Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus.

BACKGROUND: Insulin resistance significantly correlated with a non-dipper type of essential hypertension. Thiazolidinediones (TZD), oral hypoglycaemic agents that act as insulin sensitizers, have been demonstrated in multiple in vivo and in vitro studies to possess antihypertensive properties. This study examined the efficacy of TZD therapy with pioglitazone at transforming the circadian rhythms of blood pressure from a non-dipper to a dipper type. MATERIALS: We examined 31 patients with type 2 diabetes mellitus during both a baseline period and a period of treatment with pioglitazone. Patients received 15 mg day(-1) pioglitazone for four weeks and 30 mg day(-1) for 12 weeks. Twenty-four hour ambulatory blood pressure monitoring (ABPM) and laboratory data (blood tests for cardiovascular risk factors) were obtained at the beginning and end of the study. RESULTS: In non-dippers (n = 16), but not dippers (n = 15), we observed a significant interaction between pioglitazone therapy and nocturnal falls in systolic and diastolic blood pressure. This examination indicated that the magnitude of the nocturnal blood pressure fall was affected by pioglitazone therapy. In non-dippers, but not dippers, a significant correlation was observed between the percent decrease in nocturnal BP and the homeostasis model assessment (HOMA) index (r = 0.774, P = 0.0007). CONCLUSIONS: The present study demonstrated that pioglitazone can restore the nocturnal BP declines in parallel to reductions in the HOMA index, suggesting that insulin resistance may play an important role in the genesis of circadian BP rhythms. TZD-based treatment may thus have the additional therapeutic advantage of reducing the risk of cardiovascular complications by transforming the circadian rhythm of BP.

New antiaxillary odour deodorant made with antimicrobial Ag-zeolite (silver-exchanged zeolite).

The causative substances for axillary osmidrosis, which are often found in apocrine sweat, are the decomposed/denatured products of short-chain fatty acid and other biological metabolite compounds produced by axillary-resident bacteria. Conventional underarm deodorants suppress the process of odour production mostly by the following mechanism: (1) suppression of perspiration, (2) reduction in numbers of resident bacteria, (3) deodorization and (4) masking. The most important and effective method to reduce odour is to suppress the growth of resident bacteria with antimicrobials, which have several drawbacks, especially in their safety aspect. To solve these problems, we focused on Ag-zeolite (silver-exchanged zeolite) that hold stable Ag, an inorganic bactericidal agent, in its structure, and therefore, poses less risk in safety. Its bactericidal effect on skin-resident bacteria was found to be excellent and comparable with that of triclosan, a most frequently used organic antimicrobial in this product category. The dose-response study of Ag-zeolite powder spray (0-40 w/w%) using 39 volunteers revealed that 5-40 w/w% Ag-zeolite could show a sufficient antimicrobial effect against skin-resident bacteria. The comparison study using 0.2 w/w% triclosan as the control and 10 w/w% Ag-zeolite indicated that: (1) one application of the powder spray containing 10 w/w% Ag-zeolite could show a sufficient antimicrobial effect against the resident bacteria and its effect continued for 24 h, (2) a powder spray containing 0.2 w/w% triclosan was unable to show a sufficient antimicrobial effect, and (3) no adverse event was observed. These studies show that Ag-zeolite has a superior antimicrobial ability that is rarely found in conventional antimicrobials used in deodorant products and a strong antiaxillary odour deodorant ability because of its long-lasting effect. During clinical study, patch tests with humans and other clinical studies of this product showed no adverse events related to the treatment with the Ag-zeolite product.

Hypoleptinemia, but not hypoinsulinemia, induces hyperphagia in streptozotocin-induced diabetic rats.

