Endothelial dysfunction in MELAS improved by l-arginine supplementation.

The authors evaluated endothelial function in patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) by flow-mediated vasodilation (FMD) and found a significant decrease vs controls. Two years of supplementation with oral l-arginine, a nitric oxide precursor, significantly improved endothelial function to control levels and was harmonized with the normalized plasma levels of l-arginine in patients. l-Arginine therapy improved endothelial dysfunction and showed promise in treating strokelike episodes in MELAS.

[A case of acupuncture needle dermatitis].

A 65-year-old female visited our clinic with painful red vesicular dermatitis of the forehead and around the left eye. She had received acupuncture for headache and shoulder stiffness 6 days before visiting our clinic. A patch test with nickel sulfate gave positive results. We treated her with the greater occipital nerve block and trigger point injection which relieved her pain. We reached the diagnosis of greater occipital trigeminal syndrome with contact dermatitis from the acupuncture needle.

Management of acute metabolic decompensation in maple syrup urine disease: a multi-center study.

BACKGROUND: Therapeutic modalities in acute metabolic decompensation in maple syrup urine disease (MSUD) are variable, and outcomes of each therapeutic measure have been known only individually. Factors that affect neurological outcome are not clear. METHODS: A questionnaire was sent throughout Japan to each pediatrician treating any of the 42 MSUD patients. RESULTS: Necessary information was available for 13 patients through the questionnaire, and through a publication for one patient. In nine of the 14 patients episodes of metabolic decompensation developed in the neonatal period. In the other five, the onset of disease was delayed until infancy or later. In the nine patients with neonatal onset, a pretreatment level of plasma leucine greater than 40 mg/100 mL or a duration of altered level of alertness longer than 10 days was associated with a poor neurological outcome. The therapeutic measures employed included intravenous infusion of glucose and electrolyte solution or hypertonic glucose and electrolyte solution, exchange transfusion, peritoneal dialysis, a large dose of thiamine and intravenous hyperalimentation. All patients had survived the episodes and were alive at the time of the survey. Five of the nine patients with neonatal onset have developed neurological sequelae to varying degrees. Episodes of metabolic decompensation in infancy or thereafter did not affect, or only minimally affected, the neurological outcome. CONCLUSION: Therapeutic goals to improve neurological outcome are to shorten the duration of the altered level of consciousness, and to minimize the peak plasma leucine level as much as possible.

Cloning of rabbit TR4 and its bone cell-specific activity to suppress estrogen receptor-mediated transactivation.

To clone a new nuclear receptor, we screened a rabbit heart complementary DNA (cDNA) library with degenerate oligonucleotide probes corresponding to the DNA-binding domain of nuclear receptors, which is highly conserved among receptors. One of the cDNA clones, clone 23, encodes a novel protein of 596 amino acids, and predicted molecular mass is 66 kDa. Homology search analysis identified this protein as rabbit TR4 (TR4-0). We also cloned the cDNA encoding a rabbit TR4 isoform (TR4-1), which lacks the putative C-terminal ligand-binding domain (350 amino acids) caused by a 23-bp exon deletion, which probably occurred during messenger RNA (mRNA) splicing. Northern blot analysis showed that TR4s are expressed with two kinds of mRNAs (9.0 kb and 2.8 kb), both of which are relatively abundant in brain, testis, and bone. RT-PCR analysis, using pairs of primers specific for each TR4, showed that both types of receptor express in various tissues. Furthermore, both are present in primary osteoblasts and bone marrow cells, though the mRNA levels of TR4-0 were much higher than those of TR4-1. A functional study, using a transient transfection assay, showed that both receptors suppressed retinoid X receptor (RXR)-retinoid acid receptor, RXR-TR, and RXR-VDR-mediated transactivation significantly in COS-1 and osteosarcoma cells (UMR-106, ROS17/2.8) and that TR4-0 was much more effective than TR4-1. Unexpectedly, we found that the TR4s effectively suppressed estrogen receptor-mediated transactivation in bone cells, but neither in kidney (COS-1) nor breast cancer cells (MCF-7, one of the major target cells of the estrogen action). Thus, the present study shows a novel property of the TR4 orphan receptor, acting as a bone cell-specific repressor in the estrogen receptor-mediated signaling pathway.

Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac beta-myosin heavy chain (c beta MHC), cardiac troponin T (cTnT), alpha-tropomyosin (alpha TM), cardiac myosin binding protein C (cMBPC), ventricular myosin essential light chain (vMLC1) and ventricular myosin regulatory light chain (vMLC2) genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene.

Development of a de novo tumorous necrotic lesion in the liver after transcatheter arterial embolization combined with iodized oil infusion: report of a case.

We report herein the case of a 69-year-old woman in whom a hepatic tumorous necrotic lesion was discovered following transcatheter arterial embolization combined with iodized oil infusion (Lp-TAE) for a hepatoma. The lesion, which had not been evident prior to the Lp-TAE, was resected and analyzed pathologically. The portal area distribution in the necrotic lesion was the same as that in the surrounding hepatic tissue, suggesting that the lesion was derived from the nonneoplastic hepatic tissue. Moreover, extensive wall thickening and obstruction were observed in the intrahepatic portal vein and hepatic artery. These findings suggest that the lesion was a focus of hepatic infarction triggered by Lp-TAE.

An event-related potential study on the impairment of automatic processing of auditory input in schizophrenia.

Mismatch negativity (MMN) and P300 to auditory stimuli was carried out using global field power (GFP) in 25 schizophrenics and 25 normal controls. The peak latencies of MMN and P300 were significantly longer in schizophrenics than in normal controls, and the differences in MMN were marked in the frontal regions. The peak amplitudes of MMN and P300 were significantly smaller in schizophrenics. The scalp distribution of MMN to 1050 Hz tone differed between the two groups, although that to 1100 Hz was similar to each other. The results indicate an impairment in the automatic discrimination process of auditory input in schizophrenics.

Evidence of redox-linked signaling for producing a giant signal complex.

Previously we showed that a thiol-reactive heavy metal, HgCl2, crosslinked multiple cell surface receptors through a ligand-independent pathway, which produced massive aggregates of phosphotyrosine (PTYR)-containing proteins beneath plasma membrane [Nakashima et al. (1994): J Immunol 152: 1064-1071]. In this study we characterized these unique aggregates at the molecular level. The lysates in Brij 96 of thymocytes treated with HgCl2 were separated into the supernatant and pellet fractions by simple centrifugation. Selected PTYR-containing proteins and p56lck appeared in the pellet fraction as quickly as 5 s after exposure to HgCl2, and were further increased in amount by 5 min. Although the mechanism of triggering these events was redox-linked, the majority of proteins in the Brij 96-insoluble aggregates were dissociated in SDS-PAGE under nonreducing condition. This suggested that PTYR-containing proteins and p56lck themselves do not form dimer or polymer directly by thiol-mediated bond. The pellet fraction was further found to include some other signal delivery elements, such as GTPase activating protein, phosphatidylinositol 3 kinase, and mitogen-activated protein kinase. Finally, all of these signal elements and selected PTYR-containing proteins were collected in the same fraction by the sucrose density gradient centrifugation. These results suggest a unique redox-linked pathway of formation of a giant signal complex.

Intrapleural perfusion hyperthermo-chemotherapy for malignant pleural dissemination and effusion.

