Changes of plasma L-arginine levels in spontaneously hypertensive rats under induced hypotension.

Nicardipine, a dihydropyridine type calcium channel blocker, was infused at two flow-rates into spontaneously hypertensive (SH) and control normotensive Wistar-Kyoto (WKY) rats (young, 6-week-old and adult, 23-week-old, n = 5) under pentobarbital anesthesia, to cause hypotension. Mean arterial blood pressure and the concentrations of plasma amino acids and norepinephrine (NE) were measured before infusion and at each step of the infusion. The reduction in blood pressure caused by nicardipine induced a decrease in plasma L-arginine concentration in both young and adult SH rats, this effect being larger in adult rats. There was no significant change in plasma levels of L-arginine in age-matched WKY rats. The concentration of other amino acids did not change in both rat strains. On the contrary, there was an increase in plasma NE concentration in both SH and WKY rats after infusion with nicardipine. Plasma L-arginine concentration showed a good inverse correlation with the logarithm of plasma NE concentration in SH and WKY rats and the correlation was expressed as Y = -alpha log(X) + m (Y, plasma L-arginine concentration (nmol/mL); X, plasma NE concentration (pmol/mL); alpha, a slope; and m, an intercept). alpha, 43.0 and 4.35 for 23-week-old SH and WKY rats, respectively, and 17.0 and 4.0 for 6-week-old SH and WKY rats, respectively. The present data together with previous data suggest a direct noradrenergic stimulation of the synthesis of nitric oxide (NO) from L-arginine. The findings also indicate an impairment of the L-arginine metabolism or pools in SH rats compared with WKY rats. The deficiency of L-arginine increases with the age of SH rats and could be related to the development and maintenance of hypertension due to inefficient production of NO.

Age-related weakening of baroreflex-mediated sympathetic activity in spontaneously hypertensive rats in response to blood pressure reduction.

Nicardipine, a dihydropyridine type calcium channel blocker, was infused into 4-, 6-, and 23-wk-old spontaneously hypertensive (SH) and age-matched normotensive Wistar-Kyoto (WKY) rats (under sodium thiobutabarbital anesthesia and ventilation, n = 4) through the left femoral vein, resulting in the reduction of blood pressure. In each rat, mean arterial blood pressure, heart rate, and the concentration of plasma catecholamines (CAs), norepinephrine (NE), and epinephrine (E) were concomitantly determined, and the correlations between these three variables were studied. During the infusion of nicardipine, the plasma concentration of CAs was measured with an automatic detection system in blood samples collected from the right femoral artery of each rat. The reduction in blood pressure induced by nicardipine brought about an increase in plasma CA levels. The blood pressure correlated well with the logarithm of plasma NE or E concentration according to the formula Y= -alpha log (X) + m (Y, blood pressure; X, concentration of plasma NE or E; a, slope; and m, intercept). The slopes (as) of 6-wk-old and 23-wk-old SH rats were significantly greater than those of aged-matched WKY rats, meaning that the increment in plasma CAs in response to a decrease in blood pressure was smaller in SH than in WKY rats of similar ages. However, no significant differences were found between the as of 4-wk-old SH and WKY rats. We conclude that the increment in the baroreflex-mediated sympathetic activity in response to a drop in blood pressure induced by nicardipine is similar or greater in prehypertensive SH than in normotensive WKY 4-wk-old rats, while the increment becomes smaller in SH rats with the onset of hypertension (6-wk-old rats), and is much less in fully hypertensive adult (23-wk-old) SH rats than in age-matched WKY rats. On the basis of these findings and previous data obtained by neurography, we conclude that plasma CAs can be used to evaluate baroreflex-mediated sympathetic activity countering the blood pressure reduction caused by calcium antagonists.

[Clinical significance of serum soluble interleukin-2 receptor (sIL-2R) determination in patients with rheumatoid arthritis].