To assess the dominance between hypoinsulinemia and hypoleptinemia as factors in the development of hyperphagia in streptozotocin (STZ)-induced diabetes mellitus (STZ-DM) rodents with respect to hormone-neuropeptide interactions, changes in gene expression of agouti gene-related protein (AGRP) in the arcuate nucleus of the hypothalamus were investigated using STZ-DM rats, fasting Zucker fa/fa rats and STZ-DM agouti (STZ-DM A(y)/a) mice. AGRP mRNA and neuropeptide Y mRNA were both significantly up-regulated in STZ-DM rats, which are associated with body weight loss, hyperglycemia, hypoinsulinemia and hypoleptinemia. We proceeded to analyze whether insulin or leptin played the greater role in the regulation of AGRP using Zucker fa/fa rats. The AGRP mRNA did not differ significantly between fasted fa/fa rats, which have both leptin-insensitivity and hypoinsulinemia, and fed Zuckers, which have leptin-insensitivity and hyperinsulinemia. We further found that up-regulation of AGRP expression was normalized by infusion of leptin into the third cerebroventricle (i3vt), but not by i3vt infusion of insulin, although up-regulation of AGRP was partially corrected by systemic insulin infusion. The latter finding supports hypoleptinemia as a key-modulator of STZ-DM-induced hyperphagia because systemic insulin infusion, at least partially, restored hypoleptinemia through its acceleration of fat deposition, as demonstrated by the partial recovery of lost body weight. After STZ-DM induction, A(y)/a mice whose melanocortin-4 receptor (MC4-R) was blocked by ectopic expression of agouti protein additionally accelerated hyperphagia and up-regulated AGRP mRNA, implying that the mechanism is triggered by a leptin deficit rather than by the main action of the message through MC4-R. Hypoleptinemia, but not hypoinsulinemia per se, thus develops hyperphagia in STZ-DM rodents. These results are very much in line with evidence that hypothalamic neuropeptides are potently regulated by leptin as downstream targets of its actions.

The invariant cubic rod (cylinder) packings: symmetries and coordinates.

Six packings of symmetry-related cylinders, with cylinder axes in invariant positions (coordinates completely determined by symmetry), are described. Two have axes along <100> and four have axes along <111>. It is shown that there can be no cubic cylinder packing with axes along <110>. Earlier errors concerning the numbers of such packings and their symmetries are corrected.

Tissue-specific expression of the uncoupling protein family in streptozotocin-induced diabetic rats.

The vulnerability of streptozotocin (STZ)-induced diabetic rats to cold stress has been established. One of the elements controlling body temperature is thermogenesis, in which uncoupling protein (UCP) is known to play an important role. We have examined UCP2 and UCP3 expressions in brown adipose tissue (BAT), white adipose tissue (WAT), and skeletal muscle (MSL) during the acute and chronic phases of STZ-induced diabetes in rats. The long-term effect and the effect of insulin treatment thereafter were also unexplored previously and are examined in this study. In the acute phase of diabetes (2.5 days after STZ injection), UCP2 gene expression in BAT, WAT, and MSL, and UCP3 expression in the muscle were significantly increased. In the chronic phase of diabetes (21 days after STZ injection), UCP2 and UCP3 expression in the MSL were restored to the control levels without insulin supplementation. UCP2 in BAT and WAT remained high in the chronic phase, whereas UCP3 expression in BAT and WAT, which did not change in the acute phase, was significantly decreased. Insulin supplementation restored UCP2 expression in BAT and WAT, but over-corrected UCP3 in WAT above the control and did not affect UCP3 expression in BAT. Insulin supplementation depressed UCP3 expression in the MSL below control. These results indicate that the effects of STZ-induced diabetes on UCPs gene expression are tissue-specific as well as dependent on the duration of diabetes.

Rapid electrical stimulation of contraction reduces the density of beta-adrenergic receptors and responsiveness of cultured neonatal rat cardiomyocytes. Possible involvement of microtubule disassembly secondary to mechanical stress.

