Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166).

1. (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166), a novel oral hypoglycaemic agent is a non-sulphonylurea insulin secretagogue. 2. We investigated the insulin-releasing action and hypoglycaemic effect of A-4166 compared to sulphonylureas in vitro and in vivo. 3. A-4166 stimulated insulin secretion from rat freshly isolated pancreatic islets at concentrations from 3 x 10(-6) M to 3 x 10(-4) M in the presence of 2.8 mM glucose. There was no obvious difference in glucose dependency between the insulinotropic effect of A-4166 and that of glibenclamide, and no additive or synergistic effect was observed between these two drugs. 4. A-4166 displaced [3H]-glibenclamide bound to intact HIT-T15 cells in a concentration-dependent manner. The Ki value was 4.34 +/- 0.04 x 10(7) M, and the displacement potency of A-4166 was between that of glibenclamide and tolbutamide, being similar to that of gliclazide. 5. Inf fasted beagle dogs, A-4166 showed a dose-dependent hypoglycaemic effect after oral administration over the range 1 to 10 mg kg-1. The hypoglycaemic action of A-4166 showed an earlier onset and a shorter duration than that of sulphonylureas. 6. Simultaneous measurement of plasma insulin levels revealed that the hypoglycaemic effect of A-4166 was caused by a rapid-onset and brief burst of insulin secretion. 7. The pharmacokinetic profile of A-4166 was consistent with the changes of the blood glucose and plasma insulin levels. 8. Although the in vitro insulin-releasing effect of A-4166 was similar to that of sulphonylureas, its hypoglycaemic effect was more rapid and shorter-lasting, associated with rapid absorption and clearance. Thus, A-4166 may be useful in suppressing postprandial hyperglycaemia in patients with non-insulin-dependent diabetes mellitus.

Saccharomyces cerevisiae IRE2/HAC1 is involved in IRE1-mediated KAR2 expression.

The Saccharomyces cerevisiae IRE1 gene, encoding a putative receptor-type protein kinase, is known to be required for inositol prototrophy and for the induction of a chaperon molecule, BiP, encoded by KAR2, under stress conditions such as tunicamycin addition. We have characterized a yeast gene, IRE2, which was isolated as a suppressor gene that complements the inositol auxotrophic phenotype of the ire1 mutation. Sequencing analysis revealed that IRE2 is identical to HAC1, which encodes a transcription factor having a basic-leucine zipper motif. Introduction of IRE2/HAC1 into the ire1 mutant clearly restored the expression of KAR2 upon tunicamycin treatment. ire2/hac1-disrupted yeast cells showed not only the inositol auxotrophic phenotype but also the tunicamycin sensitivity, and failed to induce the expression of KAR2. These results clearly indicate that the IRE2/HAC1 gene product plays a critical role in the induction of KAR2 expression and in the inositol prototrophy mediated by IRE1.

Somatostatin and insulin secretion due to common mechanisms by a new hypoglycemic agent, A-4166, in perfused rat pancreas.

N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) is a nonsulfonylurea hypoglycemic agent that decreases blood glucose levels in nondiabetic and diabetic animals. In the present study, we attempted to determine the effect of A-4166 on hormone secretion from the in vitro-perfused rat pancreas and to examine the underlying secretory mechanisms. In the presence of basal glucose (3 mmol/L), A-4166 markedly stimulated insulin and somatostatin release in a concentration-dependent manner over 0.03 to 3 mmol/L. A sulfonylurea, tolbutamide, also stimulated insulin and somatostatin release. A-4166 and tolbutamide elevated the level of glucagon release; however, the change lacked a clear concentration-dependent property. A-4166 at 0.3 mmol/L and tolbutamide at 3 mmol/L exhibited maximal stimulation of insulin release to a similar extent, indicating that A-4166 is one log-order more potent than and as effective as tolbutamide. By contrast, A-4166 stimulated somatostatin release to a threefold greater extent than tolbutamide. A-4166 evoked an increase in the cytosolic free-Ca2+ concentration ([Ca2+]i) in rat pancreatic beta cells. [Ca2+]i and insulin secretory responses to A-4166 were inhibited by nitrendipine (NTD), a blocker of the L-type Ca2+ channel, and by diazoxide (DAZ), an opener of the adenosine triphosphate (ATP)-sensitive K+ channel. Furthermore, A-4166-stimulated somatostatin release was also inhibited by NTD and by DAZ. The results indicate that A-4166 and tolbutamide stimulate the release of insulin and somatostatin, and that A-4166 is much more effective than tolbutamide in releasing somatostatin, a hormone that attenuates hyperglycemia under certain circumstances. It is concluded that A-4166-induced insulin release is mediated by an increase in [Ca2+]i in beta cells. An inhibition of ATP-sensitive K+ channels and a consequent activation of L-type Ca2+ channels appear to play a key role not only in insulin secretion from beta cells, but also in somatostatin secretion from delta cells in response to A-4166.

A new hypoglycemic agent, A-4166, inhibits ATP-sensitive potassium channels in rat pancreatic beta-cells.

