Levodopa challenge test and (123) I-metaiodobenzylguanidine scintigraphy for diagnosing Parkinson's disease.

OBJECTIVES: To explore the possibility of a generally applicable tool for the immediate diagnosis of Parkinson's disease (PD) in its early stage, we compared the sensitivity and specificity of an acute levodopa challenge test with that of (123) I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. MATERIALS AND METHODS: A consecutive series of 45 patients with extrapyramidal symptoms were recruited to the acute levodopa challenge and evaluated for improvement by use of the Unified Parkinson's Disease Rating Scale motor scores. Of these patients, 32 of them were also examined by MIBG scintigraphy. The patients were followed up for at least 24 months, and 22 patients were diagnosed as having clinically definite PD. RESULTS: The sensitivity and specificity of the acute levodopa challenge test to predict clinical diagnosis of PD were 81.8% and 81.8%, respectively, which were better than those obtained by MIBG scintigraphy (62.5% and 62.5%). In both early- and middle-stages of PD, the test gave better sensitivity than MIBG scintigraphy. CONCLUSIONS: Considering that the well-established and frequently referred clinical diagnostic criteria require longitudinal observation for at least 24 months, the acute levodopa challenge test can be used as an immediate diagnostic tool for PD with sensitivity and specificity comparable to those of MIBG.

Diagnostic and prognostic biomarkers in acute myocarditis. Interleukin-10.

Acute myocarditis is a major inflammatory heart disease with a variety of clinical courses from the acute to chronic phases represented by unexpected circulatory deterioration during hospitalization and progression to dilated cardiomyopathy. Predicting these disease courses is important for patient management. However, biomarkers have not been fully investigated. In addition, clinical profiles including symptoms, serological data, and electrocardiographic findings in acute myocarditis often mimic more common disorders such as coronary artery disease, which have reduced the diagnostic accuracy of acute myocarditis. These issues hamper the development of safer and earlier therapeutic interventions specific for acute myocarditis. Against this background, identifying simple prognostic and diagnostic biomarkers would contribute dramatically to the improvement in outcomes. Interleukin-10 may be a strong candidate for an excellent biomarker.

Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind trial.

OBJECTIVE: To compare the efficacy and safety of sitagliptin (a dipeptidyl peptidase-4 inhibitor) and voglibose (an alpha-glucosidase inhibitor) monotherapy in Japanese patients with type 2 diabetes who have inadequate glycaemic control (HbA1c > or =6.5% and <10.0%) on diet and exercise. METHODS: In a multi-center, randomized, double-blind, parallel-group study, 319 patients were randomized (1:1) to 12-week treatment with sitagliptin 50 mg once daily or voglibose 0.2 mg thrice daily before meals. The primary analysis assessed whether sitagliptin was non-inferior to voglibose in lowering HbA1c. RESULTS: After 12 weeks, sitagliptin was non-inferior to voglibose for HbA1c-lowering efficacy. Furthermore, sitagliptin was superior to voglibose, providing significantly greater reductions in HbA1c from baseline [least squares mean changes in HbA1c [95% confidence intervals (CI)] = -0.7% (-0.8 to -0.6) and -0.3% (-0.4 to -0.2), respectively; between-group difference = -0.4% (-0.5 to -0.3), p < 0.001]. Sitagliptin was also superior to voglibose on other key efficacy endpoints, including change from baseline in 2-h postmeal glucose (-2.8 mmol/l vs. -1.8 mmol/l, p < 0.001) and fasting plasma glucose (-1.1 mmol/l vs. -0.5 mmol/l, p < 0.001). After 12 weeks, the incidences of clinical adverse experiences (AEs), drug-related AEs and gastrointestinal AEs in the sitagliptin group (48.5, 10.4 and 18.4%, respectively) were significantly (p < 0.05) lower than those in the voglibose group (64.7, 26.3 and 34.6%, respectively). The incidences of hypoglycaemia, serious AEs and discontinuations due to AEs were low and similar in both groups. CONCLUSIONS: In Japanese patients with type 2 diabetes, once-daily sitagliptin monotherapy showed greater efficacy and better tolerability than thrice-daily voglibose over 12 weeks.

Purification and characterization of rat urinary esterase A1.

