High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins

To elucidate the anti-atherogenic effect of probucol, high-density lipoprotein (HDL) was isolated from probucol-treated patients (n = 14) and compared with that from control subjects (n = 12). The HDL obtained from probucol-treated patients was low in cholesteryl ester (CE) in comparison with that from control subjects (21.3 ± 3.9 mol per cent vs. 27.6 ± 3.2 mol% of total lipids, P < 0.001), and the peak diameters of patients' HDL were significantly smaller than those of control subjects on 4–30% non-denaturing polyacrylamide gradient gel electrophoresis (10.6 ± 0.6 nm vs. 12.1 ± 0.4 nm, P < 0.001). These data may be explained by the increased cholesteryl ester transfer protein (CETP) activities of probucol-treated patients (129 ± 12% of control subjects, P < 0.001). The in vitro ability of HDL to remove CE from lipid-laden macrophages induced by incubation with acetylated low-density lipoprotein (Ac-LDL) was studied. The small and CE-poor HDL obtained from probucol-treated patients had a greater capacity to promote CE efflux from macrophages than did control HDL (59.8 ± 6.9% vs. 44.2 ± 5.4%, P < 0.01). Furthermore, the ability of HDL to promote cholesterol efflux correlated negatively with the CE content and particle diameter of HDL (r = ?0.561 and r = ?0.583 respectively; P < 0.01). When the inhibitory effect of HDL on the incorporation of [¹⁴C]-oleate into cellular cholesteryl ester was compared, the HDL from patients and control subjects inhibited CE formation to a similar extent. The enhanced ability of probucol-treated patients' HDL may, therefore, be involved in the acceleration of hydrolysis of the CE pool in macrophages. Taken together, we conclude that CETP plays a crucial role in making HDL more active in its anti-atherogenic function by reducing CE and making HDL smaller, and that probucol may enhance reverse cholesterol transport by activating CE transfer in vivo. The current study demonstrated, for the first time, that HDL modified by enhanced CETP activity in vivo is potentially anti-atherogenic.     

Site of the Arrhythmogenic Focus and Cardiac Vulnerability to Ventricular Fibrillation

MURAKAWA, Y., et al. : Site of the Arrhythmogenic Focus and Cardiac Vulnerability to Ventricular Fib-rillation. The aim of this study was to test the hypothesis that a subendocardial arrhythmogenic focus makes the heart more susceptible to VF due to electrical interaction with the Purkinje network. Monofocal ventricular tachycardia (mVT) was created by injecting 5-μg aconitine into the left ventricular subepicardium (  EPI-mVT, n = 8  ) or subendocardium (  ENDO-mVT, n = 13  ) in anesthetized dogs. Despite the similar cycle length of mVT, the incidence of VF was significantly different between EPI-mVT and ENDO-mVT (  100 [8/8] vs 46% [6/13], P < 0.05  ). VF was invariably preceded by hemodynamic deterioration. Three-dimensional cardiac mapping (  n = 10, 221 ± 11 recording sites  ) revealed that VF was triggered solely by focal firing unrelated to the primary arrhythmogenic focus in both mVT models. No interaction between the primary focus and adjacent endocardial tissue was indicated. These results suggest that the proximity of the arrhythmogenic focus to the Purkinje network has little role in cardiac vulnerability to VF, and that progression of mVT to VF is largely caused by sporadic focal firing regardless of the site of the arrhythmogenic focus in the present animal model.     

Assessing the clinical utility of the magnetic stimulator for measuring response latencies in the laryngeal muscles

Our purpose was to assess the use of magnetic stimulation for measuring conduction time of the recurrent and superior laryngeal nerves in 10 normal volunteers (7 male, 3 female). Subjects underwent laryngeal electromyography and magnetic stimulation of the vagus nerve bilaterally at the mastoid tip with a figure 8 coil. Mean muscle response latencies were measured and examined for consistent differences. Thyroarytenoid muscle response latencies were consistently longer than those in the cricothyroid muscle. Left thyroarytenoid muscle latencies were consistently longer than those on the right in agreement with bilateral asymmetry of these nerves. No appreciable differences were observed in cricothyroid muscle latencies when the right side was compared with the left. Results were consistent and reproducible within a broad range, but appreciable intersubject variability was observed. The limited sample size was unable to support a correlation with anthropometric variables, although an association was indicated. Magnetic stimulation with this technique has great potential for use in neurolaryngologic studies. (Otolaryngol Head Neck Surg 1996;114:761-7.)     

