门静脉注射白细胞介素-12治疗肝转移肿瘤的实验研究

目的　探讨通过门静脉系统局部应用白细胞介素 12 (IL 12 )对于肝转移肿瘤的治疗作用。方法　通过门静脉注射 2× 10 5个MCA 2 0 5肿瘤细胞建立小鼠肝转移肿瘤模型 ,同时脾脏被移植到皮下 ,作为反复多次向门静脉系统注射的途径。第 3～ 7天 ,0 1μgIL 12通过腹腔或脾脏注射 ,同时对照组中通过脾脏注射等体积的平衡盐水。第 2 1天检查肝转移肿瘤的情况。结果　在肝转移模型中 ,IL 12腹腔注射组和IL 12脾脏注射组的肝脏重量 (1 33± 0 0 8)g和 (1 2 9± 0 0 7)g明显小于对照组 (1 92± 0 17)g ,P <0 0 5 ,IL 12腹腔注射组和IL 12脾脏注射组的肝脏转移结节数目 (1 5 3± 0 5 8,0 6 0± 0 89)明显少于对照组 (18 2 5± 5 71,P <0 0 5 )。在IL 12脾脏注射组中 (n =6 ) ,3只小鼠的肝脏肿瘤完全消失。结论　通过门静脉系统局部应用IL 12是治疗肝转移肿瘤的有效方法。     

Prophylactic effect of UFT on the recurrence of bladder cancer

To evaluate the effect of UFT, a mixture of ftorafur and uracil in a ratio of 1:4, in preventing postoperative recurrence of bladder cancer, we performed a randomized controlled study with a non-medication group as control. UFT was given orally 400 mg a day for 6 months. Of 111 patients, 56 were given UFT and 55 were followed up without any medication. The non-recurrence rate in the group treated with UFT was 62.8% after 1 year and 36.3% after 2 years of follow up, and that of the control group was 45.7% and 39.5%, respectively. The rate of non-recurrence in the UFT group was significantly higher (p less than 0.05) than that of the control group during the period of follow up for 2 years. The incidence of side effects was 6.8% in UFT patients. These results indicate the clinical usefulness of prophylactic administration of UFT for bladder cancer patients.     

Effect of systemic zinc administration on delayed neuronal death in the gerbil hippocampus

The divalent cation zinc has been reported to possess several physiological properties such as blocking apoptotic cell death through an inhibitory effect on Ca²⁺-Mg²⁺ endonuclease activity, or modulating the neurotoxicity via glutamate receptor subtypes. In the present study, we investigated the effect of peripherally injected zinc on delayed neuronal death seen in the hippocampus after transient global ischemia, in order to elucidate a possible beneficial role on zinc in ischemic neuronal cell death. Forty-five adult Mongolian gerbils of both sexes underwent transient bilateral clipping of the common carotid arteries for 3 min. In the pretreated animals, ZnCl₂ (20 mg/kg) was injected subcutaneously once, 1 h before ischemia (superacute group; n=6) or twice at 24 and 48 h before ischemia (subacute group; n=14). Histological survey was carried out 3 days later by in situ DNA fragmentation method and 4 days later by hematoxylin-eosin staining by semiquantatively counting dead neurons in the CA1 sector. Subacute zinc pre-administration significantly reduced the nuclear damage and subsequent neuronal death; however, superacutely pre-administered zinc did not protect hippocampal neurons against ischemia but it did not aggravate the effect of ischemia, either. The present study suggested that transfer of exogenous zinc into the intracellular space is required for neuroprotection, presumably via the anti-endonuclease activity.     

DIFFERENCES IN ENDOTHELIUM-DEPENDENT RELAXATION IN VARIOUS ARTERIES FROM WATANABE HERITABLE HYPERLIPIDAEMIC RABBITS WITH INCREASING AGE

1. Endothelium-dependent relaxation in response to acetylcholine (ACh) and the calcium ionophore A 23187 was examined in aorta, coronary, basilar and renal arteries isolated from Watanabe heritable hyperlipidaemic (WHHL) rabbits of 2, 6 and 12 months of age, with normolipidaemic heterozygous WHHL rabbits as controls. 2. In the rings of WHHL rabbit aortae and coronary arteries preconstricted with vasoconstrictors, endothelium-dependent relaxation in response to ACh was attenuated with age compared to the heterozygous WHHL rabbits. A significant negative correlation was found between the total cholesterol content and the relaxation response to ACh in the aortae or coronary arteries from 6 and 12 month old WHHL rabbits. 3. In the rings of basilar arteries, endothelium-dependent relaxations to ACh were not modified with age. Similarly, in the rings of renal arteries, the relaxation response to ACh was not changed with age, but in the 6 and 12 month preparations, after the age of 6 months, a contraction following the relaxation appeared at higher concentrations of ACh (10^?7 to 10^?6 mol/L). The contraction was endothelium-dependent and inhibited by indomethacin. 4. A 23187-induced endothelium-dependent relaxations were also markedly attenuated in the aorta and significantly in the coronary artery with age. 5. Endothelium-independent relaxation to sodium nitroprusside was not changed in all arteries from WHHL rabbits of different ages. 6. These findings indicate that in the aorta and coronary artery of the WHHL rabbit, the endothelium-dependent relaxation to ACh and A 23187 becomes impaired with increasing age (i.e., with the progression of cholesterol deposition in the arterial wall) but is preserved in the basilar and renal artery.     