An enzyme, esterase A1, which hydrolyzes tosyl-arginine methyl ester (Tos-Arg-OMe) was separated from esterase A2 and kallikrein of male rat urine and purified by a procedure involving ammonium sulfate fractionation, ion exchange chromatography, hydrophobic chromatography and gel filtration. The resulting preparation was apparently homogeneous, as assessed by polyacrylamide gel electrophoresis. The molecular weight of the preparation was estimated to be 27,000 by SDS-polyacrylamide gel electrophoresis and 30,000 by gel filtration. The enzyme was more specific for arginine methyl esters than for lysine methyl esters. The optimum pH determined with Tos-Arg-OMe as a substrate was 8.0 and the Km was 11.8 mM. The Tos-Arg-OMe esterolytic activity of esterase A1 was inhibited by soybean trypsin inhibitor, but not by aprotinin. In immunodiffusion analysis, the antiserum to esterase A1 formed immunoprecipitin arcs with this enzyme and the urine collected from rat bladder, but not with esterase A2, kallikrein, plasma and the urine collected from ureters. These results indicate that rat urinary esterase A1 differs from esterase A2 and kallikrein. The esterase A1 appears to be produced by accessory sex glands and excreted via the spermiduct into the urine.

Purification and partial characterization of a thiol proteinase activating prokallikrein from the rat kidney cortex.

The rat kidney cortex contains at least three kinds of prokallikrein-activating proteinase, and among these the one with the highest molecular weight was purified by a procedure including chromatography on CM-cellulose, concanavalin A-Sepharose, organomercurial-Sepharose 4B and Sephadex G-100. The resulting preparation was apparently homogeneous, as assessed by SDS-polyacrylamide gel electrophoresis. The molecular weight was estimated to be 57,000. The optimal pH for the activation of prokallikrein by the preparation, termed activator I, was around 4.5. Activator I was inhibited by E-64, iodoacetate and leupeptin, but not by PMSF and phosphoramidon. In immunodiffusion analysis, the antiserum to activator I formed an immunoprecipitin arc with the extract from the kidney cortex or submandibular gland, but not with that from the pancreas. These results indicate that activator I is a thiol proteinase with a molecular weight of 57,000. A proteinase immunologically identical with activator I appears to be present in the submandibular gland.

Estimation of plasma and saliva levels of coenzyme Q10 and influence of oral supplementation.

Coenzyme Q10 (CoQ(10)) levels in human saliva were measured by HPLC with a highly sensitive electrochemical detector (ECD) and a special concentration column. This HPLC system showed satisfactory analytical results within the standard range of 0.78-50 ng/ml. We also found a significant correlation between CoQ(10) levels in plasma and in saliva from parotid glands, while this correlation was lacking between plasma CoQ10 and CoQ10 in whole saliva. Unlike in plasma, there are some fluctuations of saliva CoQ(10) levels throughout the day. A good correlation was obtained by collecting parotid gland saliva at times between meals. The mean saliva CoQ(10) level for 55 healthy volunteers was 17.0 ng/ml (S.D. 6.8 ng/ml); approximately one fiftieth of that in plasma. Regarding the influence of oral supplementation, CoQ(10) was analyzed in plasma and parotid gland saliva from 20 healthy volunteers supplemented daily with 100 mg of CoQ(10) for the first week and 200 mg for the second. The plasma CoQ(10) levels of all volunteers increased to different extents in accordance with the CoQ(10) daily intake and the corresponding change in saliva showed almost the same trend.

Molecular cloning and nucleotide sequence analysis of mRNA for human kidney ornithine aminotransferase. An examination of ornithine aminotransferase isozymes between liver and kidney.

The cDNA encoding ornithine aminotransferase (EC 2.6.1.13; OAT) was isolated from a human kidney cDNA library. The isolated cDNA contained the entire protein coding region and partial 3'- and 5'-untranslated regions. The nucleotide sequences of human kidney OAT cDNA were absolutely homologous with those of human liver OAT cDNA, and human kidney and liver OAT fused completely against the antibody to human kidney OAT in an Ouchterlony double diffusion test. These findings settled the controversy as to which characteristics of liver and kidney OAT isozymes are different. An N-terminal sequence analysis of purified mature human kidney OAT clarified that the leader peptide was cleaved between Gln-35 and Gly-36.

Vasorelaxant mechanism of the new vasodilator, FK409.

