Teruo Shima

Protein C activation in NIDDM patients

Summary Enhanced activation of the clotting system has been recently implicated in the pathogenesis of vascular complications in patients with diabetes mellitus. Abnormalities of the anticoagulant system may constitute a potential trigger factor for the haemostatic activation observed in diabetic subjects. The current study aimed to evaluate anticoagulant activity in diabetic patients by assessing the plasma levels of activated protein C-protein C inhibitor complex; and by measuring the anticoagulant response to exogenous thrombomodulin. This study comprised 61 patients (34 men, 27 women) with non-insulin-dependent diabetes mellitus (NIDDM) of whom 22 showed microalbuminuria and 39 normoalbuminuria. Data obtained in 31 non-obese and non-diabetic subjects were available for comparison. The plasma levels of fibrinogen (p < 0.02), prothrombin fragment 1 + 2 (p < 0.05), fibrin monomer (p < 0.0001), protein C antigen (p < 0.005), total protein S antigen (p < 0.02), soluble thrombomodulin (p < 0.005) and soluble E-selectin (p < 0.005) were significantly higher in diabetic patients than in healthy subjects. The plasma level of activated protein C-protein C inhibitor complex (7.4 ± 3.8 vs 3.0 ± 0.4 pmol/l) was significantly higher (p < 0.0001) and the anticoagulant response to exogenous thrombomodulin (23.4 ± 2.6 vs 35.3 ± 3.0 ng/ml) was markedly lower (p = 0.005) in all diabetic patients than in healthy subjects. Cases with microalbuminuria presented low plasma levels of activated protein C-protein C inhibitor complex (5.5 ± 0.6 vs 8.6 ± 0.7 pmol/l, p < 0.05) and significantly decreased values of the anticoagulant response to exogenous thrombomodulin (16.5 ± 2.9 vs 23.4 ± 2.6 %, p = 0.03) as compared to those with normoalbuminuria. The present study suggests that the hyper-coagulable state in NIDDM is associated with an increased activation of protein C but with a poor plasma reactivity to the anticoagulant effect of thrombomodulin. [Diabetologia (1996) 39: 1455–1461]

Helicobacter pylori infection in patients with gastric carcinoma in biopsy and surgical resection specimens

The discrepancy between the high seropositivity for Helicobacter pylori (H. pylori) and the low diagnostic yield of H. pylori organism in gastric biopsies of patients with gastric carcinoma has yet to be clarified. The present study attempted to clarify this controversial point by performing a comparative evaluation between the detection rate of H. pylori in biopsy and in surgical specimens.

Alteration of Coagulation and Fibrinolysis Systems After Multidrug Anticancer Therapy for Lung Cancer

Recently, an increased frequency of thromboembolic events has been reported after the administration of anticancer drugs. The precise mechanism by which these vascular phenomena occur is unknown. The current work aims at evaluating the alterations of the coagulation and the fibrinolysis systems during the administration of antineoplastic agents by means of newly developed markers of haemostasis. This investigation comprised 25 lung cancer patients treated with multidrug combination chemotherapy. D-dimer, plasmin-alpha 2-antiplasmin complex, fibrin degradation products, fibrinogen, antithrombin III, thrombin-antithrombin III complex, prothrombin time and activated partial thromboplastin time were measured from samples taken before and on days 2, 5, 7, 14 and 21 after the administration of antineoplastic drugs. A significant reduction in plasma concentration of fibrinolytic activity markers, DD and PAP, was observed on days 5 and 7, and on days 2, 5, 7 and 14, respectively, following the administration of chemotherapeutic drugs. Statistically significant shortening of PT and APTT on days 2, 5, 7 and 14, as well as significant elevation of the thrombin generation marker TAT were observed on days 5 and 7 after chemotherapy. These results show that relatively higher levels of coagulation activation and a lower fibrinolytic activity occur during cytotoxic drug therapy compared with basal values. Small variations of haemostatic values and a short follow-up period may explain why no thrombotic events were observed during this study. Although further studies must be done to clarify these findings, the results of this investigation suggest that an imbalance of the coagulation-fibrinolysis system might be a contributing factor in the pathogenesis of thrombotic complications during chemotherapy.