Macrocyclic peptides II. Synthesis and structure of a novel dipeptide, (2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid,and its use as the unit of cyclic peptides

A new cyclic compound [(2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid] obtained using (2S,7S)-2,7-dimethyl-3,6-diazaoctanedioic acid as a starting material was derived from N-t-butyloxycarbonyl-(2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid in order to determine the molecular structure by X-ray crystal analysis. Two new macrocyclic peptides were prepared using the above cyclic compound and sarcosine as peptide units.     

Actions of procaterol (OPC-2009), a new β2-adrenoceptor stimulant,on pulmonary resistance,contractions of the soleus muscle,and cardiovascular system of the anaesthetized cat

The β-adrenoceptor stimulant actions of procaterol hydrochloride [5-(1-hydroxy-2-iso-propylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrate] were compared with those of isoprenaline, orciprenaline and salbutamol on pulmonary resistance, contractions of the soleus muscle, heart rate and diastolic blood pressure in the anaesthetized cat. All four drugs reduced the 5-HT-induced increase in pulmonary resistance, decreased the tension of incomplete tetanic contractions of the soleus muscle and the diastolic blood pressure, and increased the heart rate in a dose-related manner. The duration of the bronchodilator action of procaterol was far longer than that of orciprenaline or salbutamol while isoprenaline had the shortest duration. Procaterol was about 1·5 times more potent, and orciprenaline and salbutamol about 80 and 10 times less potent than isoprenaline in reducing the 5-HT-induced increase in pulmonary resistance and in decreasing the tension of incomplete tetanic contractions of the soleus muscle. Procaterol, orciprenaline and salbutamol were 3·5, 91·9 and 43·9 times less potent than isoprenaline in increasing the heart rate. Procaterol, orciprenaline and salbutamol were 3·4, 130·2 and 12·9 times less potent than isoprenaline in decreasing the diastolic blood pressure. Calculation of selectivity for bronchial vs cardiac β-adrenoceptors indicates that procaterol and salbutamol have a similar degree of selectivity for β₂-adrenoceptors mediating the bronchodilation, and that orciprenaline was an essentially unselective stimulant. Furthermore, the results support the suggestion that at present it is not possible to separate the bronchodilating and tremor-enhancing properties of β-adrenoceptor stimulants.     

Therapeutic effects of preferential induction of mite-specific T helper 0 clones

The predominance of Th2 cytokine-secreting pattern in allergic asthma has been known as a cause and an accelerating factor, and Th1 suppresses these allergic phenomena, but the role of Th0 clones is obscure. Because Th1/Th2 differentiation has been determined by cytokine environment, we investigated how mite-specific helper T cells stimulated in different cytokine environments actually influenced IgE and IgG4 synthesis, which are known to be regulatory immunoglobulins for allergic response. Th0 clones, which were mainly established in the presence of IL-12, provided a great deal of help for IgG4 and IgG1 synthesis, but did not provide help for IgE synthesis, whereas Th2 clones helped IgE synthesis prominently, and IgG4 and IgG1 synthesis marginally. These characteristics of Th0 clones were also true for Th0 clones obtained from patients who were successfully treated with desensitization therapy. Furthermore, the differences in helper activity between Th0 and Th2 clones were not ascribed solely to soluble factors. These data indicate that IgE and IgG4 synthesis is differentially regulated by antigen-specific T cells, and that conversion or selection from Th2 to Th0 by the addition of IL-12 may exhibit therapeutic effects.     

Immunohistochemistry of collagen types II and X, and enzyme-histochemistry of alkaline phosphatase in the developing condylar cartilage of the fetal mouse mandible

We investigated the immunohistochemical localisation of types II and X collagen as well as the cytochemical localisation of alkaline phosphatase in the developing condylar cartilage of the fetal mouse mandible on d 14–16 of pregnancy. On d 14 of pregnancy, although no immunostaining for types II and X collagen was observed, alkaline phosphatase activity was detected in all cells in the anlage of the future condylar process. On d 15 of pregnancy, immunostaining for both collagen types was simultaneously detected in the primarily formed condylar cartilage. Alkaline phosphatase activity was also detected in chondrocytes at this stage. By d 16 of pregnancy, the hypertrophic cell zone rapidly increased in size. These findings strongly support a periosteal origin for the condylar cartilage of the fetal mouse mandible, and show that progenitor cells for condylar cartilage rapidly or directly differentiate into hypertrophic chondrocytes.