The magnetic properties of free radicals and paramagnetic compounds such as hemoglobin and oxygen are principal factors in evaluating the biological stress of magnetic fields. These compounds exist in high concentrations, i. e. 0.2-10 mM, in human bodies and their environment. Irons in hemoglobin play an important role in the stress induced by magnetic fields. For instance, concentrations of oxygen, nitric oxide and carbon dioxide, which are transported by hemoglobin, are modulated by a magnetic field in the brain, and physiological and biochemical changes, such as accelerated circulation and metabolism, may occur thereafter. Moreover, free radicals, i. e. oxygen, nitric oxide, cerullophasmin-Cu, and transferrin-Fe, may be controlled by an external static magnetic field, and these mechanisms may be related to physiological functions such as circulation. A therapeutic effect of magnetic medical instruments may result, in part at least, from the control of free radicals by magnetic fields and accelerated metabolism described above.
Between July 1991 and December 1993, 80 patients with gallstone and/or gallbladder polyp were considered candidates for laparoscopic cholecystectomy. We attempted 7 cases of laparoscopic cholecystectomy for patients with nonvisualizing gallbladder by DIC, and in 6 cases, the laparoscopic cholecystectomy was successfully completed. In the remaining 1 case the operation was converted to open cholecystectomy due to severe acute cholecystitis. During the same period, there were 8 patients who had previous upper abdominal surgery, and in 4 of these patients, laparoscopic cholecystectomy was successfully completed. All patients were free of major complications intra and postoperatively. We can extend the indications for laparoscopic cholecystectomy as skill with this procedure increases. We believe that this procedure will become the standard operation for benign gallbladder diseases in the near future in Japan.
Myelodysplastic syndrome (MDS) is a disorder of multipotential hematopoietic stem cells. There is no effective therapy for MDS, especially for MDS associated with an excess of blasts, such as refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEBt). We previously reported the effect of K-18 (a human IgG-melphalan conjugate) in 15 patients with RAEB or RAEBt. The overall response rate was not high, but no side effects were noted. Although the mode of action of K-18 is not certain, it was suggested that the effect was associated with the activity of melphalan itself. Therefore, low-dose melphalan therapy was initiated in elderly patients with RAEB or RAEBt. Six patients with RAEB and 12 patients with RAEBt received 2mg oral administration daily. Median age of the patients was 64. Six patients achieved complete remission (CR), one patient showed a partial response and four patients had a minor response. Total dosage of melphalan for patients who achieved CR was 143±18mg. Median duration of CR was 14.5 months. Serious toxicity was not encountered in any case and neither marrow suppression nor pancytopenia were observed in cases that achieved CR during the administration of melphalan. Changes in cell surface markers (CD34, CD33, CD13) were examined during the time course of CR in two cases. CD34+cells decreased rapidly during the first two weeks and CD34-CD33+cells increased after four weeks of melphalan administration. Studying the clinical course of CR with cell surface marker analysis provided evidence that melphalan therapy induced differentiation of transformed hemopoietic precursors. We conclude that daily chronic administration of melphalan is a useful therapy for elderly patients with RAEB or RAEBt.
Although premenstrual worsening of asthma is recognized, little is known about the pathophysiology. Monthly variation in endogenous progesterone and β-estradiol may be associated with the etiology of premenstrual asthma (PMA). Tlymphocytes play an important role in the pathogenesis of asthma. Therefore, to clarify the pathogenesis of PMA, the clinical features and effects of progesterone and β-estradiol on lymphocyte activation were studied. 1) Thirty one asthmatic females of reproductive age were surveyed. Fourteen asthmatics (45%) claimed their asthma symptoms worsened just prior to or during the menses. Comparing asthmatics with and without PMA, the former group showed significantly more severe steroid dependent asthma. 2) Progesterone and β-estradiol suppressed lymphocyte blastogenesis stimulated by phytohemagglutinin (PHA), mite and Candida antigen. There was no significant difference in the suppression rate between asthmatics and normal subjects, or between male and female. These findings suggest that T lymphocytes may be activated by causal allergens when progesterone and β-estradiol levels decrease during the premenstrual period. Activated T lymphocytes may contribute to the pathogenesis of PMA.