High plasma level of plasmin-α2-plasmin inhibitor complex is predictor of poor prognosis in patients with lung cancer

The occurrence of thrombotic complications is commonly associated with poor prognosis in patients with malignancy. However, the prognostic significance of the subclinical activation of the clotting system, frequently observed in cancer patients, is unknown. The purpose of the present study was to evaluate the value of the pre-thrombotic state for predicting survival of lung cancer patients. This investigation comprised 70 lung cancer patients without clinical or laboratory diagnosis of intravascular coagulation. There were 49 cases with non-small and 21 with small cell carcinomas. Samples taken in controls were available for comparison. The clotting system was assessed measuring thrombin-antithrombin III complex (TAT) and plasmin-alpha 2-plasmin inhibitor complex (PAP). The independent value of these clotting markers to predict survival was evaluated in relation with previously well-established prognostic factors for lung cancer patients. Plasma concentration of each parameter was significantly higher in cancer patients as compared to that of controls. The plasma level of PAP was a predictor of survival independently from the stage of disease, sex, age, histological type, performance status, tumor size and the presence of distant metastasis. Discriminant analysis of PAP plasma concentration identified 2 groups with significant difference in survival rate in all patients, cases in advanced stages of disease and in those with small and non-small cell lung cancer. The results of the present study showed prognostic significance of the subclinical activation of the clotting system, particularly of the fibrinolytic pathway, in lung cancer. Newly developed markers of fibrinolysis might be potentially applicable for predicting outcome in malignancy.

Acromegaly and Hyperthyroidism Associated with McCune-Albright Syndrome

A 36-year-old man is described having McCune-Albright syndrome, acromegaly likely due to somatotroph hyperplasia and hyperthyroidism due to adenomatous goiter. Sexual precocity was not noted. The sella was narrow in size and no mass was seen. The decline of elevated GH by hyperglycemia and increase by GHRH-44(NH2) may support somatotroph hyperplasia, but plasma GHRH-44(NH2) levels were not elevated. A mass in the right lobe and enlargement of the left lobe of the thyroid were noted. Thyroid hormone levels in serum and thyroidal radioiodine uptake values were elevated, while TSH measurements in serum were low. The radioiodine scan showed a cold nodule in the right lobe and a hot area in the left of the thyroid. Thyroidal radioiodine was not suppressed following T3 given orally. These findings are compatible with functioning glands autonomously as the mechanism for the endocrinopathies associated with the McCune-Albright syndrome.

High acid secretion may protect the gastric mucosa from injury caused by ammonia produced by Helicobacter pylori in duodenal ulcer patients

The aim of the present study was to investigate the mechanism by which gastric atrophy does not tend to occur in patients with duodenal ulcer despite frequent Helicobacter pylori infection. This investigation was performed in 60 patients with duodenal ulcer and 63 age‐matched gastritis patients. Endoscopic findings in the antrum and corpus were classified as normal, atrophic and superficial changes. Biopsy specimens were taken from the antrum and corpus. Ninety per cent of patients with duodenal ulcer and 63.5% of patients with gastritis had H. pylori infection (P<0.01). The incidence of normal findings in duodenal patients was 30% in antral regions and 50% in the corpus (P<0.05). Atrophic change was observed in 21.7% of patients in the antrum and 3.3% of patients in the corpus (P<0.01). The grade of inflammation in duodenal ulcer specimens was significantly higher in the antrum than in the corpus (P<0.01). >H. pylori density was significantly higher in the antrum than in the corpus in ulcer patients (P<0.01). No significant difference in endoscopic findings, >H. pylori density or the grade of inflammation was found between the antrum and corpus in patients with gastritis. The mean intragastric ammonia concentration was 10.3 mg/dL in duodenal ulcer patients and 6.2 mg/dL in gastritis patients (P<0.01). The mean pH was 3.5 and 4.6 in ulcer and gastritis specimens, respectively (P<0.01). Our data suggest that gastric mucosa injury is less frequently associated with duodenal ulcers than with gastritis due to the low >H. pylori density in the corpus and to the higher acid output that neutralizes the ammonia produced by H. pylori.

A case of allergic liver injury induced by tegafur.

