STUDIES ON PEPTIDES LXXXI. Application of a New Arginine Derivative,NG-Mesitylene-2-Sulfonylarginine,to the Synthesis of Substance P and Neurotensin

A new devised arginine derivative, N^G-mesitylene-2-sulfonylarginine, Arg(Mts), was employed for the synthesis of hypothalamic substance P and neurotensin. The former was obtained in 74% yield by treatment of the protected undecapeptide amide, Z - Arg(Mts) - Pro - Lys(Z) - Pro - Gln - Gln - Phe - Phe - Gly - Leu - Met(O)-NH₂, with methanesulfonic acid in the presence of anisole followed by reduction of the sulfoxide with 2-mercaptoethanol. The latter was obtained in 54% yield by the similar treatment of the protected tridecapeptide ester, Z-Pyr-Leu - Tyr - Glu(OBzl) - Asn - Lys(Z)-Pro-Arg(Mts) - Arg(Mts) - Pro - Tyr-Ile-Leu-OBzl, with methanesulfonic acid. As scavenger, a mixture of anisole-thioanisole-o-cresol (1:1:1, by vol.) was employed to suppress the side reaction, O-mesitylene-2-sulfonation of the Tyr residue.     

Age-related endothelium-dependent vascular relaxation in rat thoracic aorta in response to colforsin

BACKGROUND: Colforsin, a novel water-soluble forskolin derivative, increases intracellular cyclic AMP by direct stimulation of adenylate cyclase and has strong positive inotropic and vasodilative effects. However, it is not known whether colforsin causes nitric oxide (NO) release and enhances endothelium-dependent vascular relaxation. METHODS: We studied NO production and relaxation on exposure to colforsin in thoracic aorta from rats aged 4, 12 and 60 weeks. RESULTS: When a low concentration of colforsin was added to a solution bathing ring segments of aorta from 12-week-old rats, relaxation was greater in the ring segments with intact endothelium than in those from which the endothelium had been removed. A high concentration of colforsin induced the same degree of relaxation of ring segments with or without endothelium, probably by a direct effect on vascular smooth muscle cells. Production of NO in response to colforsin by cultured endothelial cells from 12-week-old rat aorta was demonstrated by the electron paramagnetic resonance spin trapping method. A low concentration of colforsin relaxed aortic segments with intact endothelium from 4-week-old rats more than those from 12-week-old or 60-week-old rats. Reversal of relaxation by NG-nitro L-arginine, an NO synthesis inhibitor, was most significant in arteries from 4-week-old rats. Production of NO after exposure to colforsin was greater in aortic segments from 4-week-old rats than older rats, as detected by an NO-selective electrode. CONCLUSIONS: Colforsin induces vasodilation in part by releasing NO from the endothelium in rat thoracic aorta. In addition to a direct vasodilative effect on the vascular smooth muscle cells, an endothelium-dependent vasodilative effect is also important in younger arteries.     

Color Doppler ultrasonography as a routine clinical examination in male infertility

AIM: We assessed the value of scrotal color Doppler ultrasonography as a routine examination in infertile men. METHODS: Color Doppler ultrasonography was performed in 545 infertile men with a mean age of 35.8 years to detect intrascrotal abnormalities. Findings were compared with those of physical examination. RESULTS: Intrascrotal abnormalities were detected by ultrasonography in 65.3% of patients. Of 374 abnormalities, 58.3% were undetected by physical examination. Left varicocele was found in 313 patients (57.4%); testicular microlithiasis in 30 (5.5%); epididymal cyst in 21 (3.9%); right varicocele in 4 (0.8%); and testicular cysts in 3 (0.6%). One occurrence each (0.2%) was found for testicular tumor, intrascrotal hemangioma, and hydrocele of the spermatic cord. Compared to ultrasonography, sensitivity in detecting left varicocele by physical examination was 58.4%; specificity, 79.3%; accuracy, 67.3%; and positive predictive value, 79.3%. Venous diameters in the pampiniform plexus were 3 mm or more in 61.5% of 130 subclinical left varicoceles. Of 30 patients with testicular microlithiasis, 14 had varicocele, 2 had epididymal cyst,s 3 had a history of mumps orchitis, 1 had retractile testis, and 1 had a history of orchiectomy for contralateral testicular tumor. CONCLUSIONS: The routine Color Doppler ultrasonography is valuable for diagnosing scrotal abnormalities in infertile men, frequently detecting non-palpable lesions.     

