ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease.

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

Alleviation of myocardial ischemia after Kawasaki disease by heparin and exercise therapy.

BACKGROUND: Heparin promotes angiogenesis. We evaluated the effects of combined treatment with heparin and exercise on myocardial ischemia in the chronic stage of Kawasaki disease. METHODS AND RESULTS: This study was conducted in 7 patients (aged 6 to 19 years) who had a totally occluded coronary artery and stress-induced myocardial ischemia in the collateral-dependent areas. Twice-daily exercise using a bicycle ergometer was performed with increments of 0.5 W/kg every 3 minutes up to maximal exertion for 10 days. Heparin, which immediately increased circulating hepatocyte growth factor, was given intravenously 10 minutes before each exercise period. Newly developed myocardial infarction, ventricular tachyarrhythmia, anginal attack, or hemorrhagic complication was not observed in any patient. Dipyridamole-loading single photon emission computed tomography documented improved myocardial perfusion in the collateral-dependent areas and a significant reduction in total defect scores in all patients after the completion of 20 sessions (P=0.01). In control patients who did not receive the heparin-exercise therapy, however, stress defect scores remained unchanged (n=1) or increased (n=2) during follow-up. Computerized quantitative coronary angiography provided evidence that the heparin-exercise therapy increased the diameter of the occluded artery to which collaterals terminated (P=0.001) but not that of the reference artery with which collaterals were not connected (P=0.96). CONCLUSIONS: The findings suggest that a series of heparin and exercise treatments over 10 days may have a dramatic effect on the alleviation of myocardial ischemia in collateral-dependent regions. This may be a safe, noninvasive revascularization therapy for patients with coronary artery occlusion in the chronic stage of Kawasaki disease.

Dramatic decrease of circulating levels of monocyte chemoattractant protein-1 in Kawasaki disease after gamma globulin treatment.

Kawasaki disease (KD) is a systemic vasculitis preferentially affecting coronary arteries. Extensive monocytes/macrophages infiltrate in the vascular lesions, implying the involvement of a chemotactic cytokine in their recruitment. We investigated the role of monocyte chemoattractant protein-1 (MCP-1, also termed monocyte chemotactic and activating factor) in KD. In the immunohistochemical studies using the cardiac tissues of patients with fatal KD, MCP-1 but not interleukin (IL) -8 or macrophage inflammatory protein-1alpha was localized at the extracellular matrix associated with mononuclear cellular infiltration. The sites of MCP-1 expression correlated with the distribution of the acute inflammation, including early coronary vasculitis. In prospectively studied patients with KD, circulating levels of MCP-1, IL-8, tumor necrosis factor alpha (TNF-alpha), and IL-1alpha were elevated in 73, 77, 57, and 0% of samples before gamma globulin (GG) treatment (400 mg/kg x 5 days = total 2 g/kg), respectively, compared with respective control values. GG treatment correlated with a rapid decrease in the circulating levels of MCP-1 (P = 0.001) but not IL-8 (P = 0.19) or TNF-alpha (P = 0.33). In the sensitive Western blotting, MCP-1 bound to GG. Furthermore, GG inhibited the MCP-1-induced Ca2+ influx in a human monocytic cell line in vitro. These findings suggest a role of MCP-1 in KD, and indicate that GG treatment may block MCP-1 activity, thus alleviating KD vasculitis.

Stereoselectivity of a potent calcium antagonist, 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

Four enantiomers (3a-d) of the title compound, YM-09730 (3), were synthesized by the reaction of (-)- or (+)-5-(methoxycarbonyl)-2, 6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1a or 1b) with (S)- or (R)-1-benzyl-3-pyrrolidinol (2a or 2b). [3H]Nitrendipine binding affinity and coronary vasodilating activity of these compounds were evaluated. The absolute configuration of the most potent enantiomer (3a) with the longest duration was unequivocally determined to be (S)-1,4-dihydropyridine-C4 and (S)-pyrrolidine-C3 (S,S) by X-ray crystallographic study on 3a X HBr as well as 3a X HCl. The configuration of 1a corresponds to R, and the other enantiomers of 3 were respectively determined by chemical correlation. The potency order of the four enantiomers was (S,S)-3a greater than (S,R)-3b greater than (R,R)-3d greater than (R,S)-3c. Latent chiral characters of nifedipine derivatives with the identical ester groups were assigned by comparison of their puckering modes of 1,4-dihydropyridine (DHP) rings with those found in 3a X HCl or 3a X HBr. On the basis of the assignment, it has been revealed that the (S)-DHP nifedipine derivatives possess the synperiplanar carbonyl group at C5. The conformational restriction may be a factor causing stereoselectivity of antagonism.

Imbalance among T-cell subsets in patients with coronary arterial aneurysms in Kawasaki disease.

