Subacute sarcoid myositis with ocular muscle involvement; a case report and review of the literature.

Sarcoidosis is a chronic granulomatous disease that can affect multiple organs. The lungs, eyes, and skin are known to be highly affected organs in sarcoidosis. There have been reports based on random muscle biopsy that 32-80% of systemic sarcoidosis comprises noncaseating granulomas; however, muscle involvement in sarcoidosis is generally asymptomatic and has an unknown frequency. We describe a case of acute to subacute sarcoid myositis of the skeletal and extraocular muscles. Typical ophthalmic involvement (manifested by infiltration of the ocular adnexa, intraocular inflammation, or infiltration of the retrobulbar visual pathways) and extraocular sarcoid myositis (as with the present case) is infrequently reported. It is important to keep in mind the rare yet perhaps underestimated entity of sarcoid myositis, and to utilize muscle biopsy and imaging tests for appropriate diagnosis and management of patients with sarcoidosis.

Evaluation of cutoff scores for the Parkinson's disease sleep scale-2.

BACKGROUND: The Parkinson's Disease Sleep Scale (PDSS)-2 is a recently developed tool for evaluating disease-related nocturnal disturbances in patients with Parkinson's disease (PD). However, its cutoff score has not been clinically assessed. We determined the optimal cutoff score of the Japanese version of the PDSS-2. METHODS: Patients with PD (n = 146) and controls (n = 100) completed the PDSS-2 and the Pittsburgh Sleep Quality Index (PSQI). Poor sleepers were defined as having global PSQI scores >5. Optimal cutoff scores for determining poor sleepers were assessed using the receiver operating characteristic curve. RESULTS: A PDSS-2 total score ≥ 14 exhibited 82.0% sensitivity and 70.6% specificity, whereas a PDSS-2 total score ≥ 15 provided 72.1% sensitivity and 72.9% specificity in distinguishing poor sleepers (PSQI score >5) from good sleepers (PSQI ≤ 5). Nocturnal disturbances were more frequently observed in patients with PD than in controls (PDSS-2 total score ≥ 14 or ≥ 15; 51.4% vs 20%; 45.9% vs 19%). Nocturnal disturbances were associated with higher Hoehn and Yahr stages and Unified Parkinson's Disease Rating Scale motor scores, impaired quality of life, daytime sleepiness, and depressive symptoms. CONCLUSION: We suggest that PDSS-2 total scores ≥ 15 are useful for detecting poor sleepers among patients with PD.

Nanometer-scale water droplet free from the constraint of reverse micelles at low temperatures.

Temperature dependence of the configurational fluctuation of water confined in a reverse micellar solution has been studied by absorption spectroscopy of a probe molecule. We have found that the configurational fluctuation is liquidlike below the homogeneous nucleation temperature. This is proposed to be due to a large reduction in the confinement of water, and is explained in terms of water shedding from the reverse micelle. Further, the configurational fluctuation is frozen at ~210 K. A reverse micellar solution is considered to be a promising candidate for studies of supercooled water.

In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist.

Olmesartan medoxomil is a new non-peptide angiotensin (A) II antagonist under development for treating hypertension. It is a pro-drug containing an ester moiety that, after oral administration, is rapidly cleaved to release the active form olmesartan (RNH-6270). In vitro, olmesartan is a highly potent, competitive and selective All AT1 receptor antagonist with almost no antagonistic activity on AT2 and AT4 receptors. Olmesartan produces selective insurmountable inhibition of All-induced contractions of the guinea-pig aorta and is much more potent than losartan in reducing maximal responses. In vivo, intravenous olmesartan produces a rapid and long-lasting inhibition of All-induced pressor responses in conscious rats. Oral olmesartan medoxomil also inhibits All-pressor response but onset of the action is slower compared with intravenous administration. Following oral administration, olmesartan has a faster onset but similar potency when compared with candesartan cilexetil, and clearly exceeds losartan in both respects. Oral olmesartan medoxomil exhibits dose-dependent antihypertensive effects in several rat and dog models, with the most marked effects seen in high plasma renin models, when compared with normal or low renin types. Haemodynamic studies in spontaneously hypertensive rats and normotensive dogs showed intravenous olmesartan selectively reduces renal vascular resistance, which suggests that vasodilatation in the renal vascular bed contributes most to the antihypertensive action of the drug. Long-term treatment with olmesartan medoxomil exhibits, beside antihypertensive effects, beneficial effects in animal models of various types of nephrosis and heart failure, and anti-atherogenic effects in hyperlipidaemic animals. Olmesartan medoxomil is worthy of clinical development in essential and renal hypertension, particularly where renal function is threatened by underlying diabetic disease.