Mexiletine and Propafenone: A Comparative Study of Monotherapy, Low, and Full Dose Combination Therapy

The electrophysiological effects of combination therapy of mexiletine and propafenone were assessed using standard 12-Iead electrocardiogram (standard ECG), signal-averaged EGG (SAECG), and ambulatory ECG in 31 patients with ventricular arrhythmias. All patients underwent mexiletine monotherapy (M-mono), propafenone monotherapy (P-mono), low dose combination therapy (low M 4- P), and full dose combination therapy (full M + P). Full M + P increased the PQ interval and QRS duration to the same extent as P-mono did. Low M + P increased PQ interval and QRS duration to a lesser extent than P-mono and full M + P did. P-mono and full M + P significantly decreased root mean square (RMS) and increased f-QRS in SAECG, while M-mono and low M + P showed only a weak trend. SAECGs with late potentials increased in number with treatments; 9 in predrug control, 11 on M-mono, 15 on P-mono, 10 on low M + P, and 14 on full M + P. The percent suppression of frequent premature ventricular contractions (PVCs) (> 1,000/day) with M-mono, P-mono, low M + P, and full M + P were 46.4 ± 9.0,56.6 ± 10.4,64.4 ± 9.2, and 71.4 ± 7.1, respectively, and those of frequent couplets (> 10/day) were 58.3 ± 17.7, 62.6 ± 23.6, 87.5 ± 6.2, and 92.1 ± 4.0, respectively. Thus, full dose combination of mexiletine and propafenone exhibited the maximum antiarrhythmic efficacy without enhancement of effects on standard ECG and SAECG. Low dose combination therapy showed better antiarrhythmic efficacy in association with lesser effects on standard ECG and SAECG compared with propafenone monotherapy.     

Higher cerebral dysfunction in a case with atypical multiple sclerosis with concentric lesions

Abstract A patient with atypical multiple sclerosis (MS) with clear concentric structure was studied using high field magnetic resonance imaging (MRI). This case was considered to be Balo's concentric sclerosis. Magnetic resonance imaging showed diffuse multiple concentric demyelinating lesions in the bilateral centrum semiovales, which finally regressed with the necrotic lesions remaining when the patient was discharged. During his clinical course, he showed some higher cerebral dysfunctions, such as memory disturbance, constructual apraxia and acalculia. He was treated with glycerin, prednisone and rehabilitation; all of which were effective in his recovery. Over a 4 month period, the patient recoveredclinically, but some intellectual impairment remained.     

Proliferative activity and genetic changes in adrenal cortical tumors examined by flow cytometry, fluorescence in situ hybridization and immunohistochemistry

BACKGROUND: To determine differences in biological features among different adrenal tumors, we investigated the DNA ploidy, numerical chromosomal aberration and proliferative activity in human adrenal cortical neoplasms. METHODS: Our study included six adrenal cortical adenomas with Cushing syndrome, 12 adenomas with hyperaldosteronism, three non-functioning adenomas and three adrenal cortical carcinomas. Isolated nuclei from frozen samples were used for fluorescence in situ hybridization (FISH) analysis, and formalin-fixed, paraffin-embedded tissues from the same materials were analyzed using flow cytometry (FCM) for DNA ploidy. Sections from paraffin blocks were stained immunohistochemically with antibodies against Ki-67 and p53. For FISH analysis, we used an alpha-centromeric enumeration probe for chromosome 17. RESULTS: The mean Ki-67 labeling index (LI) of adrenal cortical carcinomas was markedly higher than that of adrenal cortical adenomas (209.4 vs 8.7). In functional adrenal cortical adenomas, the LI was significantly lower in adenomas with hyperaldosteronism than in those with Cushing syndrome (P = 0.004), although FCM results indicated that tetraploid patterns were more frequently observed in the former type. Tumor size was significantly smaller in adenomas with hyperaldosteronism than in those with Cushing syndrome (P = 0.004). Chromosome 17 showed disomy in all adrenal cortical adenomas, whereas chromosome 17 abnormalities were found in two of three adrenal cortical carcinomas. Only the latter two cases strongly expressed p53 protein. CONCLUSIONS: Our study characterized various biological features of benign and malignant adrenal cortical tumors. The use of a combination of markers might provide additional information to assist our understanding of the clinical behavior of an individual adrenal cortical tumor.     

Exfoliative Cytopathology of Atypical Pulmonary Carcinoid: A Case Report

A 35-year-old man was diagnosed as having lung cancer and diedsix years later. In spite of an initial histological diagnosisof squamous cell carcinoma from the biopsy material, the correctdiagnosis of atypical carcinoid was made by sputum cytology.The carcinoid cells had exfoliated into the sputum collectedimmediately after bronchofiberscopic examination although thebronchial tissues obtained at this time did not reveal any histologicalfindings suggestive of neo-plasia. The distinctive cytologicalfeatures in sputum of atypical carcinoid that differentiateit from small cell carcinoma are considered to be the relativelyabundant vesicular cytoplasm and the finely reticular or granularchromatin pattern observed in well-preserved tumor cells. Thepresent case also suggests that clinical data may be indispensableto the differential cytological diagnosis of such tumors.     

Papillary cystadenocarcinoma of the prostate

A giant cystic formation was found behind the prostate of a 69-year-old man who presented with urinary retention. Ultrasonography, computed tomography scans and magnetic resonance imaging revealed a large cystic intrapelvic mass and biopsy of the cyst wall diagnosed papillary cyst adenocarcinoma. Immunohistochemically, the tumor originated from the prostate.