Effects of a new hypoglycemic drug, N-[trans-4-isopropylcyclohexy-carbonyl]-D-phenylalanine (A-4166), on membrane current were investigated using the patch-clamp technique in single pancreatic beta-cells isolated from rats. A-4166, at a concentration of 10 microM, depolarized membrane potential of beta-cells and evoked action potentials in the presence of 2.8 mM glucose. The single ATP-sensitive K+ channel (K-ATP channel) current recorded in cell-attached membrane patches was reversibly inhibited by A-4166 (> 0.1 microM) without a change in the single-channel conductance of the K-ATP channel. Both A-4166 and tolbutamide inhibited the whole cell K-ATP channel current with half-maximum inhibition (IC50) of 0.23 and 12.8 microM, respectively (Hill coefficient = 1). In inside-out membrane patches, the IC50 with A-4166 occurred at 4.5 nM, in contrast to 0.7 microM for tolbutamide. A-4166 did not affect L- and T-type Ca2+ channels or the time-dependent outward current. We conclude that A-4166 specifically blocks the K-ATP channel and that the blockade is more potent than that of tolbutamide. The action of A-4166 underlies the mechanism by which the drug stimulates insulin secretion from beta-cells.

Possible role of the sympathetic nervous system in responses to interleukin-1.

Interleukin-1 (IL-1) is a key mediator of changes in immune, endocrine and metabolic activities, collectively called the acute phase response, seen during infection and tissue injury. The purpose of the present study was to clarify a possible role of the sympathetic nervous system in the responses to IL-1 in rats. Intraperitoneal injection of IL-1 elicited an increase in rectal temperature and white blood cell count and a decrease in the plasma levels of glucose, iron and triglyceride. Pretreatment of rats with 6-hydroxydopamine or a ganglionic blocking agent abolished some of the responses, such as hypoglycemia and the increased white blood cell count. IL-1 injection also accelerated norepinephrine turnover, an index of sympathetic nerve activity, in the spleen and lung without appreciably affecting many other organs, such as the liver, heart, pancreas and brown adipose tissue. It was concluded that IL-1 activates the sympathetic nerves specifically in the spleen and lung, and can thereby influence the immune and metabolic functions of these organs.

Interleukin-1 increases norepinephrine turnover in the spleen and lung in rats.

To clarify effects of interleukin-1 on sympathetic nerve activity, norepinephrine turnover in various organs was assessed in rats after intraperitoneal injection of recombinant human interleukin-1 beta. Interleukin-1 administration increased norepinephrine turnover in the spleen, lung and hypothalamus without appreciable effect in the heart, liver, submandibular gland, thymus, pancreas, brown adipose tissue and medulla oblongata. Similar changes in norepinephrine turnover were also found after the administration of bacterial endotoxin. It was concluded that interleukin-1 activates the sympathetic nerves specifically in the spleen and lung.

Ototoxic effects of a pseudodisaccharide aminoglycoside antibiotic, dactimicin, on the inner ears of guinea pigs.

The effect of dactimicin on the inner ear of guinea pigs was investigated by comparing it with the effects of ribostamycin, astromicin and amikacin. At doses of 200 and 400 mg/kg/day for 4 weeks, no pinna reflex loss was observed, but 2 animals receiving 400 mg dactimicin/kg/day showed unilateral loss of the outer hair cells in the cochlea and very scattered loss of the hair cells in the vestibular organ. At doses of 400 and 500 mg dactimicin/kg/day for 5 weeks, all surviving animals showed no abnormality of the outer hair cells, the inner hair cells and the spiral ganglion cells in the cochlea except for scattered unilateral loss of the outer hair cells and loss of the stria vascularis. Based on these observations, it is concluded that the ototoxicity of dactimicin on the inner ear of guinea pigs is the same as or a little stronger than that of ribostamycin, weaker than or the same as that of astromicin and weaker than amikacin.

[Evaluation of ototoxic effect of micronomicin by intravenous drip infusion].

Ototoxic effect of micronomicin (MCR) in intravenous drip administration was investigated in guinea pigs (300--400 g) receiving MCR for 30 days at dose of 50 and 100 mg/kg, respectively. MCR was dissolved in physiologic saline and 1.5 ml of the solution was infused through polyethylene tube into the left external jugular vein with Perista mini-pump for 60 minutes every day after measurement of body weight. Auditory impairment was monitored by pinna reflex audiometry. Pinna reflex loss was not detected in any animal in frequency range (0.5 to 20 kHz). Cochlear hair cell damage generally was of mild degree. Two out of 6 animals treated with MCR 50 mg/kg (Table 1) showed outer hair cell loss confined to unilateral basal end and posterior 3/4 of the first turn, respectively. Outer hair cell loss was noticed in 4 of 9 animals receiving MCR 100 mg/kg (Table 2); much less extensive in 3 animals, unsymmetrical slightly extensive in remaining 1. Unilateral circumscribed loss of inner hair cells was noticed at lower part of the hook in the latter one. Vestibular hair cell loss was scattered and less extensive and occurred in 4 of the 6 50 mg/kg given animals and in 7 of the 9 100 mg/kg ones. Comparison in incidence and extension of the outer hair cell loss of the cochlea (Tables 3, 4) in the present study and previous ones on the ototoxic effect of MCR in intramuscular and intravenous administration suggests that there was no distinct difference in enhancement of the ototoxic effect in the intravenous drip administration.