Severe brain atrophy in a case of thalamic variant of sporadic CJD with plaque-like PrP deposition.

A 30-year-old woman presented with ataxic gait and progressive mental deterioration, and 3 years later developed myoclonus in the limbs. Subsequently, she lapsed into an akinetic state and died more than 6 years after the onset of disease. The brain weighed 670 g, and preferential degeneration was found in the medial thalamus and the inferior olivary nucleus. In the cerebrum and cerebellum, gliosis and neuronal depletion were only mild and disintegration of the parenchymal structures was inconspicuous, despite pronounced atrophy. The patient had methionine homozygosity at codon 129 of the PrP gene and protease-resistant PrP type 2 in the brain. On PrP immunostaining, plaque-like deposits were detected in the cerebral and cerebellar cortices. Severe brain atrophy such as in the present case has never been described in the thalamic variant of sporadic CJD.

Antimutagenic activity against trp-P-1 of the edible Thai plant, Oroxylum indicum vent.

A methanolic extract of Oroxylum indicum strongly inhibited the mutagenicity of Trp-P-1 in an Ames test. The major antimutagenic constituent was identified as baicalein with an IC50 value of 2.78+/-0.15 microM. The potent antimutagenicity of the extract was correlated with the high content (3.95+/-0.43%, dry weight) of baicalein. Baicalein acted as a desmutagen since it inhibited the N-hydroxylation of Trp-P-2.

A lectin from an edible mushroom Pleurotus ostreatus as a food intake-suppressing substance.

In an experiment in which rats were allowed free access to food and water, the rats did not eat the diet containing a mushroom Pleurotus ostreatus even if they were emaciated. A P. ostreatus lectin (POL) was isolated from the mushroom as the food intake-suppression principle. In hemagglutination inhibition assays, Me-alphaGalNAc was the most potent inhibitor among the monosaccharides tested. Among all the sugars tested, 2'-fucosyllactose (Fucalpha1-->2Galbeta1-->4Glc) was the strongest inhibitor and its inhibitory potency was five times greater than that of Me-alphaGalNAc. POL exhibited a binding ability to bovine submaxillary mucin (BSM) and asialo-BSM and the other glycoproteins were inert to the binding. The food intake-suppressing activity of POL was dependent on the dose. The diet containing 0.1% POL caused a 50% decrease in the food intake of rats against the control.

Mumefural, citric acid derivative improving blood fluidity from fruit-juice concentrate of Japanese apricot (Prunus mume Sieb. et Zucc).

The effects of food components on blood fluidity were studied by in vitro assay using a dedicated microchannel instrument for model capillaries. We found that the fruit-juice concentrate of the Japanese apricot (Prunus mume Sieb. et Zucc), a traditional Japanese food, markedly improved the fluidity of human blood. Using HPLC, we isolated the active compounds and characterized them using UV, MS, IR, and NMR. They included a novel compound, 1-[5-(2-formylfuryl)methyl] dihydrogen 2-hydroxypropane-1,2, 3-tricarboxylate (mumefural), and a related compound, 5-hydroxymethyl-2-furfural (HMF). Mumefural markedly improved blood fluidity in all subjects, while HMF worked differently in different individuals. The flow rate of blood spiked with mumefural or HMF was compared to that of the two predominant organic acids in the fruit. Citric acid, malic acid, and furfuryl alcohol also improved fluidity in all subjects. The activity of P. mume is derived from not only artifacts produced during thermal processing, such as mumefural, but also from endogenous organic acids.

Extraction and identification of antioxidants in the roots of yacon (Smallanthus sonchifolius).

Yacon, Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson, Asteraceae, an important economic species grown for its juicy tuberous root, is potentially beneficial in the diet to diabetics. The antioxidative activity of yacon root was studied by 1, 1-diphenyl-2-picrylhydrazyl (DPPH) assay. Antioxidants were extracted by methanol and isolated and purified by gel permeation chromatography and preparative reverse-phase HPLC. Two of the major antioxidants were identified as chlorogenic acid and tryptophan by NMR and mass spectrometry.

Phlebosclerosis of the colon with positive anti-centromere antibody.