The populations of T cells were studied in 46 patients with Kawasaki disease, separated into 2 groups: group I--11 patients with coronary aneurysms; and group II--35 patients with normal coronary arteries. Patients from both groups with early acute illness, before day 5, had a significant reduction in the population of OKT3+ (p less than 0.001), OKT4+ (p less than 0.02) and OKT8+ cells (p less than 0.002), but normal OKT4/OKT8 ratios compared with age-matched control subjects. These abnormal values quickly returned to normal levels during week 2 in patients with normal coronary arteries. In contrast, patients in whom coronary aneurysms developed within 3 weeks of the onset had an imbalance between OKT4 and OKT8 during week 2, characterized by a decrease in the number of OKT8+ cells and an increase in the number of OKT4+ cells, resulting in a high OKT4/OKT8 ratio (p less than 0.01). Three patients in whom large coronary aneurysms developed had ratios higher than 4.50. Follow-up analysis of T-cell subsets from individual patients with coronary aneurysms showed that the OKT4/OKT8 ratio during the acute stage was reduced during the convalescent stage (p less than 0.005). In contrast, the ratio in patients with normal coronary arteries was normal during the course of the illness. These observations suggest that an immune regulatory process operating in coronary aneurysm formation is present.

Vascular endothelial growth factor in acute Kawasaki disease.

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is an important regulator of angiogenesis and blood vessel permeability. Kawasaki disease (KD) is characterized by systemic vasculitis with increased vascular permeability, implying a possible role of VEGF in KD. To elucidate the involvement of VEGF in the pathogenesis of KD, we investigated 30 patients with acute KD, comparing the time course of plasma VEGF levels (n = 123) with clinical symptoms and laboratory findings. Compared with control values, the peak levels of plasma VEGF were significantly elevated (38+/-26 vs 244+/-248 pg/ml, p <0.001). The VEGF levels at the appearance of skin rash and/or edema of hands and feet were also elevated to 176+/-163 pg/ml (p <0.001). In 7 patients (23%), the plasma VEGF levels remained increased after the resolution of the skin rash and peripheral edema. The VEGF levels were independent of gamma globulin therapy and levels of serum albumin and C-reactive protein. We also measured the plasma levels of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor alpha, both of which can upregulate VEGF in vitro. The plasma levels of VEGF were highly correlated with those of TGF-beta1 (n = 63, r = 0.73, p <0.001) but not with those of tumor necrosis factor alpha. These findings suggest that the production of VEGF is increased and may be upregulated by TGF-beta1 in acute KD. VEGF may be involved in the hyperpermeability of local blood vessels in acute KD.

Effect of a new potent H2-receptor antagonist 3[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]-N2- sulfamoylpropionamidine (YM-11170) on gastric mucosal histamine-sensitive adenylate cyclase from guinea pig.

The effect of 3[[[2-[(diaminomethylene)amino]-4- thiazolyl]methyl]thio]-N2-sulfamoylpropionamidine (YM-11170), a new thiazole H2-receptor antagonist bearing propionamidine at the terminus of a side chain, on histamine-sensitive adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] of gastric mucosa from the guinea pig was studied and compared with that of cimetidine. YM-11170 displaced the concentration-stimulation curve of histamine-sensitive adenylate cyclase to the right with a pA2 of 7.65 (Ki = 2.25 X 10(-8) M). Stimulation of gastric adenylate cyclase by 0.1 mM histamine was competitively inhibited by YM-11170 and cimetidine in a dose-dependent manner, with IC50 values of 5.9 X 10(-7) M and 1.4 X 10(-5) M respectively. Hippocampal histamine-sensitive adenylate cyclase in the presence of 0.1 mM histamine was also competitively inhibited by YM-11170 with an IC50 of 1.1 X 10(-7) M. YM-11170 did not affect Gpp(NH)p-, NaF-, PGE2-stimulated or basal activity of the gastric adenylate cyclase. These data, together with other results, indicate that YM-11170 is a highly selective and potent H2-receptor antagonist which competes with histamine at the receptor site on the histamine-sensitive adenylate cyclase.

Class II major histocompatibility antigen expression on coronary arterial endothelium in a patient with Kawasaki disease.

To investigate the class II major histocompatibility antigen expression on coronary arterial endothelium of Kawasaki disease and immunophenotypes of the infiltrating cells in the coronary vascular lesions, myocardial sections from a patient who died during the acute stage of Kawasaki disease were studied using an immunoperoxidase technique. The mononuclear cells in the lesions mainly consisted of macrophages and T cells, whereas B cells and NK/K cells were not seen. The majority of T cells reacted with Leu-3a antibodies, and only a few reacted with Leu-2a antibodies. Cells bearing the interleukin-2 receptor, indicative of activated T cells, were also found in the lesions. To determine the distribution of class II antigen, we used anti-HLA-DR antibodies. The massive expression of HLA-DR antigen on mononuclear cells was found in the lesions. In addition, the HLA-DR activation antigen was expressed on the coronary arterial endothelium at the infiltrates in which macrophages and T cells coexisted. In contrast, coronary arterial endothelium did not express HLA-DR antigens in the myocardial tissues of controls (n = 4). HLA-DR+ endothelial cells may play an important role in the development of Kawasaki vasculitis.