Effect of Chlamydia pneumoniae infection on coronary flow reserve and intimal hyperplasia after stent implantation in patients with angina pectoris.

OBJECTIVES: Chlamydia pneumoniae (C. pneumoniae) has been detected in tissue from coronary atherosclerotic vascular lesions and may be involved in the pathogenesis of atherosclerosis. However, the effect of prior C. pneumoniae infection on coronary intimal hyperplasia after stent implantation and on coronary microvascular function is unknown. METHODS: Seventy-three patients with stable angina pectoris and a single de novo coronary lesion were studied prospectively. All patients underwent successful coronary angioplasty and stent implantation for the stenotic lesion. Blood samples were tested for prior C. pneumoniae infection before the procedure, and patients were divided into two groups: Seropositive and seronegative. Coronary flow reserve was measured in the non-stenotic coronary vessel before angioplasty, and quantitative coronary arteriography was performed at the stent implantation site before angioplasty and 6 months later in all patients. RESULTS: Coronary flow reserve in the non-stenotic vessel was significantly lower in the seropositive group than in the seronegative group (2.51 +/- 0.35 vs 2.76 +/- 0.43, p < 0.05). The minimum luminal diameter was smaller and late loss was greater in the seropositive group than in the seronegative group (minimum luminal diameter: 1.52 +/- 0.59 vs 1.91 +/- 0.79 mm, p < 0.05, late loss: 1.17 +/- 0.55 vs 0.76 +/- 0.67, p < 0.05). However, there was no significant difference in the restenosis rate or target lesion revascularization rate between the two groups. CONCLUSIONS: Prior C. pneumoniae infection may accelerate intimal hyperplasia after stent implantation and impair coronary microvascular function in the non-stenotic coronary vessels.

Two N-terminally truncated forms of C-type natriuretic peptide from habu snake venom.

Two N-terminally truncated forms of the C-type natriuretic peptide (CNP) were isolated from the venom of habu snake, Trimeresurus flavoviridis, and their structures were determined by EMI-MS spectrometry and amino acid sequencing. Tf-CNP(6-22), the shorter peptide retaining the 17-membered ring structure formed by an intra-molecular disulfide bridge, has a vasorelaxant activity in rat aortic strips and a diuretic potency in anesthetized rats. Tf-CNP(3-22), the other 20 amino acid residues peptide, also comprised the 17- membered ring with a short N-terminal extension of 3 amino acid residues. Tf-CNP(6-22), the ring, is the shortest naturally occurring CNP peptide identified so far, and as potent as Tf-CNP(1-22), the supposedly intact CNP of 22 amino acid residues.

[Effect of long-term cilostazol administration on coronary flow velocity and coronary flow reserve].

Cilostazol, a novel potent inhibitor of phosphodiesterase, increases coronary flow. The effects of cilostazol on coronary flow velocity and coronary flow reserve were studied in 103 patients with coronary artery disease who underwent coronary angiography. Cilostazol 200 mg/day was administered for 3 months (31 patients) or 6 months (37 patients), and coronary flow reserve were measured before and after the cilostazol administration. Coronary flow reserve were measured twice at an interval of 6 months in the control group (35 patients). The Doppler guide wire was advanced into the coronary artery with no significant vessel stenosis. After obtaining continuous baseline coronary flow velocity, an intracoronary infusion of papaverine (10 mg) was performed to measure coronary flow reserve. There were no significant differences in coronary flow velocity just before intracoronary papaverine infusion between the initial and follow-up studies in any of the 3 groups. Coronary flow reserve increased significantly after cilostazol administration in the 3 months and 6 months groups compared with before administration (3 months group: 2.8 +/- 0.8 vs 2.4 +/- 0.9, p < 0.05; 6 months group: 2.8 +/- 1.0 vs 2.4 +/- 0.7, p < 0.01). However, there was no significant difference in coronary flow reserve in the control group between follow-up and initial studies (2.7 +/- 0.8 vs 2.5 +/- 0.8, NS). In conclusion, the long-term oral administration of cilostazol for 3 or 6 months improves coronary flow reserve.