A 51-year-old woman constitutionally susceptible to allergy presented with acute allergic liver injury. She was taking tegafur for treatment of carcinoma of the uterus. The acute liver injury appeared 3 weeks after the first drug administration. She had marked elevation of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT), moderate jaundice, and eosinophilia. The virus markers revealed hepatitis B surface antigen (HBsAg) (-) antibody to hepatitis B surface antigen (HBsAb) (+), and immunoglobulin M HA antibody (IgM HA Ab) (-). The laparoscopic and histologic findings were compatible with drug-induced liver injury. Further, the results of the lymphocyte stimulation test (LST) and challenge test by tegafur were positive. From the above findings, the liver injury was diagnosed to be an allergic reaction induced by tegafur. The hepatic function returned to normal about 20 days after tegafur administration was suspended. Allergic liver injury induced by tegafur is very rare. We report the case with a short review of the literature.

A Possible Relationship between Cord Blood Transferrin and Birth Length in Infants

Cord blood levels of transferrin (Tf) and insulin-like growth factor I (IGF-1) were measured in 33 normal and 12 preterm infants. Tf was measured by the single radial immunodiffusion technique, while IGF-1 was measured by specific RIA. Tf levels in normal term infants (195 +/- 27 mg/dl) were significantly below normal adult levels (261 +/- 12 mg/dl). Tf levels in preterm infants (159 +/- 30 mg/dl) were lower than those in normal term infants. Tf levels showed a positive correlation with birth length, weight, gestational age and albumin levels in all infants. There was no correlation between Tf and IGF-1 levels in term and preterm infants.

Serum 7S domain of type IV collagen levels in essential hypertension and hypertensive type 2 diabetic patients

Metabolic alteration of Type IV collagen occurs in micro‐ or macrovascular basement membrane of diabetic patients. Hypertension, a risk factor for clinical progression of diabetic vascular disease, may influence this metabolic alteration. The object of this study was to evaluate the serum 7S domain of type IV collagen (7S‐collagen) levels in patients with essential hypertension and in Type 2 diabetic patients with or without hypertension and to investigate the relationship between the type IV collagen metabolism and the arterial blood pressure. Serum 7S‐collagen levels in 18 patients with essential hypertension were significantly higher than in 24 normal subjects (4.2 ± 0.5 vs 3.6 ± 0.4 ng ml−1 p < 0.01). Serum 7S‐collagen levels in 28 normotensive diabetic patients (4.2 ± 0.5 ng ml−1) were significantly higher than in normal subjects (p < 0.01). The serum 7S‐collagen levels were significantly higher in 22 diabetic patients with hypertension (4.8 ± 0.6 ng ml−1) than in the other groups. There was a significant correlation between the serum 7S‐collagen levels and the systolic blood pressure in cases with essential hypertension (r = 0.59, p < 0.001) and in all diabetic patients (r = 0.52, p < 0.001), suggesting that elevation of the systolic blood pressure may influence the type IV collagen metabolism of vascular basement membrane. We conclude that the metabolic alteration of basement membrane occurring in patients with diabetes mellitus may worsen in the presence of high systolic blood pressure. © 1997 by John Wiley & Sons, Ltd.

Studies on liver hexokinase

It has been actively studied in many laboratory to differentiate alkaline phosphatase isoenzymes in serum by using electrophoretic techniques, while it also became interesting problem to separate the several types of alkaline phosphatase by heating and chemical inhibitors. Eight cases (such as 3 ofhepatoma, 1 of gastric cancer, 1 &pancreatic cancer, 1 of uterus cancer, 1 of congestive heart failure and 1 of cholangiolitic hepatitis) with relatively heat-stable alkaline phosphatase which had more than 40~ of activity after heating at 56~ for 15min. are observed in 250 cases. Seven cases out of them were died within 2 months and it seems that presence of these relatively heat-stable alkaline phosphatase is a valuable fact for determining prognosis of the patients with severe disease. Serum from 22 cases who had malignancy and died showed remarkable changes of nature of alkaline phosphatase against several inhibition techniques, compared with normal serum. These serum alkaline phosphatase were quite sensitive against inhibition by EDTA, while were relatively stable against heating. Therefore, remarkable difference in ratio of EDTA stable activity/heatstable activity (56~ 15 rain.) was observed and it was 0.47 in these cases, compared with 1.10 in normal subjects and 1.57 in liver cirrhosis. In eight cases which were mentioned above, showed quite low value (0.19) in this ratio. It seems that this ratio is also useful tool for determining the prognosis of patients with malignancy. It is quite difficult question why these characteristic alkaline phosphatase appear in serum of the patients with malignancy or severe disease. More studies are required to dissolve this problem. It was quite interesting data which bile in gallbladder had heat-stable alkaline phosphatase, although liver enzyme was sensitive against heating.