To define the vasorelaxation mechanism of FK409, we examined the effect of the compound on vascular tension and cyclic nucleotide levels in isolated rat thoracic aorta contracted with norepinephrine, and on activities of guanylate cyclase and cyclic GMP phosphodiesterase prepared from rat or rabbit thoracic aorta. FK409 (1 x 10(-9) to 1 x 10(-6) M), like nitroglycerin (1 x 10(-9) to 1 x 10(-6) M), produced a potent vasorelaxant effect associated with an increase in cyclic GMP content of the tissue. There was no change in cyclic AMP levels. The vasorelaxant effect of FK409 was independent of the integrity of the endothelium, and was unaffected by L-NG-monomethylarginine (0.1 mM) or oxyhemoglobin (1 microM). On the other hand, FK409 (3.2 x 10(-7) M) activated soluble guanylate cyclase, and the activating effect was completely inhibited by oxyhemoglobin (10 nM). Cyclic GMP phosphodiesterase was unaffected by FK409 (1 x 10(-7) to 1 x 10(-5) M). Furthermore, in rat aortic soluble fraction FK409 (3 mM) was found to liberate nitric oxide (NO) which was evaluated spectrophotometrically after diazotization of sulfanilic acid and coupling with N-(1-naphthyl)-ethylenediamine. The liberation occurred even in the absence of L-cysteine (5 mM), in contrast to the case with nitroglycerin (3 mM). These results suggest that the vasorelaxant effect of FK409 is associated with an increase in intracellular cyclic GMP, and that the cyclic GMP accumulation is due to activation of soluble guanylate cyclase. The enzyme activation is probably due to NO released from the compound molecule in the vascular smooth muscle cells.

Activation of inactive kallikrein in the rat kidney during low sodium intake.

A method was developed to measure the protease responsible for activation of inactive kallikrein in the rat kidney. The renal protease was evaluated by incubating the purified rat urinary inactive kallikrein with the renal cortical extract in the presence of cysteine at pH 5.0. The renal cortical extract produced a dose- and time-dependent activation of the inactive kallikrein. Levels of the renal protease responsible for activation of inactive kallikrein remained unchanged with dietary sodium restriction. On the other hand, urinary excretion of total, active, and inactive kallikrein increased significantly during low sodium intake, with no change in the ratio of active to total kallikrein. These results suggest that low sodium intake stimulates the biosynthesis of inactive kallikrein but not the activation of this kallikrein precursor in the kidney.

Scleroderma renal crisis complicated by hemolytic uremic syndrome in a case of elderly onset systemic sclerosis.

We report a case of renal crisis in a patient with elderly onset systemic scleroderma (SSc). A sixty-one-year-old woman was diagnosed as having SSc with rapidly advancing generalized skin sclerosis. After experiencing an upper respiratory infection, she suddenly developed renal failure, hemolytic anemia and malignant hypertension. Laboratory examination revealed uremia with a significantly high plasma renin level. Ophthalmologic study revealed Keith-Wagner's retinopathy Grade IV. Combination therapy including captopril, systemic corticosteroid and prostaglandin E1 venous infusion for the hemolytic uremic syndrome was effective and saved her from the renal crisis. However, her renal function deteriorated and she needs permanent hemodialysis. Rapidly progressive skin sclerosis in SSc, especially in elderly onset cases, suggests a high risk for renal crisis and indicates the need for careful consideration of hypertension and renal function.

[Studies of influence of animal protein intake on the urinary risk factors of calcium oxalate stone formation].

To examine the effects of excessive animal protein intake on the urinary risk factors of calcium oxalate stone formation, protein loading experiments were performed on oxalate stone formers and normal subjects and rats. By animal protein loading of 61 g/day with diet which contained 400 mg of calcium and 46.6 mg of total oxalate, urinary calcium excretion increased by 27% both in stone formers and in normal subjects. Urinary oxalate excretion had a tendency to decrease on the 3rd and 4th days after loading. Urinary uric acid excretion increased significantly after loading. No significant change was recognized in the acid glycosaminoglycan (AGAG) and magnesium excretion. Urinary calcium excretion increased both in the high and low calcium diet groups after animal protein loading in the rat experiment. Urinary oxalate excretion increased after loading only in high oxalate low calcium diet group, therefore, it was supposed that animal protein intake caused increase of intestinal oxalate absorption.

[Immunohistochemical study for growth factor and oncogene on atypical epithelium of the stomach].

Almost all atypical epithelial lesions of the stomach consist of atypical cells in the superficial part of the glands and nonatypical cells in the deeper portion of the glands. A transition zone was formed between the superficial atypical gland cells and the deeper nonatypical gland cells. Positive cells were widely demonstrated with immunohistochemical stains for PCNA in the superficial atypical glands and transition zone. The rate of PCNA positivity was 37.7%. However, a small number of positive cells for EGFR (8.5%), c-erbB-2(11.3%), p53(11.3%) and c-K-ras(1.7%) were found in ATP. The incidence of positivity for these factors was low compared with that for carcinomas. The percentages of positive cells for EGFR(1.5%) and c-erbB-2(4.5%) were very low in intestinal metaplasia.

