Honeycomb-like porous chitosan films prepared via phase transition of poly(N-isopropylacrylamide) during water evaporation under ambient conditions.

Honeycomb-like porous chitosan (CS) films are attractive tools for developing functional materials for filters, catalyses, adsorbents, biomaterials, etc. A simple method for fabricating honeycomb-like porous CS films without special reagents, facilities, and techniques would make them accessible. Here we introduce an easily available method for fabricating honeycomb-like CS films without a strong acid/base, toxic reagents, or special facilities/techniques. An aqueous solution containing CS and poly(N-isopropylacrylamide) (PNIPAm) was allowed to stand at 25 °C to evaporate water. After 3 days, CS-PNIPAm composite films with homogenously phase-separated PNIPAm particles were obtained. The PNIPAm particles were removed by immersion in methanol, and the resulting films dried under reduced pressure to become honeycomb-like porous CS films. The pore size could be varied in the range of 0.5-3.0 µm by altering the CS concentration and the molecular weight of CS where the pore size was reduced under conditions with stronger interaction between CS molecules. We reveal that the key to success with this system is the decrease of lower critical solution temperature (LCST) of PNIPAm with water evaporation. In addition, we confirmed the removed PNIPAm was recyclable in this system. Furthermore, we found this method was also applicable to alginate. The proposed facile method for fabricating honeycomb-like porous polymeric films could provide various functional porous materials.

Facile preparation of surface N-halamine chitin nanofiber to endow antibacterial and antifungal activities.

N-halamine chitin nanofiber (NF) film was prepared by the reaction of chitin NF film with sodium hypochlorite solution to endow the film with antibacterial and antifungal activities. The amount of active chlorine content loaded on the chitin NF film depended on the sodium hypochlorite concentration and reaction time. FT-IR, UV-vis, XRD, and TG analyses showed that the N-H bond was substituted to the N-Cl bond and that the reaction took place at the chitin NF surface. After chlorination, the characteristic nanochitin morphology was maintained. Although the active chlorine content of the film gradually decreased by disassociation of the N-Cl bond, chlorine was rechargeable into chitin NF by another sodium hypochlorite solution treatment. The chlorinated chitin NF film showed strong efficacies against Gram-negative and -positive bacteria of Escherichia coli and Staphylococcus aureus, respectively. Moreover, the films showed 100% and 80% inhibition of spore germination when faced against Alternaria alternata and Penicillium digitatum fungi, respectively.

Supramolecular approaches for drug development.

Various supramolecular systems can be used as drug carriers to alter physicochemical and pharmacokinetic characteristics of drugs. Representative supramolecular systems that can be used for this purpose include surfactant/polymer micelles, (micro)emulsions, liposomes, layer-by-layer assemblies, and various molecular conjugates. Notably, liposomes are established supramolecular drug carriers, which have already been marketed in formulations including AmBisome(®) (for treatment of fungal infection), Doxil(®) (for Kaposi's sarcoma), and Visudyne(®) (for age-related macular degeneration and choroidal neovascularization). Microemulsions have been used oral drug delivery of poorly soluble drugs due to improvements in bioavailability and predictable of absorption behavior. Neoral(®), an immunosuppressant used after transplant operations, is one of the most famous microemulsion-based drugs. Polymer micelles are being increasingly investigated as novel drug carriers and some formulations have already been tested in clinical trials. Supramolecular systems can be functionalized by designing the constituent molecules to achieve efficient delivery of drugs to desired sites in the body. In this review, representative supramolecular drug delivery systems, that may improve usability of candidate drugs or add value to existing drugs, are introduced.

Plasma resistin concentration determined by common variants in the resistin gene and associated with metabolic traits in an aged Japanese population.

