Nagoya Journal of Medical Science

1. The effect of tolbutamide on the oxidation rate, respiratory control index and P/0 ratio of intact rat liver mitochondria was studied.
2. Addition of more than 30 mg% tolbutamide apparently increased the state 4 respiration rate and decreased RCI, whereas, 80 mg% tolbutamide decreased markedly the state 3 respiration rate than that of control. State 4 respiration rate was accelerated by adding 100 mg% (3.8 mM) tolbutamide, while state 3 respiration rate was decreased and P/ 0 ratio was reduced to zero showing complete uncoupling.
3. Uncoupling of oxidative phosphorylation by 100 mg% tolbutamide was similar to that of DNP, i.e., sensitive to the addition of rutamyin, 100 mg% tolbutamide can induce ATPase activity of intact rat liver mitochondria, and induced A TPase. activity was reduced to zero by the addition of rutamyin just like DNP. Therefore, uncoupling site by tolbutamide may be close to the DNP sensitive site.

Tolbutamide, one of the hypoglycemic sulphonylurea drugs was fcund to decrease the respiratory control index of beef heart mitochondria as well as that of rat liver mitochondria.
The effect of the drug on beef heart mitochondria was more pronounced than on liver mitochondria in the range of concentrations of 30-80 mg%. It was of interest to find that DNP release of mitochondrial respiration was not observed after the addition of 100 mg% tolbutamide.
These findings were discussed in relation to the side;effect of this drug.

The effect of thiamine and its various derivatives on the respiratory control of rat liver mitochondria was examined. Except TDP all other thiamine derivatives tested were shown to damage mitochondrial respiration. In these experiments DCET and TATD are shown to be strong inhibitors. It was noted that thiamine and its derivatives except TDP have aldehyde group in their chemical structure. Because formaldehyde and acetalhyde are inhibitors to the respiration of the isolated rat liver mitochondria, the aldehyde group in chemical structure is speculated to have some relation to their action on liver mitochondria. Further studies are necessary concerning the mechanism of the inhibitory actions of thiamine derivatives.

Forty-six patients with liver cirrhosis were classified into three groups according to glucose tolerance test and the presence or absence of diabetic state. The results of xylitol tolerance test, galactose tolerance test, BSP retention, ICG disappearance rate and other routine liver function tests were compared between these three groups.
The results show that liver cirrhosis in patients with overt diabetes was less severe than that in non-diabetics. It is conceivable, therefore, that the glucose intolerance in most of the cirrhotic patients with overt diabetes is not due to the so called hepatogenous diabetes, but to essential diabetes with concomitant cirrhosis.
Intravenous xylitol tolerance test may be available for the differential diagnosis of hepatogenous diabetes from essential diabetes with concomitant cirrhosis, since the change in serum glucose level after the administration of xylitol was characteristic in each group. Further studies must be done to substantiate this possibility.

The hemodynamic characteristics and differences after the internal mammary artery-circumflex artery anastomosis and the aorta-circumflex artery bypass graft were evaluated in dogs to determine the indication of these two procedures for clinical application. As a graft, the femoral artery, femoral vein or the cephalic vein was utilized.
In acute experiments, compared to the normal circumflex artery, there were no differences in flow rate and reactive hyperemia between these two procedures. But flow pattern of the internal mammary artery anastomosis was characteristic. In early systolic period the flow increased to the maximal level and decreased in relatively early pericd of diastole.
In chronic experiments, resting flow rate was almost comparable with the normal circumflex flow, but reactive hyperemic augmentation was not sufficient. This may be due to scar formation surrounding the vessels or their intimal thickening. Flow pattern of the internal mammary artery anastomosed to the circumflex artery changed from the immediate postoperative pattern to that resembling that of the normal circumflex artery.
Histological examination revealed a little thicker intimal proliferation in the vein graft than in the internal mammary artery or artery graft.
Presently, the method of the two procedures in which the diameter of the vessel matches the coronary artery proposed the anastomosis, should be utilized in the clinical cases.
Two clinical cases where the right coronary artery was bypassed from the aorta by a saphenous vein graft are reported.