Aggressive resection for advanced pancreatic carcinoma

An aggressive pancreatectomy was performed on a 53 year old Japanese man with advanced cancer of the pancreas. The tumor originated from the body of the pancreas and invaded the stomach, duodenum, left kidney, transverse colon and common hepatic artery. An unexpected cancer was also found in the head of the pancreas during the operation. Therefore, total pancreatectomy, total gastrectomy, left adrenonephrectomy, resection of the left transverse colon and dissection of the regional lymph nodes were performed. Resection of the common hepatic artery was also performed, followed by an end-to-end anastomosis between the common hepatic artery and celiac trunk. The postoperative course was uneventful and the patient was doing well until nine months after the operation when multiple metastatic lesions were noted in the liver. He died 391 days after the operation from hepatic failure.     

Effects of elevated d-alpha(RRR)-tocopherol dosage in man

A study was conducted to investigate the effects of a megadosage of free RRR-alpha-tocopherol in healthy college student volunteers. Of 19 volunteers, 14 were given daily doses of 600 mg (900 IU) of RRR-alpha-tocopherol for 12 weeks, and the remaining 5 were given identical placebo capsules. The investigation was performed by the single-blind method. Alpha-tocopherol levels were measured in plasma, red blood cells (RBCs), platelets, leucocytes (WBCs), and buccal mucosal cells. Alpha-tocopherol in plasma, RBCs, and WBCs rose, reached a maximum level 4 weeks after commencement of administration, and then remained at a plateau, while platelet and buccal cell levels reached a maximum level after 12 weeks of administration. The maximum levels in all the subjects were 2.5 to 3 times the baseline values. During the study, there were no changes in laboratory values for thyroid, liver, or kidney functions, and coagulation activity (including the vitamin K-dependent Hepaplastin test and PIVKA-II) or immunoglobulin levels. Healthy status continued without any abnormal symptoms, and without any subjective complaints on the questionnaire. In the control group also, no changes occurred during the investigation. Gamma-tocopherol changes were measured in plasma and RBCs. As plasma and RBC tocopherol levels rose after administration, the isomer levels were suppressed in both plasma and RBCs.     

Pressure overload-induced transient oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II.

Oxidative stress is implicated in the pathogenesis of various cardiovascular diseases. We have shown that in Wistar rats with a suprarenal aortic constriction (AC), pressure overload-induced transient perivascular inflammation (monocyte chemoattractant protein-1 [MCP-1] induction and macrophage accumulation) in the early phase is the determinant of reactive myocardial fibrosis and resultant diastolic dysfunction in the late phase. Thus, we investigated the role of reactive oxygen species production in cardiac remodeling in AC rats. Superoxide production and the footprint of lipid peroxidation were assessed using dihydroethidium staining and immunohistostaining against 4-hydroxy-2-nonenal (4-HNE), respectively. In sham rats, dihydroethidium and 4-HNE signals were scarcely found in the heart. At day 3, AC rats showed dihydroethidium signals mainly in the intramyocardial arterial wall, whereas modest 4-HNE staining was observed diffusely in the myocardium. These signals declined to lower levels by day 14 despite sustained hypertension. Chronic administration of a subdepressor dose of an angiotensin II type 1 receptor blocker candesartan reduced the pressure overload-induced dihydroethidium and 4-HNE signals at day 3. Moreover, candesartan decreased MCP-1 induction and macrophage infiltration at day 3 and prevented myocardial fibrosis at day 14, without affecting left ventricle and myocyte hypertrophy. In conclusion, acute pressure overload induced self-limited superoxide production mainly in the vascular wall. The reactive oxygen species production would contribute to the perivascular inflammation and subsequent myocardial fibrosis. Angiotensin II was suggested to have a pressure-independent effect on the reactive oxygen species production.     

Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system.

Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.     

PEUTZ‐JEGHERS SYNDROME ASSOCIATED WITH RENAL AND GASTRIC CANCER THAT DEMONSTRATED AN STK11 MISSENSE MUTATION

A 75‐year‐old male was admitted to the gastroenterology unit of Nagoya City University Hospital due to epigastralgia after surgical treatment for right renal cancer. Endoscopy revealed advanced type 1 gastric cancer in the corpus of the stomach and multiple polypoid lesions in the stomach and duodenum. X‐ray examination of the small intestine using barium showed multiple polyps in the upper jejunum. Faint pigmentation on the palm was also detected. Peutz‐Jeghers syndrome (PJS) was diagnosed, despite a lack of family history. Total gastrectomy, resection of part of the upper jejunum and intraoperative endoscopic polypectomy of duodenal polyps was performed. This is the second reported case of PJS associated with renal cancer. We also detected a missense mutation in the tumor suppressor gene STK11 that, when mutated, is causative for PJS.