It has been recently shown that soluble interleukin-2 receptor (sIL-2R) is related to the pathogenesis of autoimmune diseases. We determined serum levels of sIL-2R in patients with rheumatoid arthritis (RA). Fifty-three patients (3 males and 50 females from 35 to 70 years old) and sex- and age-matched 50 healthy subjects were included in this study. The sIL-2R concentrations positively correlated with Lansbury index of RA (r = 0.602, p < 0.01). There was a significant correlation between sIL-2R levels and the prevalence of CD3+.HLA-DR+ lymphocytes (r = 0.420, p < 0.01).

Effect of barnidipine on blood flow to major organs and renal function in anaesthetized dogs and spontaneously hypertensive rats.

1. The effects of barnidipine on blood flow to major organs and on renal function were investigated in anaesthetized dogs and conscious spontaneously hypertensive rats (SHR), and the results were compared with those for nicardipine, nitrendipine, nisoldipine, manidipine and amlodipine. 2. In anaesthetized dogs, barnidipine (0.3-3 mu g/kg i.v.) dose-dependently decreased blood pressure and increased or preserved blood flow in the vertebral, coronary, femoral and renal arteries. The effect of barnidipine on blood flow was the most potent of the compounds tested. In conscious SHR, barnidipine (0.3-3 mg/kg p.o.) produced a dose-dependent antihypertensive effect and decreased renal vascular resistance. Barnidipine also dose-dependently increased urinary volume. The antihypertensive and diuretic effects of barnidipine were the most potent of the drugs tested. 3. In summary, barnidipine was shown to preserve or increase blood flow to major organs and to produce diuretic activity with a decrease in blood pressure. These findings suggest that barnidipine maintains or promotes renal function at antihypertensive doses.

Primary osteosarcoma of the skull--a case report and review of the literature.

Primary osteosarcoma of the skull (POS) in a young man with intracranial involvement is reported. After an initial transient remission by surgical intervention and chemotherapy, he began to deteriorate due to tumor recurrence and intracranial hemorrhage, and died 15 months following the time of diagnosis. The rarity and poor prognosis of POS are emphasized together with the review of the clinical and therapeutic aspects in the previously reported 98 cases in the literature.

[Changes in serum cytokine levels in patients with malignant bone and soft tissue tumors in the course of chemotherapy].

We studied seven patients with malignant bone and soft tissue tumors to examine the influence of chemotherapy on production of serum cytokines. Four types of cytokines (IL-1 beta, IL-2, IL-6, TNF alpha) were measured by ELISA method. A significant increase of IL-6 and TNF alpha production was observed after intravenous infusion of antitumor drugs. After intraarterial infusion of drugs there was a slight increase in the production of these cytokines. On the other hand, there were no changes in the IL-1 beta and IL-2 levels after infusion of the drugs. IL-6 and TNF alpha increased almost at the same time that the numbers of WBC (neutrophils) decreased after infusion. And this phenomenon was clear in the patients who had a good performance status.

[A clinical study of the continuous intra-arterial infusion chemotherapy of Ewing's sarcoma].

Eight cases of Ewing's sarcoma were treated by continuous intra-arterial infusion chemotherapy (i.a. infusion). Five cases gave no evidence of disease (mean 4 yr. 7 mos.), and 3 cases died (3 mos, 1 yr. 11 mo, 2 yrs. 5 mos.). The term of i.a. infusion was 3 mos. to 2 yrs. 3 mos. (mean 12 mos). Except in 2 cases, the primary tumors were suppressed by i.a. infusion, so these cases were not operated and no relapse resulted. The cumulative survival rate by Kaplan-Meier's method was 56.3%. The i.a. infusion for Ewing's sarcomas implies the possibility of limb-saving treatment with no operation.

[Clinical studies on preoperative continuous intra-arterial chemotherapy in the treatment of malignant soft tissue tumors].