BACKGROUND: Although tachycardia is commonly present in patients with congestive heart failure, its role in the development of congestive heart failure remains unclear. We studied the effect of rapid electrical stimulation of contraction on beta-adrenergic receptor (beta-AR) signal pathway in cultured cardiomyocytes of neonatal rats. METHODS AND RESULTS: Contraction of cardiomyocytes was induced by electrical stimulation at 50 V with twice the threshold pulse width. beta-ARs were identified by [(3)H]CGP-12177 and [(3)H]dihydroalprenolol. Electrical stimulation reduced cell-surface but not total beta-AR density; the effect was dependent on pacing frequency (a reduction of 11%, 28%, and 18% in cells paced at 2.5, 3. 0, and 3.3 Hz, respectively). This reduction was apparent at 3 hours, in contrast to reduced beta-AR density after exposure to isoproterenol (ISP) for 1 hour. The fraction and inhibition constant of beta-AR binding agonist with high affinity were not affected by rapid electrical stimulation. In cardiomyocytes paced at 3.0 Hz for 24 hours, the response to ISP decreased compared with unpaced cells, 142% versus 204% of baseline with 1 micromol/L ISP, whereas the responses to forskolin or acetylcholine were not different. Treatment of cardiomyocytes with 2,3-butanedione monoxime (10 mmol/L) or taxol (10 micromol/L) inhibited the rapid pacing-induced reduction in beta-AR density. CONCLUSIONS: Our results suggest that contractile activity is involved in regulation of cardiac function by modulating the beta-AR system independently of hemodynamic and neurohormonal factors. This may help to elucidate the role of mechanical stress in the development of heart failure.

Diminished expression of sarcoplasmic reticulum Ca(2+)-ATPase and ryanodine sensitive Ca(2+)Channel mRNA in streptozotocin-induced diabetic rat heart.

The diabetic heart has an abnormal intracellular calcium ([Ca(2+)]i) metabolism. However, the responsible molecular mechanisms are unclear. The present study aimed to investigate mRNAs expressed in the proteins which regulate heart [Ca(2+)]i metabolism in streptozotocin (STZ)-induced diabetic rats. Expression of sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase (SR Ca(2+)-ATPase) mRNA was significantly less in the heart 3 weeks after STZ injection than that in the age-matched controls. Together with the down-regulation of SR Ca(2+)-ATPase, expression of ryanodine sensitive Ca(2+)channel (RYR) mRNA was also decreased 12 weeks after STZ injection. Insulin supplementation fully restored the decreased mRNAs expression of SR Ca(2+)-ATPase and RYR. The diminished expression and restoration with insulin supplementation of SR Ca(2+)-ATPase was further confirmed at the protein level. In contrast, expression of mRNAs coding the L-type Ca(2+)channel, Na(+)-Ca(2+)exchanger, or phospholamban were not affected 3 or 12 weeks after STZ injection. These results can be taken to indicate that the down-regulation of SR Ca(2+)-ATPase and RYR mRNAs is a possible underlying cause of cardiac dysfunction in STZ-induced diabetic rats.

Esophageal pressure and apnea hypopnea index in sleep-disordered breathing.

Severity of negative esophageal pressure (Pes) and apnea hypopnea index (AHI) were investigated in six cases of upper airway resistance syndrome (UARS) and 11 cases of obstructive sleep apnea syndrome (OSAS). The severity of negative Pes was represented by the highest peak (Pes Max) and the number of increased episodes (more than 13.5 cmH2O) per h (NPesI13.5). There was no significant correlation between Pes indices and AHI. Pes Max and NPesI13.5 were not different among severe OSAS (AHI > 30), mild OSAS (AHI < 30) and UARS. Apnea hypopnea index failed to represent the severity of negative Pes, which is an important aspect of the pathophysiology of sleep-disordered breathing.

The relationship between esophageal pressure and apnea hypopnea index in obstructive sleep apnea-hypopnea syndrome.

Severity of negative esophageal pressure (Pes) and apnea hypopnea index (AHI) were investigated in 34 patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). The OSAHS patients were diagnostically classified as having obstructive sleep apnea syndrome (OSAS) or upper airway resistance syndrome (UARS). Diagnosis of OSAS was based on an AHI of more than 5, and that of UARS on an AHI of less than 5, EEG arousals which were associated with apnea, hypopnea and/or respiratory effort occurring more than 10 times per hour, and daytime sleepiness. Negative Pes was represented by the greatest peak (NPes Max) and the number of increased (more than 13.5 cmH2O) episodes per hour (NPesI13.5). There was no significant correlation between the AHI and Pes indices, but NPes Max and NPesI13.5 showed significant correlation (p<0.01). NPes Max and NPesI13.5 showed no significant differences among the severe OSAS (AHI>50; 8 cases), moderate OSAS (50>AHI>15; 10 cases), mild OSAS (15>AHI>5; 9 cases) and UARS (7 cases) groups. We conclude that AHI does not reflect the severity of the increase in negative Pes, which is an important aspect of the pathophysiology of OSAHS. Assessment of OSAHS based on AHI alone may therefore underestimate the risk of increased negative Pes in cases with reduced AHI.