AIMS/HYPOTHESIS: Resistin is a cytokine derived from adipose tissue and is implicated in obesity-related insulin resistance and type 2 diabetes mellitus. Polymorphisms of the resistin gene (RETN) have been shown to affect the plasma resistin concentration. The aims of this study were to identify polymorphisms of RETN that influence plasma resistin concentration and to clarify the relation between plasma resistin level and metabolic disorders in an aged Japanese cohort. METHODS: The study participants comprised 3133 individuals recruited to a population-based prospective cohort study (KING study). Plasma resistin concentration, BMI, abdominal circumference, blood pressure, fasting plasma glucose and serum insulin concentrations, HbA(1c) content and serum lipid profile were measured in all participants. The HOMA index of insulin resistance (HOMA-IR) was also calculated. Eleven polymorphisms of RETN were genotyped. RESULTS: A combination of ANOVA and multiple linear regression analysis in screening and large-scale subsets of the study population revealed that plasma resistin concentration was significantly associated with rs34861192 and rs3745368 polymorphisms of RETN. Multiple linear regression analysis with adjustment for age and sex also showed that the plasma resistin level was significantly associated with serum concentrations of HDL-cholesterol, triacylglycerol and insulin, as well as with BMI. CONCLUSIONS/INTERPRETATION: Our results implicate the rs34861192 and rs3745368 polymorphisms of RETN as robust and independent determinants of plasma resistin concentration in the study population. In addition, plasma resistin level was associated with dyslipidaemia, serum insulin concentration and obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT00262691.

Granulomatous hypophysistis associated with rathke's cleft cyst: a case report.

OBJECTIVE: The value of surgical intervention in the management of hypophysitis remains controversial. PATENT: We describe a 57-year-old man presenting with general fatigue persisting for three months. Endocrine examination revealed hypopituitarism and diabetes insipidus. Magnetic resonance (MR) imaging showed a dumbbell-shaped pituitary mass lesion without a cystic component. We partially removed the lesion via a transsphenoidal approach. Histological examination yielded the diagnosis of granulomatous hypophysitis associated with Rathke's cleft cyst. No deterioration of pituitary function was observed postoperatively. Twenty months after the surgery, the lesion has spontaneously regressed on MR imaging, and he is doing well with continuing replacement therapy of hydrocortisone, levothyroxine and desmopressin acetate. CONCLUSION: The diagnosis of hypophysitis, apart from typical lymphocytic hypophysitis, is difficult even with a surgical biopsy. Because a small specimen may lead to a diagnosis of non-specific hypophysitis, partial removal of the lesion is less invasive and recommended for preservation of the pituitary function.

Heterogeneity of regional systolic function detected by tissue Doppler imaging is linked to impaired global left ventricular relaxation in hypertrophic cardiomyopathy.

OBJECTIVE: To evaluate regional and global left ventricular (LV) function and LV wall thickness (LVWT) in patients with hypertrophic cardiomyopathy (HCM). DESIGN AND SETTING: Observational study at the National Cardiovascular Centre and Nagoya University Hospital in Japan. PARTICIPANTS: Thirty-six patients with HCM and 16 patients with hypertensive LV hypertrophy (LVH). MAIN OUTCOME MEASURES: Conventional echocardiography and strain rate (SR) imaging derived from tissue Doppler imaging were performed. Systolic strain (epsilon(sys)), peak systolic SR (SR(sys)), peak early diastolic SR (SR(dia)) and LVWT were obtained from eight LV segments. LV pressure was simultaneously recorded with a high-fidelity micromanometer. RESULTS: The regional epsilon(sys) and SR(sys) were correlated with LVWT in patients with HCM (r = 0.50, p<0.001 and r = 0.63, p<0.001, respectively) but not in patients with hypertensive LVH. The standard deviations of LVWT, epsilon(sys) and SR(sys) obtained from the eight LV segments of each subject were greater for patients with HCM than for patients with hypertensive LVH. The standard deviation of LVWT was correlated with those of epsilon(sys) and SR(sys) (r = 0.55, p<0.001 and r = 0.56, p<0.001, respectively). The standard deviations of LVWT, epsilon(sys) and SR(sys) were correlated with tau (r = 0.35, p<0.05; r = 0.47, p<0.001; and r = 0.39, p<0.005, respectively). CONCLUSIONS: Heterogeneity of regional LV systolic function detected by SR imaging is in part attributable to heterogeneity of LVH and may be linked to impaired global LV relaxation in HCM.

Combined study with FDG PET and Tl SPECT in patients with idiopathic dilated cardiomyopathy.