Preoperative continuous intra-arterial chemotherapy combined with surgery in the treatment of malignant soft tissue tumors has been used since 1971 in our clinic. We treated thirty-eight patients, and twenty-five of them underwent preoperative intra-arterial chemotherapy and surgery. The diagnoses were liposarcoma (5), synovial sarcoma (4), rhabdomyosarcoma (2), angiosarcoma (2), malignant schwannoma (2), malignant lymphoma (2) and 8 other types of tumors. From the standpoint of local failures, there was only one recurrent case. Eighteen patients are alive now without evidence of disease. The 10-year cumulative survival rate for cases treated with intra-arterial chemotherapy was 69.5%, as compared with 24.9% of cases without intra-arterial chemotherapy. Therefore we conclude that preoperative continuous intra-arterial chemotherapy is a very effective method in the treatment of malignant soft tissue tumors.

[Continuous intra-arterial infusion chemotherapy for malignant bone and soft tissue tumors in pelvis and trunk areas].

We evaluated the effectiveness of intra-arterial infusion chemotherapy for 21 cases of malignant bone and soft tissue tumors in the pelvis and trunk areas. Eight cases are alive for one or two years without operation. In all cases, pain was decreased and quality of life improved. We concluded that intra-arterial infusion chemotherapy is one of the useful treatments for malignant bone and soft tissue tumors in the pelvis and trunk areas.

Radioimmunoassay of human pancreatic amylase with monoclonal antibody.

A monoclonal antibody (E-21) was obtained that specifically binds to human pancreatic amylase and shows negligible cross-reaction with human salivary amylase. Using this antibody a radioimmunoassay was developed for pancreatic amylase in human serum. The assay was shown to be sensitive (detectable up to 7 mg/L), reproducible, and specific for pancreatic amylase. In normal subjects, the mean concentration of serum pancreatic amylase determined by this method was 36.3 mg/L with a 95% confidence range of 16.5 to 79.2 mg/L. A good correlation was observed between the concentrations of immunoreactive pancreatic amylase (IR-PA) and enzymatic activities in 20 serum samples (r = 0.97). The concentration of serum IR-PA was below the detectable limit in pancreatectomised patients, and was greatly increased in patients with acute pancreatitis; the latter was accompanied by parallel changes in total enzymic activity. In patients with mumps, the serum IR-PA level was within the normal range whereas the total enzymic activity was elevated.

[Preoperative continuous intra-arterial infusion chemotherapy as part of a local regional treatment of osteosarcoma of the extremities].

Preoperative continuous intra-arterial chemotherapy combined with surgery in the treatment of osteosarcoma has been since 1968 in our clinic. Sixty-three cases with osteosarcoma of the extremities were evaluated in this study. Eighteen of these cases underwent limb salvage procedures. There were three intralesional, eleven marginal and four wide excision cases. From the standpoint of local failures, there were only two recurrent cases. One occurred after a marginal excision and the other after an intralesional excision. The 5-year cumulative survival rate for limb salvage cases was 56.0%, as compared with 40.6% of the amputation cases. Therefore we conclude that preoperative continuous intra-arterial infusion chemotherapy is a very effective method as a local regional therapy for osteosarcoma of the extremities.

[Limb-saving surgery of malignant bone tumors using massive bone grafts].

The artificial materials in limb-saving surgery pose problems such as the age of patient, tolerance and stability. Thus, massive bone grafting should be reconsidered. In our clinic, out of 78 patients having malignant bone tumors, 29 received limb-saving surgery, and 10 of these cases received massive bone grafting using autografts and/or frozen allografts between 1968 and 1987. There were 7 cases with osteosarcoma, 1 case with mesenchymal chondrosarcoma, 1 case with leiomyosarcoma and 1 case with malignant fibrous histiocytoma. There were 5 males and 5 females ranging in age from 11 years to 44 years, and averaging 21 years. According to Enneking's staging system, these were all II-B cases. The median follow-up period was 71 mos, ranging from 13 to 239 mos. According to the modified Amago evaluation method, 80% of these cases had an excellent prognosis, one had a recurrence, but in all cases good bone union and stability were achieved without immunological reaction. Therefore we conclude that massive bone grafts in cases of malignant bone tumor surgery is a very beneficial method.

[99mTc-MAA perfusion studies in the treatment of preoperative intra-arterial infusion chemotherapy of malignant bone and soft tissue sarcoma].