Frequent breathing-related electroencephalogram arousals in four patients with mild obstructive sleep apneas.

We report cases of four patients with mild obstructive sleep apnea syndrome (OSAS) with frequent breathing-related electroencephalogram (EEG) arousals which led to excessive daytime sleepiness. In spite of a relatively low apnea hypopnea index (AHI), sleep was disrupted by frequent EEG arousals associated with respiratory effort as observed in upper airway resistance syndrome. The effects of sleep stage and sleep position on EEG arousals were also investigated. We consider that AHI alone is not a sufficient index to assess severity of OSAS, and it is very important to examine microarousals by the alteration of esophageal pressure in addition to the effect of sleep position.

Clinical characteristics of upper airway resistance syndrome.

Polysomnographic findings and clinical symptoms were investigated in 14 cases of upper airway resistance syndrome. The mean scores of the Epworth sleepiness scale and self-rating depression scale in eight cases were 13.5 and 38.6, respectively. The mean sleep latency of the multiple sleep latency test in four cases was 10.2 min. Seven cases were treated with continuous positive airway pressure (CPAP), and one with hormone replacement therapy. The most common symptom was daytime sleepiness. Five cases had hypertension. CPAP reduced increasing negative esophageal pressure (Pes) and frequency of EEG arousals, and improved hypertension in one case. Hormone replacement therapy ameliorated increasing negative Pes and clinical symptoms.

Alteration of heart uncoupling protein-2 mRNA regulated by sympathetic nerve and triiodothyronine during postnatal period in rats.

To provide tissue-specific and developmental characteristics of gene expression of rat heart uncoupling protein-2 (UCP2), we investigated developmental alterations of UCPs mRNA expression in the heart and brown adipose tissue (BAT), and examined possible up-regulators of heart UCP2 expression using in vitro studies. Heart UCP2 mRNA expression was low during the early postnatal days followed by a rapid and significant increase in the 2nd postnatal week. Heart UCP3 mRNA remained undetectable until the 2nd postnatal week when the expression reached a small but significant peak. BAT UCP1 mRNA was abundantly expressed in the neonate, but the expression rapidly decreased to the adult level. The studies using cultured cardiomyocytes demonstrated that both 10(-8) M triiodothyronine and 10(-7) M isoproterenol, but not phenylephrine, increased UCP2 mRNA expression. These results indicate that the sympathetic nervous system and/or thyroid hormones may be involved in the up-regulation of heart UCP2 gene expression during postnatal development. The increase in postnatal heart UCP2 may provide a key link between the postnatal energy shift and adaptation of rat pups to their novel environment.

Mechanism of beta-adrenergic receptor upregulation induced by ACE inhibition in cultured neonatal rat cardiac myocytes: roles of bradykinin and protein kinase C.

BACKGROUND: Although bradykinin is thought to contribute to the effects of ACE inhibitors on the cardiovascular system, its precise role remains to be elucidated. Evidence suggests that bradykinin might be important in the upregulation of beta-adrenergic receptors (beta-ARs) induced by ACE inhibitors, and the role of bradykinin in this effect has now been investigated with cultured neonatal rat cardiac myocytes. METHODS AND RESULTS: The density of beta-ARs on the myocyte surface was determined with a binding assay with [3H]CGP-12177. Incubation of cultured myocytes for 24 hours with the ACE inhibitor captopril (1 micromol/L) increased beta-AR density by 35% and enhanced the response of cells to isoproterenol but not to forskolin. Neither an angiotensin-II type 1 (AT1) receptor antagonist, CV-11974, nor angiotensin-I affected beta-AR density. However, the bradykinin B2 receptor antagonist Hoe 140 abolished the effect of captopril on beta-AR upregulation in a dose-dependent manner. The protein kinase C inhibitor staurosporine (20 nmol/L) but neither indomethacin nor L-NAME also inhibited captopril-induced upregulation of beta-ARs. Exogenous bradykinin increased the spontaneous beating frequency of cultured myocytes and Hoe 140 abolished this effect. Bradykinin level in the medium increased 1.4-fold by the treatment of cultured myocytes with captopril for 24 hours. CONCLUSIONS: The results suggest that captopril enhances beta-AR responsiveness by inducing beta-AR upregulation and that the latter effect is mediated by activation of bradykinin B2 receptors and protein kinase C. These observations also offer insight into the different roles of ACE inhibitors and AT1 receptor antagonists in the treatment of heart failure.