Taking advantage of the antitumor effect of hyperthermia, we administered intrapleural perfusion hyperthermo-chemotherapy for the treatment of malignant pleural seeding or pleural effusion. This consists of irrigating the pleural space for 2 hours with 43 degrees C saline solution containing cis-platinum using specially devised extracorporeal circuits. From January 1988 through December 1993, we performed this technique in 12 patients with malignant disseminated lesions stemming from lung cancer who also underwent surgical resection of the primary lesions and in 7 patients with malignant pleural effusions who did not undergo thoracotomy or surgical resection. There were no serious clinical complications associated with this procedure. The pharmacokinetics showed that a high concentration of cis-platinum (more than 17.6 micrograms/mL in the free form) was retained in the pleural cavity during perfusion. After this therapy, the cancer cells showed marked degeneration with fibrosis in the pleural wall. The pleural effusion was well controlled in 100% of the patients. The median survival time in the 12 patients with pleural disseminated lesions who were treated with intrapleural perfusion hyperthermo-chemotherapy was 20 months. On the other hand, the median survival time in 7 patients with similar lesions who did not receive IPHC was only 6 months. Intrapleural perfusion hyperthermo-chemotherapy seems to have considerable value as an adjuvant therapy for patients with pleural dissemination who have had their primary lesions removed.

Protective effects of D-penicillamine and a thiazole derivative, SM-8849, on pristane-induced arthritis in mice.

To evaluate the antiarthritic properties of a novel thiazole derivative, the drugs SM-8849, D-penicillamine and indomethacin were administered to pristane-injected DBA/1 mice. The mice were treated daily with the agents for 32 weeks, starting from the day of the pristane injection. Treatment with SM-8849 (50 mg/kg) resulted in an amelioration of arthritic disease, as assessed by clinical, radiographic, and histologic examinations. Similar results were obtained in mice treated with 50 mg/kg D-penicillamine, although this disease modifying antirheumatic drug was slightly less effective than the same dose of SM-8849. In contrast, indomethacin at the maximum tolerated dose of 2 mg/kg did not alter the course of the disease. SM-8849 and D-penicillamine were also shown to reduce serum levels of rheumatoid factors and the acute-phase reactant, serum amyloid P component. Indomethacin failed to affect either parameter. Flow cytometric analysis revealed an elevation in the T-cell population that expressed CD44, a marker of murine memory T-cells, in spleens from pristane-injected mice. SM-8849, but not D-penicillamine, prevented the increase in this cell population. These results led us to conclude that pristine-induced arthritis was a useful model for the evaluation of antirheumatic agents, in that using this model, we were able to distinguish disease modifying antirheumatic drugs from nonsteroidal anti-inflammatory drugs. Our findings also indicate that SM-8849 shows antiarthritic activity, with a unique mechanism of action, differing from that of D-penicillamine.

Hyperbaric oxygen therapy accelerates neurologic recovery after 15-minute complete global cerebral ischemia in dogs.

BACKGROUND AND METHODS: Although hyperbaric oxygen therapy is clinically used for the treatment of several types of ischemic brain injury, few basic animal studies are available that provide a rationale for this therapy for complete global brain ischemia. Therefore, we investigated the effect of hyperbaric oxygen therapy on neurologic recovery after 15-min complete global cerebral ischemia in a canine model. Complete global ischemia was induced in 19 dogs by occlusion of the ascending aorta and the caval veins. Nine dogs were randomized to treatment with hyperbaric oxygenation (3 atmospheres absolute, 100% oxygen for 1 hr) at 3, 24, and 29 hrs after ischemia under spontaneous respiration, while the other ten dogs served as the control group without hyperbaric oxygen therapy (group C). Neurologic recovery was evaluated based on the electroencephalogram (EEG) activity score (1 = normal; 5 = isoelectric) and the neurologic recovery score (100 = normal; 0 = brain death) over a 14-day postischemic period. RESULTS: The survival rates were 3/10 (30%) in the control group vs. 7/9 (78%) in the group treated with hyperbaric oxygen (p < .05). Over the 14-day postischemic period, the best (lowest) EEG scores of each dog were significantly (1.7 +/- 0.2 vs. 2.9 +/- 0.3; mean +/- SE, p < .01) lower in the hyperbaric oxygen-treated group. The best neurologic recovery scores of each dog were significantly (69 +/- 6 vs. 48 +/- 5; mean +/- SE, p < .05) higher in the treated animals. The number of dogs that recovered to a neurologic recovery score of > 65 (assessed as a slight disability) were 1/10 in the control group and 6/9 in the group treated with hyperbaric oxygen (p < .02). CONCLUSIONS: Hyperbaric oxygen therapy performed in the early postischemic period accelerated neurologic recovery and improved the survival rate in dogs after 15-mins of complete global cerebral ischemia.