This study aimed to determine whether combined examinations of myocardial 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) and stress-redistribution 201Tl single-photon emission computed tomography (Tl SPECT) were useful in clarifying myocardial ischaemia and evaluating the prognosis in patients with idiopathic dilated cardiomyopathy (IDCM). Twenty-two patients with IDCM underwent echocardiography, cardiac catheterization, FDG PET, and Tl SPECT. In scintigraphic analysis, the total defect score (TDS) was semiquantitatively determined as the sum of scores of the 17 left ventricular (LV) segments with a 5-point scale (0 as normal to 4 as absent). Patients were classified according to the scintigraphic findings as follows: eight patients with small defects on Tl and FDG (TDS < or = 20) (group I), eight patients with small defects on FDG (TDS < or = 20) with FDG uptake increased relative to Tl or 'mismatch' (group II), and six patients with large defects on FDG and Tl (TDS >20) (group III). Eleven patients (50%) showed reversible defects on Tl and all showed preserved FDG uptake. The patients in group III had significantly lower LV ejection fraction (LVEF) (P<0.05, respectively) and a poorer prognosis as shown by the Kaplan-Meier event-free curve compared with those in groups I and II (P<0.01, respectively). Although patients in group II had significantly greater TDS on Tl compared with those in group I (P<0.01), no significant differences in LVEF and prognosis were found between patients in groups I and II. In multivariate analysis, a TDS on FDG revealed an independent predictor of subsequent cardiac events. In conclusion, such mismatched areas can be assumed to consist of impaired but viable myocardium, and may be associated with ischaemia of the microvasculature. Impaired myocardial glucose metabolism is a more powerful predictor of future cardiac events than perfusion abnormality in patients with IDCM.

Carboxy-terminal region involved in activity of Escherichia coli TolC.

The Escherichia coli TolC acts as a channel tunnel in the transport of various molecules across the outer membrane. Partial-deletion studies of tolC revealed that the region extending from the 50th to the 60th amino acid residue from the carboxy terminus plays an important role in this transport activity of TolC.

Syntheses and properties of ditelluroxanes and oligochalcogenoxanes: hypervalent oligomers with Te-O apical linkages in the main chain.

The reaction of ditelluroxanes [Ar2Te-O-TeAr]2+[X]2- (2) (Ar = p-tolyl) with a telluroxide 1, a selenoxide 7, or a carboxylate 10 to produce oligochalcogenoxanes with hypervalent Te-O apical linkages in their main chain is described. The 125Te NMR chemical shifts of 2 (2a: X- = CF3SO3-, 2b: X- = CF3CO2-, 2c: X- = CH3CO2-, 2d: X- = Cl-) are shifted downfield with decreasing nucleophilicity of the counteranions. This result reflects both the cationic character and the reactivity of the Te atoms of 2. The reaction of 2a with one, two, three, or four equivalents of telluroxide 1a (Ar = p-tolyl) selectively gave a tritelluroxane 3a, tetratelluroxane 4a, pentatelluroxane 5a, and hexatelluroxane 6a, respectively. In contrast, the reaction of 2b with an excess of 1a produced only tritelluroxane 3b. An equilibrium between the oligotelluroxanes was confirmed by crossover experiments of the reactions of 2a with 4a and of 2a with 1b (Ar = Ph). The selective equilibrium formation of a selenoxaditelluroxane 8 or a bis(selenoxa)ditelluroxane 9 was achieved by the reaction of 2a with one or two equivalents of selenoxide 7, respectively. The association constant of 2a with 7 to form 8 was estimated to be Ka = (2.18+/-0.12) x 10(4) M(-1) in CD3CN at -40 degrees C. The reaction of 2a with two equivalents of carboxylates 10a-d gave a mixture of bis(carboxylate)ditelluroxanes and diaryldicarboxytelluranes 12b-d, respectively, in which the product ratio of these depended upon the electron-withdrawing ability of 10. The reaction of 3a with two equivalents of 10a-d afforded 11a-d in all cases. The present results suggest that the sigma*-n orbital interaction plays an essential role in the reactivity of ditelluroxanes and in the formation of self-assembled oligochalcogenoxanes, and that a hypervalent bond via a sigma*-n orbital interaction is viable as a new supramolecular synthon for molecular assembly.

The effect of heat-treated human bone morphogenetic protein on clinical implantation.