When present, ascites usually disappears after portacaval shunt. In an occasional patient, however, ascites may appear after portacaval shunt even when not present before operation.
This work reviews the mechanisms of ascites formation following patent portacaval shunt. Hepatic hemodynamic studies were performed in 24 patients with alcoholic liver disease.
The results suggest that ascites is more likely to occur after end-to-side portacaval shunt in those patients who maintain a relatively high sinusoidal pressure and hepatic arterial blood flow.

The effect of several hypoglycemic sulphonylureas upon the oxidative phos- phorylation of intact rat liver mitochondria was examined. Following results were obtained and discussed in relation to hypoglycemic action and uncoupling site of these drugs.
1. All hypoglycemic sulphonylurea drugs tested, i.e., tolbutamide, carbutamide, chlorpropamide, acetohexamide, glybenclamide, and glyclopyramide were found to be uncouplers to the intact rat liver mitochonbria.
2. They were also found to decrease respiratory release of 20 ,µM DNP.
3. Sulphonylureas could induce latent ATPase activity of intact rat liver mitochondria. ATPase activity induced by glybenclamide was reduced to zero by the addition of rutamycin just like DNP.
4, Judging from the above data, uncoupling site of sulphonylureas may be near DNP site.

Persistent stimulation of immunocompetent cells, such as histocompatibility reactions, may be one of the causes of neoplastic proliferation of lymphoreticular tissues. In the present studies, the graft-versus-host reaction was induced in 18- week-old male (C 57 Bl/6Jx DBA/2J)F₁ mice·by two or four weekly intraperitoneal injections of approximately 80 x 10⁶ male C 57 Bl/6 J or C 57 Bl/Na mouse lymphoid cells. Some of the recipient mice were treated with amethopterin.
The majority of mice dying soon after injection of parental lymphoid cells showed signs of runt diesase and most animals recovering from the disease survived and were alive at the age of 24 months, at the termination of the experiments. Histological studies of 94 mice of experimental groups revealed lymphomatous changes in 10 mice and a moderate to extensive amyloidosis in 22 mice, with no abnormal changes in 15 untreated control mice. Nine out of 10 lymphomas were Type B, only one being reticulum cell sarcoma, Type A. Five out of 9 Type B lymphomas were associated with amyloidosis. Comparative analysis of mortality rates due to runt disease, and incidences of lymphoma and amyloidosis in each experimental group showed that the r esulting lymphoma incidences were apparently indifferent to the severity of runt disease.
The results obtained in the present studies, together with those in others, suggest that the overt graft-versus-host reaction may not be a necessary pre- condition for increased lymphomagenesis in parental-Ft hybrid chimeras and that factors other than the graft-versus-host reaction itself may also be involved.

Based on the concept that the lymph node is composed of four functionally distinct compartments, popliteal lymph nodes of three week-old rats were studied histologically after a single primary antigenic stimulation. A variety of antigens, i.e., SRBC, pertussis vaccine, bovine γ-globulin, crystalline bacterial amylase, egg albumin, diphtheria toxoid with or without the adjuvant always producerl a consistent pattern of development and involution sequentially in each of four compartments: the paracortical areas were always the first in making response, fol- lowed primary follicles, medullary cords and germinal centers in this order. The mitotic indices in the paracortical areas reached the maximum on the third day whereas the peak activity of the germinal centers was observed between the 1Oth to 24th day.
The development of germinal centers which had not been observed until the late stage might reflect its probable role in the development of immunological memory. The role of paracortical areas in the initiation of "true" primary response was discussed in the light of current theories on the cell-to-cell interaction as well as the relationship between humoral and cell-mediated immune response. This led to postulation that the paracortical hyperplasia was essential for the induction of primary immune response, especially in "true" primary response.