A 56-year-old woman with symptoms of chronic bowel disease presented a peculiar calcification of the mesenteric vein of the ascending to transverse colon on barium enema study. The resected colon was hard and black. Histo-pathologic examinations demonstrated fibrous change of the colon with a calcified and hyaline-deposited mesenteric vein. No cell infiltration was observed. These findings were compatible with phlebosclerosis and also with systemic sclerosis. Positive anti-centromere antibody and Raynaud's phenomenon, hallmarks of a variant systemic sclerosis, the CREST syndrome were observed. We therefore speculated that the pathogenesis of the phlebosclerosis of the colon is related to the CREST syndrome.

Cloning and expression of the Ca2+ channel alpha1C and beta2a subunits from guinea pig heart.

Complimentary DNA clones encoding the alpha1C and beta2a subunits of guinea-pig cardiac L-type Ca2+ channels were isolated using the PCR method. The open reading frame encoded 2,169 amino acids for the alpha1C and 597 amino acids for the beta2a subunit. The proteins showed 94.2 and 94.8%, respectively, identity to the respective subunit of the rabbit protein. The message size of the guinea pig alpha1C and beta2a subunits was 8.0 and 3.5/4.0 kb, respectively. RT-PCR analysis revealed that the alpha1C subunit is expressed exclusively in the heart, while the beta2a subunit is expressed in the heart, cerebellum, whole brain, and stomach. The alpha1C and beta2a subunits are transiently expressed in BHK (baby hamster kidney) cells, and the channel currents were studied using the whole-cell patch clamp technique in medium containing 30 mM Ba2+. In cells expressing alpha1C alone, the Ba2+ current was activated at -30 mV and more positive potentials and peaked at about 10 mV. The co-expression of beta2a with alpha1C did not affect the voltage-dependence of the current, but increased the peak current and accelerated current decay. In cells transfected with guinea pig alpha1C and rabbit beta1+alpha2/delta, a Ba2+ current comparable to those in native myocytes was observed. The Ba2+ current can be blocked completely by nifedipine and is enhanced 3-fold by Bay K 8644. On the other hand, neither forskolin nor okadaic acid affects the Ba2+ current, suggesting that cAMP-mediated modulation is not easily reproduced in transfected cells, unlike that seen in native cardiac myocytes.

Run-down of the cardiac L-type Ca2+ channel: partial restoration of channel activity in cell-free patches by calpastatin.

We have found previously that run-down of cardiac Ca2+ channels in cell-free patches is reversed by cytoplasm plus adenosine triphosphate (ATP). Characterization of the factor in cytoplasm revealed that it is likely to be calpastatin (CS), an endogenous inhibitor of calpain (Ca2+-activated neutral protease). We therefore investigated the possible restoring effect of CS obtained from various tissues (activity 1.3-23 U/ml) on Ca2+ channel activity after run-down in inside-out patches. Although CS from porcine erythrocytes (plus 3 mM ATP) had only a minimal effect in restoring channel activity (to 4% of the control level recorded before the run-down), CS from porcine heart restored channel activity to 19% of control. The product of recombinant complementary deoxyribonucleic acid (cDNA) of human heart CS, a membrane-bound CS partially purified from bovine heart and CS from rabbit skeletal muscle (Sigma) restored channel activity to 28%, 23% and 10% of control levels, respectively. These results suggest that tissue-type CS, but not erythrocyte-type (truncated) CS, seems to have an effect on the cardiac Ca2+ channel to maintain its activity. Purified CS had relatively small effects compared to that of crude cytoplasm, implying that some other factor(s) might contribute also to the regulation of Ca2+ channel activity.

Regional chemotherapy to prevent hepatic metastasis after resection of pancreatic cancer.