Thermotolerance in regional hyperthermia in vivo--an experimental study using the MH134 tumor.

In the clinical application of hyperthermia, determining the thermotolerance that influences the anti-tumor effect is an important problem. The purpose of this study was to investigate the methods of induction and disappearance of thermotolerance in vivo. After transplanting MH134 cancer cells into the paws of C3H mice, local hyperthermia with warm water was administered, and the movement of thermotolerance in vivo studied in terms of the heating intervals and tumor growth times. When the first heating was applied on the 8th day after transplantation, thermotolerance appeared within 1 hour, increasing gradually to reach a maximum at 18 hours, after which it decreased gradually and disappeared after 48 hours. When the first heating was applied on the 13th day after transplantation, which fell during the rapid tumor proliferation period, the movement of thermotolerance presented a similar pattern of appearance and disappearance. The results of this study made it clear that there was no difference in the movement of thermotolerance between the two periods even though each had a different rate of tumor proliferation.

Prognostic factors in liver metastases after transcatheter arterial embolization or arterial infusion.

From January 1986 to December 1988, 85 patients (55 men and 30 women, mean age 59 years) with metastatic liver tumors were treated with hepatic artery embolization (TAE) or infusion (HAI). Sixty-eight patients with successful catheterization were treated with TAE using iodized oil (Lipiodol) mixed with anticancer agent (ACA). In 12 of 68 patients with hypervascular tumors gelatin sponge was added. Patients with unsuccessful catheterization were treated with hepatic artery infusion of ACA. Forty-three patients received oral chemotherapy following TAE or HAI. Overall, the 6-month, and 1- and 2-year survival rates were 69.5, 31.8 and 4.1 per cent, respectively (mean 233 days). A univariate analysis of prognostic factors showed that number of metastases, stage, treatment times and oral chemotherapy were all significant factors (p less than 0.05). Ascites, jaundice, percentage of hepatic replacement and treatment protocol also had some influence (p less than 0.1). Sex, age, primary site, elevation of tumor markers, other metastatic lesions, portal vein involvement and difference in anticancer agent had no prognostic significance. A multivariate analysis using Cox's proportional hazard model revealed that the number of treatments had the most important prognostic significance, followed by oral chemotherapy, stage and percentage of hepatic replacement.

[Pulmonary complication following intra-arterial infusion of lipiodol-adriamycin emulsion for hepatocellular carcinoma, report of a case].

A case of acute pulmonary complication following intra-arterial infusion of Lipiodol-Adriamycin emulsion for hepatocellular carcinoma was reported. Intra-arterial infusion chemotherapy was performed on a 75-year-old male with Lipiodol-Adriamycin emulsion (Lipiodol 8 ml + Adriamycin 40 mg). Severe dyspnea and cyanosis started about 30 minutes after the infusion, and blood gas analysis revealed hypoxemia and hypocapnia. Chest X-ray revealed diffuse infiltrative shadow throughout the both lungs. He was on positive end-expiratory pressure breathing for 4 days. Clinical symptoms and chest X-ray improved rapidly in the course of two weeks, he became almost asymptomatic. We concluded that the nature of this pulmonary damage was pulmonary edema due to the large amount of Adriamycin that flowed into pulmonary artery via arterio-venous shunt present in the hepatocellular carcinoma.

Inhibition of mitochondrial functions by margosa oil: possible implications in the pathogenesis of Reye's syndrome.