[Histological study of heterotopic pancreas tissue of the stomach--histogenesis and immunohistochemical findings].

Forty resected cases of heterotopic pancreas (15 of Heinrich's type I and 25 of type II) in the stomach were investigated. Acinic cells were more remarkably positive by pancreatic polypeptide and amylase in the cases of type I consisting of acinic cells, ducts and islet cells compared with those in type II consisting of acinic cells and ducts. Staining behavior by insulin, gastrin, glucagon, somatostatin and serotonin was similar to that of normal pancreas. However, the intestinal epithelium containing goblet cells and pyloric gland-like glands consisting of the cells with clear cytoplasm were not infrequently produced from the ducts in the lesions of type II. Muscle fibers with transition to muscularis mucosae were more frequently intermingled in the lesions of type II compared with type I. Acinic cell-differentiation in the mucosa apart from the main lesion was found in several cases of type II. It was suspected that there are two types of histogenesis for the heterotopic pancreas in the stomach; one arises from the fetal immigration of pancreas tissue in the stomach and the other from the immature gastric mucosal penetration into the submucosa with secondary differentiation to the pancreas tissue.

[Immunohistochemical study of growth factors and oncogenes in gastric carcinomas].

Immunohistochemical staining for EGF, EGFR, c-erbB-2, p53, K-ras and PCNA was performed on the formalin-fixed, paraffin embedded sections of resected gastric carcinomas. A relatively high positive rate was observed for EGFR and c-erbB-2 in the well-differentiated adenocarcinomas and p53 in the poorly-differentiated adenocarcinomas. The positive rate of these factor was higher in the advanced cases than in the early cases, and also in the deep invasive area than the superficial area. According to the PCNA staining, a relatively high positive rate was observed in the well-differentiated adenocarcinomas compared with the early cases of poorly-differentiated adenocarcinomas, but the positive rate was markedly higher in the advanced cases of the latter. Typical signet-ring cell carcinomas showed the lowest positivity rate compared with the other histological types of gastric carcinomas.

[Immunohistochemical study of the lymph-follicles and lymphocytes in the gastric mucosa].

Immunohistochemical stainings according to ABC method (UCHL-1,L-26,MT-1,MB-1,IgG,IgA,IgD,IgM, kappa, lambda, LN-1 and LN-2) for the lymphocytes in the germinal center, mantle zone and infiltrative lymphocytes in the gastric mucosa of 30 cases of chronic gastritis and 10 cases of reactive lymphoreticular hyperplasia (RLH) were performed. Lymphocytes in the germinal center and mantle zone consisted usually of B-cells positively stained by L-26 and MB-1. However, in the interstitially infiltrative cells,T-cells positively stained by UCHL-1 and MT-1 were not infrequently contained. Immunoglobulin stainings revealed marked positivity for IgG,IgA,IgD,IgM, kappa and lambda in the interstitial lymphocytes and plasma cells. As to the RLH, small number of T-cells scattered in the germinal center and surrounding area of lymph follicles, and large number of T-cells were found among the follicles, where B-cells were more infrequently found than in the interstitial area of propria mucosae. Confusion of enlarged germinal centers and monotonous proliferation of lymphocytes among the lymph follicles showing monotonous positivity for the stains of heavy and light chains in the cases of RLH were suggestive of malignant change.

[A clinical survey on 24 cases of primary ureteral tumors].

A clinical survey was performed on 24 cases of primary ureteral tumors treated in our University Hospital between Jan. 1972 and Dec. 1981. The incidence of primary ureteral tumors was 0.17% among the outpatients in our urologic clinic. The patients ranged from 41 to 84 years old in age (average age: 65 years), and the male to female ratio was 3 to 1. The left ureter and the lower third of the ureter were involved more frequently. The most frequent initial symptom was macrohematuria seen in 19 cases (79%), followed by loin pain seen in 6 cases (25%). A cytologic study of the voided urine or ureteral urine was carried out in 18 cases and positive results were obtained in 9 cases (50%). Cystoscopic examination revealed a tumor protruding through the ureteral orifice in 16.7% (4 of 24 cases), followed by bulging orifice in 8.3% (2 of 24 cases). Excretory pyelography showed ureteral filling defects in 41.7% (10 of 24 cases). Retrograde pyelography showed ureteral filling defects in 100% (10 of 10 cases). CT showed a mass region in 44.4% (4 of 9 cases). A total of 14 patients underwent nephroureterectomy with partial or total cystectomy (66.7%). The overall 5-year-survival rate was 56.5% and could be directly associated with grade and stage of tumors.