Activation of lymphocytes is thought to be an important mechanism in the allergic response in intractable asthma. To establish a new therapy using a selectively suppressive agent for T-cells, small doses of ciclosporin (Cs) were administered to three patients with intractable asthma. The effects on the clinical courses and immunological parameters were examined. The results were as follows: (1) Clinical improvements were observed at doses above 4mg/kg/day. (2) The percentage of CD3+ and CD4+ lymphocyte in peripheral blood showed a tendency to reduce, and lymphocyte blastogenic responses and IL-2 production against specific antigens were suppressed to within or below the normal range. There was significant inverse correlation between whole blood Cs level and IL-2 production against specific antigens (Candida, and house dust) (γ=-0.95p<0.005, and γ=-0.99 p<0.005, respectively). (3) Serum IgE level decreased markedly, but there was no significant change in serum levels of IgG, IgA, or IgM. Between the whole blood Cs level and serum IL-4 level, there was a significant inverse correlation (γ=-0.73 p<0.05), but a relative correlation between serum IL-4 level and serum IgE level (γ=0.66) was noted. The effects disappeared after medication without Cs. These data indicate that lymphocytes may play an important role in the attack mechanism of intractable asthma and that Cs therapy is benefical when temporarily administered for the disease, though the potential risks such as infection, nephrotoxicity, liver damage and carcinogensis remain problems in the treatment.
δ-Guanidinovaleric acid (GVA) is an endogenous convulsant and is thought to be a specific GABA antagonist. In the present study, we examined the effects of GVA and GABA agonists, GABA, muscimol and baclofen, on dopamine and serotonin releases in rat striatum using a brain dialysis technique. GVA produced a significant increase in DA released transiently (1mM) and throughout the experiment (10mM) compared with the controls. It also produced a significant increase in 5-HT release in both concentrations throughout the experiment. GABA (10mM) inhibited DA and 5-HT releases induced by GVA. Muscimol (10mM) inhibited DA and 5-HT releases induced by GVA. Especially muscimol was more effective in the inhibition of 5-HT release. Baclofen (10mM) inhibited only DA release induced by GVA. These results suggest that the activation of GABA receptor inhibits the release of DA and 5-HT in the striatum, and that the DAergic system regulates the GABA-B receptor while the 5-HTergic system mainly regulates the GABA-A receptor.
We examined the heart rate response to face immersion in 17 normal subjects and 9 diabetics. The subjects immersed their face fully in a basin filled with ice water at 4-6°C in a forward leaning position for 20 sec. Two-lead electrocardiogram (ECG) was continuously recorded from 20 sec before the immersion to 5 min after. The R-R intervals were measured on the recorded ECG. In the control group, heart rate response to face immersion showed 4 phases: an initial increment after the immersion of the face (phase 1), decrease after the initial increment (phase 2), second increment after phase 2 (phase 3) and second decrease after the second increment (phase 4). Repeated face immersion test with a 10 min interval revealed reproducibility of the test. Parasympathetic blockade with atropine sulphate attenuated the phase 2 response, suggesting that cardiac parasympathetic nerve tone increases in response to the initial increment in the heart rate due to sympathetic response. In diabetic patients, phase 2 response was reduced in patients with a shorter history of diabetes, while in patients with a longer history, heart rate response was diminished in all phases. Therefore, heart rate response to face immersion was attenuated relative to the duration of the illness. The present study suggests that the analysis of the heart rate response to face immersion is useful as an autonomic nervous function test.