For the clinical usage of human-derived bones, it is necessary to treat bones to reduce the risk of contamination by microorganisms. Bone morphogenetic protein is vulnerable to chemicals, but shows resistance to thermal heat to 70 degrees C in a short time. In this experiment, crude human bone morphogenetic protein was extracted from heat-treated bones at 60 degrees C for 10 hours and from nonheated bones. Sodium dodecyl sulfate polyacrylamide gel electrophoresis for these specimens was done. Gelatin capsules containing 5 mg of crude human bone morphogenetic protein extracted from heated and nonheated bones were implanted into thigh muscle pouches of five mice. At 20 days after implantation, the heterotopic bone formation was compared by evaluating the radiographic and histologic analyses. The sodium dodecyl sulfate polyacrylamide gel electrophoresis pattern of the human bone morphogenetic proteins showed five main bands (16, 22, 28, 35, and 67 kDa) that were almost identical. Heterotopic bone formation observed on the radiograph was induced by crude human bone morphogenetic protein from heated bones in a manner similar to that used for nonheated bones. The results from this study show that heat-treated bone preserves osteoinduction.

Association of a G994 --> T (Val279 --> Phe) polymorphism of the plasma platelet-activating factor acetylhydrolase gene with myocardial damage in Japanese patients with nonfamilial hypertrophic cardiomyopathy.

Plasma platelet-activating factor acetylhydrolase (PAF-AH) acts as a key defense against oxidative stress by hydrolyzing PAF and oxidized phospholipids. Deficiency of the activity of this enzyme may thus potentially result in predisposition to myocardial damage. The possible role of the G994 (V allele) --> T (F allele) polymorphism of the PAF-AH gene in modulating cardiac function was investigated in 142 Japanese subjects with nonfamilial hypertrophic cardiomyopathy (HCM). Logistic regression analysis adjusted for age, sex, height, and body weight revealed that the frequency of the F allele was significantly higher in HCM patients than in 284 healthy controls. Echocardiographic examination revealed that left ventricular (LV) end-diastolic and end-systolic dimensions were significantly greater in HCM patients with the FF genotype than in those with the VV genotype. Cardiac catheterization revealed that LV end-diastolic pressure was significantly higher, whereas the LV ejection fraction was significantly smaller, for HCM patients with the F allele than for those with the VV genotype. Interstitial fibrosis was significantly more severe in HCM subjects with the FF genotype than in those with the VV genotype. These results suggest that the G994 --> T (Val279 --> Phe) polymorphism in the plasma PAF-AH gene may exacerbate cardiac damage in Japanese individuals with nonfamilial HCM, although this polymorphism is unlikely to be a causative factor for this condition.

Reduced myocardial sarcoplasmic reticulum Ca(2+)-ATPase mRNA expression and biphasic force-frequency relations in patients with hypertrophic cardiomyopathy.

BACKGROUND: The relationship between left ventricular (LV) contractile functional reserve and gene expression of Ca(2+)-handling proteins in patients with hypertrophic cardiomyopathy (HCM) remains to be clarified. METHODS AND RESULTS: We calculated the maximum first derivative of LV pressure (LV dP/dt(max)) and the LV pressure half-time (T(1/2)) during pacing in 14 patients with nonobstructive HCM (LV ejection fraction >55%) and 7 control subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na(+)/Ca(2+) exchanger were quantified by use of a real-time quantitative reverse transcription-polymerase chain reaction method. Group A consisted of 7 HCM patients who showed a progressive rise in the LV dP/dt(max) with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate-LV dP/dt(max) relation was biphasic at physiological pacing rates. Both the mean maximal wall thickness and the LV hypertrophy score in group B were greater than in group A (20+/-5 versus 15+/-3 mm and 7+/-1 versus 5+/-2 points, respectively). SERCA2 mRNA levels were significantly lower in group B (SERCA2/GAPDH ratio 0.34+/-0.15) compared with group A (0.72+/-0.27) and control subjects (0.85+/-0.47), whereas the mRNA expression of ryanodine receptor-2, phospholamban, calsequestrin, and Na(+)/Ca(2+) exchanger were similar in all groups. CONCLUSIONS: These results suggest that downregulation of SERCA2 mRNA, resulting in altered Ca(2+) handling, may contribute to impaired LV contractile reserve in HCM patients with severe hypertrophy, even in the absence of detectable baseline systolic dysfunction.

Biphasic changes in left ventricular end-diastolic pressure during dynamic exercise in patients with nonobstructive hypertrophic cardiomyopathy.