Alteration of esophageal pressure in sleep-disordered breathing.

We investigated the alteration of esophageal pressure (Pes) in 10 patients with upper-airway sleep-disordered breathing (UASDB) and the relationship among Pes, breathing patterns and EEG arousals. Increased negative Pes without apnea or hypopnea, appeared not only in upper airway resistance syndrome but also in obstructive sleep apnea syndrome. This phenomenon produced frequent EEG microarousals leading to sleep fragmentation and daytime sleepiness. Moreover, increased negative Pes occasionally continued for more than 20 min without an EEG arousal, which might be considered to be one of the factors to cause complications of UASDB.

Two cases of sleep-disordered breathing in climacteric.

Two cases of sleep disordered-breathing in climacteric were reported. Polysomnography including esophageal pressure (Pes) measurement was performed. Case 1 was diagnosed as upper airway resistance syndrome. Case 2 was diagnosed as obstructive sleep apnea syndrome, while many episodes of upper airway resistance also existed. Hormone replacement therapy improved clinical symptoms, and in case 1, Pes nadir was improved but incidence of arousals which was induced by breathing disturbances was not significantly changed. Sleep disordered-breathing should be suspected as a cause of sleep disorder even in females, especially in climacteric age. Pes measurement and evaluation of arousals is required. Hormone replacement therapy may release the upper airway resistance.

Aortitis syndrome (Takayasu's arteritis) with cataract and elevated serum level of vascular endothelial growth factor.

The aortitis syndrome is a chronic inflammatory process that affects the aorta and its primary branches. Patients with aortitis syndrome exhibit various ocular changes. We present a patient in whom cataract was the initial objective finding. The serum concentration of vascular endothelial growth factor, a cytokine that affects neovascularization, and vasopermeability, was elevated before the initiation of prednisolone treatment. Cataract should be considered as a possible characteristic initial finding in patients with aortitis syndrome. Vascular endothelial growth factor may be involved in the progression of aortitis syndrome.

A new antitumor antibiotic, BE-19412A, produced by a streptomycete.

A new antitumor substance, designated BE-19412A, was isolated from the culture broth of Streptomyces sp. A19412. The active principle was extracted from the mycelium by methanol and purified by Silica gel and Sephadex LH-20 column chromatographies. BE-19412B was prepared by methylation of BE-19412A. BE-19412A and B exhibited cytotoxic activity against murine and human tumor cell lines. BE-19412A prolonged the survival of CDF1 mice bearing i.p. implanted Ehrlich carcinoma cells.

[Advantages and disadvantages of fast fluid-attenuated inversion recovery sequence in the evaluation of brain infarction].

This study was performed to determine the advantages and disadvantages of fast fluid attenuated inversion recovery (fast FLAIR) images in diagnosing brain infarction compared with fast spin-echo (fast SE) images. Fast FLAIR and fast SE images were obtained in 32 patients with brain infarction. Infarctions close to the sulci were difficult to differentiate from the real sulci on fast SE images, but were clearly depicted on FLAIR images. Linear foci along with cortex were especially well demonstrated on FLAIR images. On the other hand, foci that showed high signal intensity on fast SE images were sometimes appeared as having low or iso signal intensity on FLAIR images. These foci, suspected of being cystic lesions, were sometimes difficult to identify on fast FLAIR images. For the above reasons, we concluded that fast FLAIR and fast SE each have advantages and disadvantages in the detection of brain infarctions.