Plasma kallikrein was detected in bronchoalveolar lavage fluid (BALF) obtained from bronchial asthma patients and compared to that of normal adults. Characterization using chromogenic substrates S-2302, S-2266, S-2222, and using inhibitors SBTI, Trasyrol, DIFP, suggested that the amidolytic activity in BALF from bronchial asthma patients was compatible with plasma kallikrein. Using immunoblotting method with specific antibody, we concluded that the plasma kallikrein-like activity in BALF was surely plasma kallikrein itself. The plasma kallikrein activity in BALF obtained from patients with late asthmatic response (LAR) was significantly higher than that in fluid from patients with immediate asthmatic response (IAR). Kininogenase activity was also detected by cleavage of bradykinin from acid-treated plasma. To investigate whether the plasma kallikrein in BALF originated from human lung mast cell or basophil, the supernatant of lung mast cells and that of basophils were tested using three chromogenic substrates and the immunoblotting method. We conculuded that the plasma kallikrein in BALF did not originate from lung mast cells or basophils. These results suggested that elevated amounts of plasma kallikrein in BALF of patients with LAR might contribute to the pathogenesis and modification of LAR.
To establish a new classification in bronchial asthma, antigen-induced immediate asthmatic response (IAR) and late asthmatic response (LAR) to mite and Candida were compared with antigen specific IgE antibody (IgE RAST) and lymphocyte blastogenesis (Ly-BL) in asthmatics. Half of asthmatics with a high score on mite IgE RAST could not be provoked to IAR, although almost all of patients with house dust-induced IAR showed a high score on mite IgE RAST. However, asthmatics with enhanced Ly-BL following exposure to mite and Candida showed highly provoked LAR by antigen inhalation, and LAR patients showed significantly enhanced Ly-BL by both antigens (p<0.01). Bronchial asthmatics were classified into the following 4 groups using those parameters; A group (IgE RAST+, Ly-BL-), B group (IgE RAST+, Ly-BL+), C group (IgE RAST-, Ly-BL+), D group (IgE RAST-, Ly-BL-). Half of the patients with IAR belonged to the A and B groups, and almost all of the LAR patients were in the B or C group. Patients in the A group predominantly showed early onset, however patients in the B and C groups showed late onset. A and B group patients were mild or moderate asthmatics, but severe asthmatics belonged to the C and D groups. These data suggest that the C group showed only Ly-BL led LAR by “cell-mediated allergy” in late onset severe asthma.
Hypokinesia in the unilateral limbs was induced in 8 monkeys (Macaca fuscata fuscata) by a lesion in the contralateral mesencephalic ventromedial tegmentum (VMT). Daily oral administration of L-Dopa/carbidopa (40mg/kg, 4mg/kg) relieved the hypokinesia and thereafter induced continuous abnormal (choreo-athetoid) involuntary movements (AIM) in upper and lower limbs contralateral to the lesion. These movements were always uniform and continued for a few hours. The author performed a series of pharmacological studies using these VMT-lesioned monkeys. 1) Direct injection of dopamine (500-1000μg/10μl) and apomorphine (500-1500μg/10μl)into the dorsomedial part of the head of the caudate nucleus ipsilateral to the VMT lesion induced the same AIM as those induced by oral administration of L-Dopa/carbidopa. However, intraputaminal injection of these agents induced AIM in bucco-lingual region only. 2) After oral administration of L-Dopa/cabidopa, direct injection of methionine-enkephalin (300μg/10μl), GABA (500-1000μg/10μl) and serotonin (100-200μg/10μl) into the dorsomedial part of the head of the caudate nucleus (HCN) slightly decreased the AIM. However, substance p (200-400μg/10μl) or atropine (100-200μg/10μl) had no effect on the AIM. Neither the direct injection of GABA (500-1000μg/10μl) nor substance P (200-400μg/10μl) into the internal segment of the globus pallidus had any effect on the AIM. 3) The dopaminergic receptor (DA-2) binding study was performed on caudate tissues which were removed 5 weeks after creating the lesion in the unilateral VMT. DA-2 receptor binding of the dorsomedial part of the caudate nucleus, ipsilateral to the lesion, had a higher affinity than that of the ipsilateral ventrolateral part or the contralateral caudate tissue. These results suggest that denervation supersensitivity of the post-synaptic DA-2 receptors in the dorsomedial part of the caudate nucleus is a basic condition for the development of L-Dopa induced AIM, and the postdopaminergic neuronal systems in the caudate nucleus are slightly suppressed by the intra-caudate neurons, of which transmitter substances are methionine-enkephalin, GABA and serotonin.