OBJECTIVES: The aim of this study was to clarify the serial changes in left ventricular (LV) end-diastolic pressure (LVEDP) during dynamic exercise in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Although HCM is characterized by impaired resting LV diastolic function, serial changes in LVEDP during exercise have not been characterized. METHODS: We simultaneously measured LV pressure and LV dimensions during symptom-limited supine bicycle exercise in 5 healthy individuals and 20 patients with HCM. Exercise thallium-201 scintigraphic studies were also performed. RESULTS: The LVEDP (baseline: 12 +/- 5 mm Hg) progressively increased to a maximum value at peak exercise (28 +/- 8 mm Hg) in 11 patients with HCM (group I). In the remaining nine patients with HCM (group II), changes in LVEDP during exercise were biphasic, with an initial progressive increase and a subsequent gradual decline up to peak exercise (14 +/- 4 mm Hg at baseline, 27 +/- 5 mm Hg at the critical heart rate, 16 +/- 3 mm Hg at peak exercise). Exercise-induced changes in LV dimensions and LV peak systolic pressures were similar in both groups. However, the maximum first derivative of LV pressure was greater and the LV pressure half-time was shorter in group II than in group I at a similar peak exercise heart rate. The biphasic changes in LVEDP disappeared by pretreatment with propranolol. The LV hypertrophy scores were higher in group I than in group II. Exercise thallium-201 images showed more severe perfusion defects in group I than in group II patients. CONCLUSIONS: The biphasic changes in LVEDP seen during exercise may be related to improved coronary microcirculation in response to beta-adrenergic stimulation in patients with mild to moderate HCM.

Cardiac functional and structural alterations induced by endotoxin in rats: importance of platelet-activating factor.

OBJECTIVE: In this study, we evaluated the time course of the alterations in left ventricular (LV) dimensions, LV wall thickness, and LV systolic function in rats with endotoxemia by using echocardiography as well as myocardial histopathologic assessments. Our second goal was to examine whether pretreatment with a platelet-activating factor (PAF) antagonist would ameliorate the lipopolysaccharide (LPS)-induced cardiovascular collapse during the early phase. DESIGN: A prospective, controlled, in vivo animal laboratory study. SETTING: Research laboratory at a university. SUBJECTS: Male, Wistar rats (8-9 wks old; n = 83). INTERVENTIONS: In pentobarbital-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein also was catheterized for the administration of drugs. LPS (2 mg/kg) derived from Klebsiella pneumoniae or physiologic saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with an 8- to 13-MHz transducer. MEASUREMENTS AND MAIN RESULTS: LPS administration immediately induced progressive hypotension. The maximal hypotensive response was observed at 10 mins after LPS infusion with mean arterial pressure decreasing from 119 +/- 2 to 56 +/- 3 mm Hg (p < .001). LV end-diastolic internal dimensions decreased from 6.4 +/- 0.1 to 3.1 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced compared with control rats. LV end-systolic dimensions also decreased dramatically from 3.5 +/- 0.2 to 0.5 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45 +/- 1% to 84 +/- 2% (p < .001) at 30 mins after LPS and remained elevated compared with control rats. LV wall thickness increased strikingly from 15 mins until 2 hrs after LPS infusion. Pathologic studies demonstrated marked congestion of capillaries and mild edema in the LV myocardium. The hematocrit increased after the administration of LPS. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma concentrations of epinephrine and norepinephrine. There was no elevation of concentrations of nitrite and nitrate. Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated LV functional and structural changes. TCV-309 administration reduced the LPS-induced adrenergic activation and hemoconcentration. CONCLUSIONS: The hypotension that occurred during the initial phase of LPS-induced shock was accompanied by LV functional and structural alterations. The marked increase in LV wall thickness can be ascribed to the congestion of capillaries and edema in the LV myocardium. Pretreatment with a PAF antagonist reduced LPS-induced alterations. PAF may play a pivotal role during the initial phase of LPS-induced cardiovascular responses.

Different beta-adrenergic regulation of myocardial contraction and relaxation between apical and nonobstructive hypertrophic cardiomyopathy.