Acute effects of nicotine content in cigarettes on coronary flow velocity and coronary flow reserve in men.

We investigated the acute effects of smoking on coronary flow reserve in terms of the nicotine content of cigarettes in 21 smokers. Coronary flow velocity was measured with a Doppler flow wire. Subjects smoked cigarettes containing >1 mg nicotine (n = 8, group 1) or <1 mg (n = 6, group 2). Subjects in the control group mimicked smoking without a cigarette (n = 7). Coronary flow reserve decreased after smoking in group 1, but not in group 2 or the control group. This reduction may have mediated nicotine or some other unknown substances influenced by smoking.

[Impaired coronary flow reserve due to long-term smoking recovers after quitting].

Cigarette smoking is a major risk factor for coronary artery disease. The present study examined whether impaired coronary flow reserve by smoking can be recovered by quitting. Coronary flow velocity was measured by Doppler guide wire during coronary angiography and coronary flow reserve was determined by injecting 10 mg intracoronary papaverine in 45 patients who were present or former smokers. Twenty-three patients were smoking more than 800 cigarettes/day x years and 22 patients less than 800, and 13 patients had smoked more than 800 but had quit smoking at least for 5 years. None of the patients had any significant coronary stenosis in the left anterior descending artery where the Doppler probe was positioned, nor any coronary risk factors except smoking. Twenty-six non-smokers served as control subjects. There was no difference in the coronary flow reserve between controls and light smokers (3.3 +/- 0.7 vs 3.3 +/- 1.0), but it was significantly reduced in heavy smokers (2.6 +/- 0.8) compared to controls or light smokers (p < 0.05, p < 0.05, respectively), There was no significant difference in coronary flow reserve between controls, light smokers and ex-smokers (3.3 +/- 1.2). These results suggest that the deteriorating effect on the coronary flow reserve by smoking is corrected after its cessation.

Effect of time interval between two balloon inflations on ischemic preconditioning during coronary angioplasty.

Ischemic preconditioning, defined as a reduction in myocardial ischemia caused by repeated brief episodes of coronary occlusions, is observed during percutaneous transluminal balloon angioplasty (PTCA). To elucidate the effects of the length of the interval between consecutive balloon inflations on ischemic preconditioning during PTCA, we examined 62 patients with chronic stable angina (48 males and 14 females; mean age 62 +/- 10 yr). PTCA was performed on the left anterior descending artery lacking in collateral vessels. A 2-min balloon inflation was performed twice and the extent of ST segment elevation in the electrocardiogram and the severity of chest pain (scored from 0 to 10) for each inflation were determined and compared. Patients were divided into three groups according to the interval between the two inflations: 1 min, Group 1; 2 min, Group 2; and 5 min, Group 5. In Groups 2 and 5, ST-segment elevation was significantly decreased during the second balloon inflation, as compared with that during the first inflation (P < 0.01, P < 0.001). A significant decrease was also observed in the severity of chest pain (P < 0.05, P < 0.01). However, Group 1 showed no significant decrease in ST-segment elevation or severity of chest pain between the first and second inflations. ST-segment elevation and chest pain were reduced to a greater extent in Group 5 than in Group 2. Results suggest that an interval of more than 2 min between balloon inflations is required to achieve ischemic preconditioning during PTCA.

PDGF-BB decreases systolic blood pressure through an increase in macrovascular compliance in rats.

The cardiovascular roles of platelet-derived growth factor (PDGF) were examined in anesthetized rats by monitoring blood pressure and in isolated blood vessels and heart preparations. Intravenous injection of PDGF-BB lowered blood pressure. The decrease in systolic pressure was greater than that in diastolic pressure, so the pulse pressure decreased. PDGF-AA and -AB, other isoforms of PDGF, did not have any effect on blood pressure. Pretreatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, shortened duration of the hypotensive effect of PDGF-BB. The administration of L-arginine with L-NAME partially prevented the effect of L-NAME. PDGF-BB relaxed aortic rings precontracted with phenylephrine with a 50% effective concentration of 3 ng/ml. In contrast, in isolated mesenteric vascular preparations, the vasodilating activity of PDGF-BB was observed only at a high concentration (>12.5 ng/ml). In isolated heart preparations, PDGF-BB had no effect on the beat rate or contractile activity. These results suggest a new role of PDGF-BB that may contribute to the regulation in circulation through the increase in macrovascular compliance mediated by NO.