[A case of the coexistence of renal cysts and renal cell carcinoma associated with direct invasion of the liver (stage IV)].

A 63-year-old male was admitted with a complaint of right abdominal mass. A right renal tumor associated with direct invasion to liver and with lobulated cystic lesion and renal solitary cyst were diagnosed preoperatively by aortography and computed tomography. Transperitoneal radical nephrectomy and partial resection of liver metastasis were performed. Histological diagnosis was clear cell carcinoma with dilated tubuli. Tumor invasion to the inferolateral portion of the liver and to the renal solitary cyst wall were demonstrated by both gross and microscopic examinations. The coexistence of tumor and cyst in the same kidney is rare. Our case probably had both the type I and II or III tumors according to Gibson classification. Twenty months after radical nephrectomy, pulmonary metastases were detected by chest x-ray, tomography and bronchial arteriography. All metastatic lesions were replaced by fibrous change 7 months after the four bronchial arterial infusions (BAI) of ADM 30 mg and irradiation with a dose of 5,000 rads to each lesion. After 9 tumor-free months, recurrence of pulmonary metastases were pointed out by chest x-ray and tomography. They (four coin lesions) were treated with anticancer therapy, mainly irradiation and twice insufficient BAI. Three of them were occupied entirely by fibrous change and another solid one remained in the right pulmonary apex without enlargement for the past 4 months. Radical nephrectomy and partial resection of the liver for the primary renal cell carcinoma with direct invasion to liver, BAI and irradiation for the two pulmonary metastases have kept the patient alive for 4 years.

[Clinical observation of urolithiasis in Mie University Hospital].

The urinary tract calculus patients seen at our Department between January, 1974 and December, 1983 were reviewed to determine the trend of urolithiasis. The urinary tract calculus patients accounted for 10.1% of all the outpatients. Recurrent calculus diseases were seen in 16.9% of male patients and in 12.1% of female patients. The frequency of recurrence was very high in the patients in their forties. Upper urinary tract calculi were seen most frequently in the patients in their forties. We could expect spontaneous passage of stone for at least 6 months in the case of a middle-sized stone (less than 6 X 10 mm). The percentage of calcium oxalate-containing stone was 73.2% in male patients and the percentage of phosphate-containing stones was 81.6% in female patients. Hypercalciuric patients were seen in 34.0% of the calculus inpatients. Urinary bacterial culture revealed positive in 33.0% of the calculus inpatients.

[Immunohistochemical study of PCNA, EGFR, c-erbB-2 and p53 in carcinomas of large intestine].

Immunohistochemical stainings for EGFR, c-erbB-2, p53 and PCNA were performed on 36 and 30 cases of intramucosal and advanced carcinomas of large intestine. Positive rate was 58.3%, 41.6%, 58.3% and 60.6% for EGFR, c-erbB-2, p53 and PCNA in the intramucosal cases, and 66.7%, 50%, 66.7% and 72.6% in the advanced ones, respectively. Relationship between EGFR and c-drbB-2 was more significant in the advanced carcinomas than that in the intramucosal ones. It seemed likely that relationship between p53 and c-erbB-2 was more significant than that between p53 and EGFR. Positive rate of PCNA was of intimate relationship among that of EGFR, c-erbB-2 and p53, and the positive rate increased in the advanced carcinomas.

[Recent advances in imaging diagnosis of pancreatic neoplasma with special reference to early diagnosis of the cancer].

Recent advance in various diagnostic imagings has enabled the early diagnosis of pancreatic tumors. In pancreatic cancer, the tumor-demonstrability by US, CT, and MRI has reached 80% in the recent 6 years, which is superior to the rate in the past decade from 1978 and 1987. However, the prognosis of pancreatic cancer is still poor even if the cancer can be resected. To improve the outcome of surgical intervention, early detection of small cancers (< or = 2 cm in diameter) and appropriate intervention based on preoperative diagnosis of the tumor extension are proposed. The tumor detectability of small pancreatic cancer by US, CT, MRI was 67%, 25%, 20%, respectively, and thus US was the most valuable tool. In the prediction of tumor extension of serosal invasion (S factor), retroperitoneal invasion (Rp factor) and vessel invasion (PV factor), both US and CT were efficacious with an accuracy of more than 70%. In conclusion, recently-advanced imaging seems to be useful for detecting a small pancreatic cancer and evaluating the tumor extension, but it remains difficult to diagnose a carcinoma in situ; a truly early cancer.