Preoperative intra-arterial continuous chemotherapy combined with surgery in the treatment of malignant bone and soft tissue sarcomas has been used since 1968 in our clinic. This approach offers a theoretical advantage over systemic chemotherapy in that it delivers higher concentrations of chemotherapeutic agents to the tumor bed without increasing systemic toxicity. Tumor response depends on tumor sensitivity and the maximum amount of agent which is deliverable to the tumor tissues, so it is important to maintain a proper catheter placement to obtain good tumor response. 99mTc-Labeled macroaggregated albumin (99mTc-MAA) perfusion studies were carried out 19 patients who had histologically proven malignant bone and soft tissue sarcomas. The use of 99mTc-MAA perfusion studies in the treatment of intra-arterial chemotherapy offers an excellent way to evaluate catheter placement and tumor perfusion, in addition to providing a way to evaluate tumor A-Vshunts with lung scanning. The dynamic images of 99mTc-MAA obtained at each stage of the chemotherapy period also demonstrate the degree of tumor tissue response to intra-arterial chemotherapy. Therefore we conclude that 99mTc-MAA perfusion combined with preoperative intra-arterial infusion is a very useful method in cases involving limb salvage surgery.

[Clinical evaluation on the sensitivity test for anti-cancer agents in malignant bone and soft-tissue tumors].

We will report the result obtained from sensitivity tests on various anti-cancer agents for malignant bone and soft-tissue tumors based on SDI (Succinic Dehydrogenase Inhibition Test) method with the use of enzymic activities as marker since 1976. Our study comprised 27 cases altogether 15 cases of osteosarcoma, one case each of Ewing's sarcoma, malignant fibrous histiocytoma and malignant lymphoma, 3 cases of metastatic bone tumor and one case each of angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, 2 cases of metastatic lung tumor among soft-tissue sarcomas. In all cases, sensitivity tests were done on the tumor tissues according to SDI method at the same time as biopsy for the determination of the appropriate medications. Four to six weeks of pre-operative intra-arterial infusion was done followed by radical operation. The results obtained are as follows. Observing the long-term results between subjects that applied anti-cancer agents decided by sensitivity test and those without sensitivity test. The 5 years cumulative survival rate jumped from 30.5% to 50.5%, showing a clear improvement.

The development of real-time two-dimensional Doppler echocardiography and its clinical significance in acquired valvular diseases. With special reference to the evaluation of valvular regurgitation.

A noninvasive method for real time blood-flow imaging using ultrasound has long been required in the fields of cardiology and cardiovascular surgery. Recently, we developed a method of two-dimensional Doppler echocardiography (hereafter abbreviated as "2-D Doppler") for clinical use which allows us to obtain noninvasively, intracardiac blood-flow images in real time. The main purpose of this paper is to describe the newly developed blood-flow imaging system "2-D Doppler" and to demonstrate its clinical usefulness in acquired valvular diseases, particularly in the evaluation of valvular regurgitation. The device, in principle, combines a conventional pulsed-Doppler system and a newly developed auto-correlator, in which blood-flow images within a given cross section of a beating heart are noninvasively displayed in real time, simultaneously with conventional two-dimensional echocardiograms. The system can provide three kinds of information, direction, velocity and turbulence of blood flow. The 2-D Doppler examinations were carried out on 72 patients with acquired valvular diseases whose diagnoses were confirmed by angiography and/or surgery. Studies were performed comparing the findings of the 2-D Doppler and those of angiography (for aortic and mitral lesions) or with operative findings (for tricuspid lesions) in the quantitative evaluation of valvular regurgitation. Aortic, mitral and tricuspid valvular regurgitation have been quantitatively demonstrated with 2-D Doppler, and, for each value, the severity of the regurgitation showed a high correlation between the findings of 2-D Doppler and of angiography or surgery. In conclusion, we have found that (1) 2-D Doppler is very useful in detecting and estimating the severity of valvular regurgitation, and that (2) 2-D Doppler may replace conventional angiography in some situations.