Effects of angiotensin AT1 receptor antagonist on volume overload-induced cardiac gene expression in rats.

The present study was undertaken to examine the effects of volume overload on cardiac gene expression and the possible role of angiotensin AT1 receptor in such expression. Cardiac volume overload was prepared by abdominal aortocaval shunt in rats. Rats with aortocaval shunt were treated with 1) vehicle, 2) an angiotensin AT1 receptor antagonist, CS-866 (10 mg/kg/d), or 3) an angiotensin-converting enzyme inhibitor, temocapril (10 mg/kg/d), for 7 days. Cardiac tissue mRNA was measured by Northern blot analysis with specific probes. Aortocaval shunt not only caused cardiac hypertrophy but also upregulated the gene expression of atrial natriuretic polypeptide, collagen III, and downregulated Ca(2+)-ATPase expression in the left ventricle. These changes were prevented by treatment with CS-866, while temocapril failed to normalize left ventricular Ca(2+)-ATPase expression. Unlike the left ventricle, the significant downregulation of alpha-myosin heavy chain and transforming growth factor-beta 3 by aortocaval shunt was observed in the right ventricle, and CS-866 normalized this decreased expression of transforming growth factor-beta 3. The left and right atria showed increased expression of collagen type I as well as of collagen type III and atrial natriuretic polypeptide, and these increases were more effectively prevented by CS-866 than by temocapril. Thus, the effects of cardiac volume overload on cardiac performance-related gene expression differ between the ventricles and atria. Our results suggest that AT1 receptor partially contributed to volume overload-induced changes in cardiac gene expression and that AT1 receptor antagonists and angiotensin-converting enzyme inhibitors have different effects in this model of cardiac hypertrophy.

[Effects of the time interval between the first and second balloon inflations on ischemic preconditioning during percutaneous transluminal coronary angioplasty].

Ischemic preconditioning is an attenuation of myocardial ischemia by repeated brief coronary occlusions observed during percutaneous transluminal coronary angioplasty (PTCA). The effects of the time delay between balloon inflations during PTCA on ischemic preconditioning were investigated in 48 patients with chronic stable angina but no rich collateral vessels. After successful predilatation, two 2-min balloon inflations were performed and the ST segment elevation in the electrocardiogram and chest pain were measured during each balloon inflation and compared. Patients were divided into three groups according to the interval between balloon inflations; 1 min (I1), 2 min (I2) and 5 min (I5). There were no significant differences in ST elevation (3.4, 3.2 and 3.7 mm) and chest pain during the first balloon inflation between these three groups. ST elevation and chest pain were decreased in groups I2 and I5 (2.6 and 2.8 mm) during the second balloon inflation compared with those during the first balloon inflation. However, there was no significant difference in ST elevation and chest pain during the first and second (3.7 mm) balloon inflations in group I1. ST elevation and chest pain were reduced more in group I5 than in I2. These results suggest that an interval of more than 2 min between balloon inflations is necessary to obtain the effect of ischemic preconditioning during PTCA.

Nonpeptide angiotensin II receptor antagonists: synthesis, biological activities, and structure-activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds.

A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2'-1H-tetrazol-5- ylbiphenyl-4-yl)-methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.

Pharmacology of CS-866, a novel nonpeptide angiotensin II receptor antagonist.

CS-866, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy-4-(1-hydroxy-1- methylethyl)-2-propyl-1-(4-[2-(tetrazol-5-yl)-phenyl]phenyl)met hylimidazol- 5-carboxylate, a prodrug type angiotensin receptor antagonist, is deesterified to the active acid, RNH-6270. RNH-6270 inhibited [125I]angiotensin II binding to bovine adrenal cortical membranes (angiotensin AT1 receptors) with an IC50 value of 7.7 nM, but not [125I]angiotensin II binding to bovine cerebellar membranes (angiotensin AT2 receptors), indicating the selectivity of the compound for angiotensin AT1 receptors. In guinea pig aortas, RNH-6270 reduced the maximal response of the concentration-contractile curve for angiotensin II (pD'2 = 9.9), but had no effect on the contractile response induced by phenylephrine or KCl. In conscious rats, intravenously injected RNH-6270 inhibited angiotensin II-induced pressor responses in a dose-dependent manner, and orally administered CS-866 produced a long-lasting inhibition of angiotensin II pressor responses. SK&F-525A, a P-450 inhibitor, suppressed the angiotensin II inhibitory effect of losartan, but not that of CS-866. These results demonstrate that RNH-6270 is a potent and AT1-selective angiotensin receptor antagonist and that, after oral administration, CS-866 has a long-lasting angiotensin II inhibitory action which is not affected by drug metabolizing enzymes in the liver.