Margosa oil (MO), a fatty acid-rich extract of the seeds of the neem tree and a reported cause of Reye's syndrome, has been used in the induction of an experimental model of Reye's syndrome in rats. It has been reported that MO causes a decrease in in vivo mitochondrial enzyme activity similar to that seen in Reye's syndrome. We have attempted to uncover some of the biochemical mechanisms of MO's toxicity by examining its effect in vitro on isolated rat liver mitochondria. Male rat liver mitochondria were isolated by centrifugation; oxygen uptake, reduced forms of cytochrome b, c + c1, a + a3, and flavoprotein, intramitochondrial concentrations of acetyl coA, acid-soluble coA, acid-insoluble coA, and ATP content were measured after incubation with and without MO. Our results reveal that MO is a mitochondrial uncoupler. State 4 respiration was increased while the respiratory control ratio was decreased. The intramitochondrial content of ATP was also decreased. There were substantial changes in the reduction of the respiratory chain components after incubation of mitochondria with MO. This decelerative effect on mitochondrial electron transport was alleviated by the addition of coenzyme Q and/or carnitine. These effects of MO on mitochondrial respiration may be due to changes in fatty acid metabolism caused by MO as MO caused a shift in the proportion of acid-soluble or acid-insoluble coA esters. Supplementary therapy with L-carnitine and coenzyme Q may be useful in the management of MO-induced Reye's syndrome.

An objective method of pulse diagnosis.

One component of Oriental medical diagnosis is pulse diagnosis. To make this method more objective, three pressure transducers were positioned over the radial artery and the absolute pressure of 50, 100 and 150 g was applied at three positions to simulate the classical pulse diagnosis. The transient pressure changes at the same absolute pressure were recorded. The pressure changes at the three positions were not equal even when the same absolute pressure was applied. Pressures were compared in superficial and deep locations, right and left wrist. The largest deflection was considered as excess and the smallest as depletion in twelve meridians.

Effects of propranolol and nifedipine on exercise-induced attack in patients variant angina: assessment by exercise thallium-201 myocardial scintigraphy with quantitative rotational tomography.

To examine the effects of propranolol and nifedipine on exercise-induced attack in patients with variant angina, exercise 201Tl myocardial scintigraphy with quantitative analysis by emission-computed tomography was performed in 20 patients with variant angina after oral propranolol (80 mg), nifedipine (20 mg), and placebo. Exercise-induced attack occurred in 11 patients on placebo, in 14 on propranolol, and in none on nifedipine. The exercise duration was significantly shorter in those on propranolol (p less than .05), but significantly longer in patients on nifedipine (p less than .05) than in those on placebo. The peak rate-pressure product was significantly lower in patients on propranolol (p less than .01), but did not change in those on nifedipine, as compared with that in patients on placebo. The size of the perfusion defect as measured by 201Tl tomography was significantly greater in patients on propranolol (p less than .05), but significantly less in those on nifedipine (p less than .01) than in those on placebo. In conclusion, propranolol does not suppress but rather may aggravate exercise-induced attack in patients with variant angina, while nifedipine suppresses it. This unfavorable effect of propranolol on exercise-induced attack in patients with variant angina is likely to be due to a reduction of regional myocardial blood flow.

Clinical study of objective pulse diagnosis.

The recording of the objective pulse diagnosis was performed and the meridian points were selected from this recording. The proper meridian points (five element points) according to the five element theory and the improper points (non-five element points) were stimulated. Pain threshold was elevated by the stimulation of five element points and not raised by non-five element points in a patient who had nasal polypectomy under acupuncture analgesia and also in 6 of 9 healthy volunteers. Naloxone reversal of elevated pain threshold was also observed in volunteers.

Intra- and postoperative autotransfusion in open heart surgery under simple hypothermia in children.

A new autotransfusion unit was developed by the authors and the favorable results of 21 operations of open heart surgery under simple hypothermia were described. The patients were all children with simple congenital heart diseases. The amounts of autotransfused blood ranged from 2.8 to 15.5 ml/kg. Intraoperative autotransfusion proved to be an effective means of minimizing blood loss during surgery (range 3.2 to 12.8 ml/kg) and performing open heart surgery without donor blood transfusion. Postoperative autotransfusion (range 0 to 14.3 ml/kg) served as a supplementary means of avoiding homologous blood transfusion. Among the 21 autotransfused patients, there were no complications, while two patients developed hepatitis out of 19 patients who received homologous blood in the control group.