BACKGROUND/AIMS: Liver metastasis is one of the major causes of cancer death after resection of pancreatic cancer. To deal with this problem, we developed a liver perfusion chemotherapy via the hepatic artery and portal vein. The present paper is designed to introduce the technique of this method and report on the promising results. METHODOLOGY: Between 1987 and 1995, 98 consecutive patients with adenocarcinoma of the pancreas received an extended pancreatectomy, in which a wide range of lymphatic and connective tissue clearance was performed in addition to the conventional pancreatectomy, at Osaka Medical Center for Cancer and Cardiovascular Diseases. All patients were followed-up to determine whether and where cancer recurrence developed. RESULTS: Excluding 4 patients who died of postoperative complications, our liver perfusion chemotherapy was performed on 27 patients. The other 67 patients did not receive this treatment. In the group that underwent liver perfusion chemotherapy, no patients experienced complications such as leucocytopenia (< 3000/mm3), thrombocytopenia (< 50,000/mm3), or liver disfunction. The cumulative survival rate differed remarkably between the two groups: 92% vs 62% at one year (p < 0.05); 51% vs 35% at three years (p < 0.05); and 41% vs 25% at five years (ns). CONCLUSIONS: When this method was performed after an extended pancreatectomy for adenocarcinoma of the pancreas, our preliminary report (Am J Surg. 1994; 168:361-364) indicated that it was useful not only for preventing hepatic metastasis, but also for improving patients' survival rate. Since then, further positive and supportive results have been obtained in an additional investigation.

[A case of successful management of advanced cholangiocellular carcinoma by repeated hepatic resection].

A 50-year-old woman with advanced cholangiocellular carcinoma (CCC) underwent extended left hepatectomy and catheterization into the hepatic artery. Following the procedure, intra-arterial infusion chemotherapy of the fluorouracil (5-FU) was performed. This chemotherapy was given 13 times at 2,500 mg for 10 months, so the total dose of 5-FU was 32.5 g. About two years after the operation, the patient underwent hepatic resection again for solitary recurrence of CCC. The prognosis of CCC is very poor. Aggressive surgical resection may be the only method to assure a good outcome. However, the survival rate after curative resection has been low. Adjuvant hepatic arterial infusion chemotherapy after surgery may be effective for a good prognosis.

[Adjuvant chemotherapy for advanced gastric cancer].

For recent 40 years, many authors reported the results of adjuvant chemotherapy for advanced gastric cancer including 5-fluorouracil, uracil and tegafur, mitomycin C, cytosine arabinoside. OK-432 adriamycin, methotrexate, and cis-pltatin in solitary use of combinations. It is difficult to find a standard effective adjuvant chemotherapy for advanced gastric cancer in these reports. The reasons of this unclearness were as follows; (1) In phase III studies, surgery alone was not a control group in some reports. (2) The number of patients was too small to evaluate statistically. (3) Inter-institutional differences had important roles in the results of multicenter study in the other studies. For the future plans on adjuvant chemotherapy, it is important to make a simple designed protocol, and perform it as a multicenter study including institutions with minimum inter-institutional differences.

[Effects of adjuvant surgical therapy for continuous regional therapy for advanced hepatocellular carcinoma].

In order to repeat the effective transarterial embolization (TAE) or regional chemotherapy, adjuvant surgical therapies were performed for 25 patients with advanced hepatocellular carcinomas (HCC) having collateral feeders. The procedures involved the reduction of tumors with collateral feeders, permanent decollateralization using silicone rubber sheeting of the liver (WRAP therapy), and combination therapies. The 1-, 3- and 5-year survival rates of the patients after the adjuvant surgery were 67%, 18% and 5%, respectively. The 3- and 5-year survival rates of the patients after the initial TAE or arterial chemotherapy were 57% and 12%, respectively. On the other hand, the 3- and 5-year survival rates of patients who had TAE alone (n = 443) were 29% and 14%, respectively. Consequently, this adjuvant surgical therapy may be a useful palliative treatment for HCC.

[Preoperative neoadjuvant chemotherapy with a combination of 5-fluorouracil, adriamycin and cisplatin (FAP) for advanced esophageal cancer invading trachea or main bronchus].

Conventional irradiation and systemic chemotherapy is scarcely effective for advanced esophageal cancer invading trachea or main bronchus. Therefore, to reduce the area of invasion and suppress distant metastasis, we have preoperatively treated 4 patients suffering from advanced esophageal cancer invading the trachea or main bronchus by neoadjuvant chemotherapy (FAP) as follows: 2 times every 4 weeks, CDDP 100 mg and ADR 50 mg on day 1 and continuous infusion of 5-FU 1,000 mg/day for 7 days. The response rate (PR) was 75% (3/4). In 2 of 4 patients (50%), no cancer cells except broad fibrosis were detected histologically in the region of the trachea or main bronchus suspected to be invaded. There was no severe complication. This FAP regimen is suspected to be useful chemotherapy for advanced esophageal cancer.