Negative chronotropic effect of endothelin 1 mediated through ETA receptors in guinea pig atria.

Endothelins exert potent excitatory cardiac effects by acting on specific receptors on myocytes. In this study, we have examined the signal transduction mechanism for the chronotropic effect of endothelins in guinea pig atria. A competition binding of [125I]endothelin 1 ([125I]ET-1) using the recently developed ETA receptor-selective antagonist BQ123 showed the presence of almost equal populations of ETA (44%) and ETB (56%) receptors in the guinea pig right atria. In a concentration-response study, endothelin 3 (ET-3), an agonist with higher affinity to ETB receptors than to ETA receptors, and sarafotoxin S6c (STXS6c), an ETB receptor-selective agonist, increased the rate of spontaneous beating at all concentrations tested (10 pmol/L to 100 nmol/L). In contrast, ET-1, a nonselective agonist, increased the heart rate at lower concentrations (10 pmol/L to 10 nmol/L) but decreased it at higher concentrations (30 to 100 nmol/L). When ET-1 (100 nmol/L) was applied in a single amount, heart rate was strongly increased; however, this increase was followed by a rapid decline in the response. ET-1 (100 nmol/L) but not ET-3 or STXS6c significantly reduced the heart rate when it was raised by isoproterenol (ISO, 300 nmol/L) either in the absence or presence of a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Correspondingly, ET-1 significantly reduced the ISO-induced elevation of cAMP accumulation (19.1 +/- 1.7 pmol/mg protein [n = 8] and 12.6 +/- 1.2 pmol/mg protein [n = 7] in the absence and presence of ET-1, respectively; P < .01), which was also observed even in the presence of IBMX.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of RS-2135, a new antiarrhythmic agent, on the kinetics of use-dependent decrease in maximum upstroke velocity in guinea pig ventricular myocardium.

The use-dependent decrease in maximum upstroke velocity (Vmax) caused by RS-2135, a new antiarrhythmic compound was analyzed in isolated papillary muscles of guinea pigs. RS-2135 3 and 10 microM decreased Vmax of action potential (AP) in a concentration-related manner without affecting resting membrane potential (RMP). Vmax decay in the presence of RS-2135 was exponential at stimulation rates > 0.5 Hz. This use-dependent block of Vmax was enhanced at higher stimulation frequencies. The time constants and onset rates per action potential of the use-dependent block were 10.7-26.9 s and 0.021-0.041 AP-1, respectively. The time constants of recovery from use-dependent block were 57.9 and 63.6 s, respectively, in the presence of 3 and 10 microM RS-2135. The predicted half-time of the recovery process calculated by physicochemical parameters of RS-2135 agreed well with the observed values. These results suggest that RS-2135 is a sodium channel blocking agent with slow kinetics and that the physicochemical properties underlie these characteristics.

Electrophysiologic effects of RS-2135, a new antiarrhythmic compound, on canine Purkinje fibers.

RS-2135 is the (+) isomer of a novel, fused carbazol derivative. The agent, when administered orally, shows long-lasting antiarrhythmic effects in several models of arrhythmia. We used standard microelectrode techniques to characterize the electrophysiological effects of the agent on canine Purkinje fibers. RS-2135 reduced the maximum upstroke velocity of the action potential (Vmax) and shortened the action potential duration (APD) in a concentration-related manner (0.3-3 microM). RS-2135 decreased Vmax at lower concentrations than disopyramide, flecainide, and mexiletine. RS-2135 shortened the effective refractory period (ERP), but significantly increased the ratio of ERP to APD90. Additionally, the effects of the (-) optical isomer of RS-2135 were compared with those of RS-2135, the (+) enantiomer. The (-) isomer was much less potent than RS-2135 in decreasing Vmax. These data suggest that RS-2135 belongs to the class I or "local anesthetic" type of antiarrhythmic agent and that the stereochemistry of the drug molecule is an important determinant of Na channel blocking activity.