Some of the halogenated inhalation anesthetics are metabolized partly in the liver to produce inorganic fluoride, and serum inorganic fluoride in continuous high concentration may cause renal dysfunction. In this study, the influence of elevated serum inorganic fluoride concentration and the duration of its action on renal function were studied by continuous infusion of sodium fluoride in rabbits for 24hours. The rabbits were divided into Control (group C), Low dose (group L) and High dose (group H) groups with mean serum inorganic fluoride levels of 1.9 μM, 62.4 μM and 237.7 μM, respectively. Twenty-four hour total urine volume increased in group H compared to group C. Urinary excretion of β2-microglobulin (β2MG), leucine aminopeptidase (LAP) and N-acetyl-β-D-glucosaminidase (NAG), collected every 6 hours, increased significantly in group H within 06 hours, whereas LAP increased within 1824 hours and NAG within 1218 hours in group L, compared to group C. The area under the curve of serum inorganic fluoride concentration, when the increase of NAG (the earliest among β2MG, LAP and NAG) excretion was detected (6 hours in group H, 18 hours in group L), were similar (group H; 1272±165 μM·hours, group L; 1197±189 μM·hours). Free water clearance over 24 hours increased significantly in group H only. Morphological examination showed the absence of the brush border and that cellular damage had occurred in the renal tubules in both group L and group H. These findings were more apparent in group H. In conclusion, it was revealed that not only the elevated serum inorganic fluoride concentration but also its duration were the factors inducing renal dysfunction, beginning with proximal tubuar damage and subsequently developing to decreased water reabsorption.
Neurons of the retrosplenial cortex, hippocampal subiculum, pontine nuclei, intracerebellar nuclei and some other nuclei in the mouse demonstrated a marked surface coat which was formed three or four weeks after birth. This coat was stained doubly with cationic iron colloid (pH 1.0-1.5) and aldehyde fuchsin or with alcian blue and aldehyde fuchsin. Digestion with hyaluronidase eliminated all the cationic iron colloid, aldehyde fuchsin and alcian blue stainings of the surface coat. Successive digestion with chondroitinase ABC, heparitinase and keratanase erased the cationic iron colloid and alcian blue stainings of the surface coat, but did not interfere with the aldehyde fuchsin staining of this coat. Electron microscopy of ultrathin sections revealed that the iron particles were preferentially deposited in the perineuronal tissue spaces. These findings indicate that the surface coat consists of sulfated proteoglycans, which form an extracellular matrix in the perineuronal tissue spaces and as a charge barrier assure stable signal transmission at the axosomatic synapes with inhibitory nature. It was further observed that the neurons with such surface coats in the retrosplenial cortex and hippocampal subiculum were labeled with lectin Vicia villosa agglutinin.
In a rat model, halothane causes liver injury by reductive interaction with microsomal cytochrome P-450 (P-450) and/or by a hepatotoxic effect mediated by halothane-derived free radicals. Rats that were pretreated with phenobarbital (0.1% in drinking water for 6 days) and fasted for the last day, then exposed to halothane (1.0%) under reduced oxygen tension (14%) for 2 horus developed hepatic centrilobular necrosis with marked elevation in serum GPT (GPT) 24 h after exposure. Pretreatment with a 5 mg/kg dose of zinc (Zn) 24 h prior to the exposure had no effect on GPT and liver necrosis. However, 10 mg/kg and 20 mg/kg of Zn significantly decreased GPT and liver necrosis. Zn-pretreatment (5-20 mg/kg) significantly depleted hepatic microsomal P-450 before exposure in a dose dependent manner. Hepatic metallothionein (MT)-1 and MT-2 induced by Zn in a dose dependent manner and the levels did not significantly differ prior to and after exposure to halothane under hypoxic conditions in all Zn-pretreated groups of rats. These results indicated that Zn-pretreatment has some protective effect against halothane-induced liver injury and suggested that this protective effect of Zn involves the depletion of P-450 which results in reduced interaction between P-450 and halothane in the microsomes and is not the result of MTs acting as free radical scavengers.