[The efficacy of several kinds of treatment for advanced hepatocellular carcinoma--a report of an over-five-year survivor by regional and systemic chemotherapy and adjuvant surgery].

We encountered a 53-year-old male patient with advanced hepatocellular carcinoma (HCC) uncontrolled by transcatheter arterial embolization (TAE). Numerous tumors with a huge one occupying the lateral segment were shown on abdominal ultrasonogram, computed tomogram and angiogram. The first TAE was ineffective for the lesions because of the development of collateral feeders. Lateral segmentectomy and, "wrapping therapy" for the liver remnant were performed, and catheters were put both into the hepatic artery and into the portal vein for regional chemotherapy. About a year after the procedure, anticancer drugs were administered. When tumor stains were found by following computed tomography or angiography, TAE was performed. The patient has survived for five years and four months. The combination of several kinds of treatment serves to improve the prognosis of patients with advanced HCC if the liver function is preserved.

Liver perfusion chemotherapy via both the hepatic artery and portal vein to prevent hepatic metastasis after extended pancreatectomy for adenocarcinoma of the pancreas.

Since hepatic metastasis is a common cause of treatment failure after curative pancreatectomy for adenocarcinoma of the pancreas, we developed a new method of postoperative hepatic perfusion chemotherapy via both the hepatic artery and portal vein. The present study was conducted to determine if this method decreases the hepatic recurrence and improves the survival rate. Following extended pancreatectomy with wide lymphatic and connective tissue clearance for pancreatic cancer, one catheter was placed in the hepatic artery and one in the portal vein. Immediately after surgery, 5-fluorouracil (125 mg/d) was continuously infused via these two routes simultaneously for 28 to 35 days. There were no treatment-related complications in the 20 patients who survived surgery. The 3-year survival rate was 54%, and the cumulative rate of death from hepatic metastasis was 8%. These figures were significantly better than those of our historical control groups. We conclude that this method should be evaluated in a prospective, randomized controlled study.

[Pharmacokinetics following intraperitoneal sequential administration of cisplatin and fluorouracil for gastric cancer].

Gastric cancer patients with peritoneal dissemination underwent a palliative resection of the stomach and received an intraperitoneal administration of CDDP (70 mg/m2) and 5-FU (700 mg/m2), immediately after the surgery. The levels of CDDP and 5-FU in serum and peritoneal cavity were serially monitored in order to study the pharmacokinetics of these drugs. group A (n = 9): CDDP dissolved in 500 ml saline was infused intraperitoneally at 200 ml/min, and one hour later, 5-FU dissolved in 500 ml saline was infused at the same speed. The infusion catheter was clamped for two hours after completion of 5-FU infusion. Group B (n = 3): CDDP in 500 ml saline were infused at 10 ml/min and then 5-FU in 500 ml were infused at 5 ml/min. Group C (n = 2): CDDP in 1,000 ml saline was infused at 200 ml/min. Group D (n = 2): 5-FU in 1,000 ml saline was infused at 200 ml/min. The free CDDP levels in the peritoneal cavity were 22 micrograms/ml in group A, 57 micrograms/ml in group B, and 13 micrograms/ml in group C at one hour after completion of the infusion. The 5-FU levels in the peritoneal cavity measured two hours after completion of the infusion were significantly higher in the group B (349 micrograms/ml) than in group A (132 micrograms/ml) and C (71 micrograms/ml). The Cmax of 5-FU in serum was lowest in group B. The AUCs in the peritoneal cavity of free CDDP and 5-FU were 63.6 micrograms.hr/ml and 925 micrograms.hr/ml, respectively. These values were above the 10th percentile of IC90 for gastric cancer. No serious complications were encountered in group A and B where both CDDP and 5-FU were administered as compared with group C and D, where either CDDP or 5-FU was administered.

[Evaluation of intra-arterial infusion chemotherapy and radical pancreatectomy in patients with locally advanced pancreatic cancer].