BACKGROUND: The impaired adrenergic control of both inotropic and lusitropic reserves has been evaluated in patients with hypertrophic cardiomyopathy (HCM) but not in those with apical HCM (APH). OBJECTIVES: We examined the influence of increases in heart rate and adrenergic stimulation on inotropic and lusitropic reserves in HCM and APH with normal resting left ventricular (LV) systolic function. METHODS: We evaluated LV isovolumic contraction and relaxation during atrial pacing and during supine leg exercise in 7 patients with APH and in 8 patients with HCM. RESULTS: Heart rate was significantly correlated with LV isovolumic contraction and relaxation during pacing and exercise in all patients. In all patients with APH, the increase in LV isovolumic contraction was greater during exercise (101%) than pacing alone (27%) for similar increase in heart rate. In 5 patients with HCM, the increase in LV isovolumic contraction was greater during exercise (83%) than pacing alone (24%), whereas in 3 patients with HCM the increase in LV isovolumic contraction was similar between during exercise (25%) and during pacing alone (22%). In all patients with APH, relaxation was shorter during exercise (39%) than pacing alone (16%). Conversely, in patients with HCM relaxation was similarly shortened between during pacing alone (20%) and during exercise (19%). CONCLUSIONS: The force-frequency and the relaxation-frequency relations were well-preserved in all patients. In patients with HCM, the adrenergic enhancement of force-frequency relation and/or relaxation-frequency relation was impaired. In patients with APH, however, adrenergic control of both force-frequency and relaxation-frequency relations was well-preserved, which may indicate a preserved beta-adrenergic signaling pathway.

Solid-phase synthesis of substituted guanidines using a novel acid labile linker.

A novel acid labile linker for solid-phase synthesis of substituted guanidines has been developed. Its synthetic utility is exemplified by high-yielding pyrazole displacement with structurally and electronically diverse sets of aliphatic and aromatic amines. The final cleavage is achieved by treatment with 95:5 trifluoroacetic acid/water for 1 h. The corresponding guanidines were obtained in high purity (80-95%) and good isolated yields (50-95%). The scope and limitations of this linker were further demonstrated by the solid-phase synthesis of an 880-member library of individual trisubstituted arylguanidines employing pyrazole displacement with a set of 11 anilines and two subsequent Mitsunobu N-alkylations with sets of 10 and 8 alcohols, respectively.

Acute effects of a single low oral dose of pimobendan on left ventricular systolic and diastolic function in patients with congestive heart failure.

A recent long-term multicenter trial has shown that pimobendan is more effective when administered in low doses. However, no data are available concerning the effect of a low dose of pimobendan on the systolic and diastolic pressure-volume relations in patients with heart failure. Therefore we examined the effects of a single low dose of oral pimobendan, a calcium sensitizer, on systolic and diastolic hemodynamics in patients with cardiomyopathy and congestive heart failure. We measured the left ventricular (LV) pressure-volume relations using a conductance catheter with a micromanometer tip in 10 patients with chronic congestive heart failure resulting from idiopathic cardiomyopathy before and 45 and 90 min after administration of a single oral dose of 2.5 mg of pimobendan. End-systolic elastance was used as an index of LV contractility and was measured during transient occlusion of the inferior vena cava. End-systolic elastance increased significantly by 25% at 45 min (p < 0.05) and by 55% at 90 min (p < 0.01) without an increase in myocardial oxygen consumption. The inotropic effect was accompanied by improved ventriculoarterial coupling. This effect was attenuated in patients with severely impaired myocardial contractility. LV relaxation, assessed by the time constant of isovolumic pressure decay (T(1/2)), was significantly shortened at 90 min (from 47.7 +/- 1.9 to 41.2 +/- 1.7 ms; p < 0.01), although it remained unchanged at 45 min. The diastolic pressure-volume relation showed a leftward and downward shift in all patients. These results indicate that low-dose oral pimobendan had favorable short-term inotropic and lusitropic effects in patients with congestive heart failure caused by idiopathic dilated cardiomyopathy, and may thus be a useful alternative to traditional agents. Further study in a large-scale trial is merited.

Synthesis of optically active 5-substituted-2-pyrrolidinone derivatives having atropisomeric structure and 3,5-cis-selective reaction of their enolates with electrophiles

Optically pure forms (>/=98% ee) of N-(o-tert-butylphenyl)-5-(methoxymethyl)-2-pyrrolidinone having atropisomerism and N-(o-tert-butyldiphenylsiloxyphenyl)-5-(methoxymethyl)-2-pyrrolidinon e having an atropisomerism-like structure were prepared from ortho-substituted aniline derivatives and (S)-5-(methoxymethyl)butyrolactone in a stereoselective manner. The reactions of Li-enolates from these lactams with various electrophiles and subsequent dearylation of the products gave 3, 5-cis-disubstituted-2-pyrrolidinone derivatives.