This is a retrospective study to evaluate arterial infusion chemotherapy and resection for locally advanced pancreatic cancer involving retro-peritoneal organs or large vessels such as superior mesenteric artery or celiac trunks. Intra-arterial chemotherapy was performed for 19 patients, and 15 underwent pancreatectomy. Patients in the intra-arterial chemotherapy group could live 11 months out of the hospital, against 4 months in the resected cases (p < 0.05). The period of over 2nd degree in performance status was 11 months in the arterial chemotherapy group and 3 months in resected groups (p < 0.05). The survival rates were 53, 18 and 9% at 1, 2 and 3 years in the patients with arterial chemotherapy, respectively, against 22, 15 and 15% in the resected patients (p < 0.05). These results suggested that intra-arterial chemotherapy was significantly effective in prolonging the survival period with a better quality of life.

[A case report of malignant pseudomyxoma peritonei treated by a new modality of intraperitoneal chemo-hyperthermia].

A patient with malignant pseudomyxoma peritonei underwent a palliative surgical resection and intraperitoneal lavage with 5% dextrose. One hundred and twenty-five mg of cisplatin resolved in 1,500 ml saline was infused into the peritoneal cavity through the reservoir, and the patient was treated with hyperthermia (Thermotron RH 8). As a result the tumor markers (CEA, CA 19-9, and CA-125) markedly decreased after two courses of chemo-hyperthermia. These results suggest that intraperitoneal chemo-hyperthermia is an effective treatment for non-resectable malignant pseudomyxoma peritonei.

Delayed washout of intratumor blood flow is associated with good response to intraarterial chemoembolization for liver metastasis of colorectal cancer.

BACKGROUND: We studied stagnation of the blood in hepatic metastatic lesions of colorectal cancer. METHODS: Twenty-two hepatic tumors in 11 patients with liver metastases of colorectal cancers were investigated in this study. With a catheter inserted into the roots of the proper hepatic artery, 5 to 10 mCi 133Xe was injected. The half-time (t1/2) was calculated for the tumor region based on the washout curve by the compartmental method and expressed as the intratumor retention time of the blood. RESULTS: Transcatheter arterial chemoembolization with iodized oil (Lipiodol) and cisplatin was effective in eight (50%) of 16 tumors that were hypervascular but in only one (17%) of six tumors that were hypovascular (p < 0.05). Regardless of the hypervascular tumor, transcatheter arterial chemoembolization was not effective in tumors that had shown a t1/2 of less than 80 seconds. Seven of eight good-responding lesions that were hypervascular and had a long t1/2 (187 +/- 74.6 seconds) revealed characteristic fireworks-shaped accumulation of Lipiodol. CONCLUSIONS: Transarterial infusion chemotherapy for liver metastasis of colorectal cancer was considered effective for hypervascular hepatic tumors with a long t1/2.

[An experimental study on injuries to the growth plate--effects on the growth of long bones following placement of smooth pins across the growth plate of immature rabbits].

Displaced epiphyseal separation is difficult to reduce and fix. We usually pass a few Kirschner wires from the epiphysis to the metaphysis to maintain the position of reduction. However there are various opinions about the effects of penetrating smooth pins, concerning whether it causes retarded bone growth. In this experimental study on immature rabbits, stainless steel pins 0.7, 1.2, 2.0, or 3.5 mm in diameter or a single crystal alumina ceramic pin 1.2 mm in diameter were driven into a drill hole of equivalent bore in the intercondylar portion of the right femur across the central portion of the growth plate. Using this model, we analyzed effects on the growth plate and bone growth macroscopically, radiographically and histologically. The follow-up intervals were 3, 6, 12 and 24 weeks. At 12 and 24 weeks after insertion of the 3.5 mm stainless steel pin, shortening of the operated femur was observed. In other groups there was no difference in the length of the femur. The pin position after insertion was divided into two types; in one the pin position remained located in the growth plate, and in the other the pin migrated proximally beyond the growth plate. Histologic studies showed regenerated growth cartilage in the implant canal at the plane of the growth plate. At 12 weeks after insertion of a 3.5 mm stainless steel pin there was bone bridge between epiphysis and metaphysis without clear regenerated growth cartilage. The role of regenerated growth cartilage, therefore, appears to prevent bone bridge formation. There was no significant difference between the stainless steel pin and the single crystal alumina ceramic pin. When the diameter of the pin is sufficiently large and also low growth plate activity due to aging is present, retarded bone growth would be anticipated.