Molecular cloning, enhancement of expression efficiency and site-directed mutagenesis of rat epidermal cystatin A.

A rat cystatin A cDNA clone was isolated from a lambda ZAP library representing newborn rat skin mRNA by screening with a synthetic oligonucleotide designed from amino acid sequence 15-23 of the cysteine proteinase inhibitor. The obtained clone contained a partial coding region of the inhibitor, lacking the 5'-untranslated region and coding sequence for the NH(2)-terminal 13 residues. The amino acid sequence deduced from the base sequence, Glu14-Phe103, coincided with that determined at the amino acid level. To obtain the recombinant cystatin A protein, the DNA was fused with a synthetic linker encoding its missing N-terminal 17 residues and introduced into an expression vector, pMK2. In Escherichia coli, however, the expression level of the semi-synthetic gene was low, 0. 5 mg of the purified recombinant protein per 1 liter culture being produced. Changing of the codon usage of the N-terminal region in a pET-15b expression system led to an increase in the yield depending on the instability of the putative secondary structure around an initiation codon of the mRNA. The expressed cystatin A showed identical characteristics with the authentic form except for the absence of the N-terminal acetyl blocking group. Using the expression system, two kinds of point mutation, the conservative Val54 in the first loop QxVxG region being changed to Lys and Glu, were introduced, but there was almost no effect on the inhibitory activity toward papain. This suggests that the conserved Val in the reactive site is not restricted and that the hydrophobicity of the position is not essential for the activity of rat cystatin A.

Comparison of [3H]YM-09151-2 with [3H]spiperone and [3H]raclopride for dopamine d-2 receptor binding to rat striatum.

The Kd value of [3H]YM-09151-2, a potent and highly selective dopamine D-2 antagonist, for binding to rat striatum was about 20 pM (half of that for [3H]spiperone and one-fiftieth of that for [3H]raclopride). The Bmax of [3H]YM-09151-2 binding was about 30% higher than that of [3H]raclopride or [3]spiperone. The ratio (bout 3%) of non-specific to specific binding of [3H]YM-09151-2 was smaller than that of [3H]spiperone and [3H]raclopride. The Hill coefficient values of dopamine D-2 antagonists, SCH23390, mianserin and phentolamine for the inhibition of binding of [3H]YM-09151-2 were near 1.0, and their Ki values with [3H]YM-09151-2 were consistent with those for inhibiting [3H]raclopride and [3H]spiperone binding to D-2 receptors. Thus, [3H]YM-09151-2 may be the most suitable ligand for the labelling of dopamine D-2 receptors in the brain.

Pharmacological studies on novel muscarinic agonists, 1-oxa-8-azaspiro[4.5]decane derivatives, YM796 and YM954.

We have investigated the pharmacological profiles of the novel muscarinic agonists, 1-oxa-8-azaspiro[4.5]decane derivatives, YM796 (2,8-dimethyl-3-methylene) and YM954 (2-ethyl-8-methyl-3-oxo). These compounds, like the putative M1 agonists, RS86 and AF102B, inhibited [3H]pirenzepine binding to cerebral cortical membranes in the micromolar range and weakly inhibited [3H]quinuclidinyl benzylate binding to cerebellar membranes. Their (-) isomers had Hill coefficients lower than 1.0. (+/-)-YM796, (+/-)-YM954 and RS86, but not AF102B, stimulated phosphoinositide hydrolysis in hippocampal slices, an effect which is mainly linked to M1 receptors. (+/-)-YM796 (0.031 mg/kg p.o.) and (+/-)-YM954 (0.016 mg/kg p.o.) reversed the cognitive impairment in nucleus basalis magnocellularis-lesioned rats in a passive avoidance task more effectively than did RS86 and AF102B. Similar results were obtained in scopolamine-treated rats. Finally, (+/-)-YM796 was weaker than (+/-)-YM954 and RS86 in the induction of tremor, hypothermia and contraction of isolated ileum, which are mainly mediated by M2 and/or M3 receptors. These results suggest that (+/-)-YM796, (+/-)-YM954 and RS86 have M1 agonistic activity in central nervous system and that (+/-)-YM796 has relatively weak M2 and/or M3 agonistic activity.

Further studies on (+/-)-YM-12617, a potent and selective alpha 1-adrenoceptor antagonist and its individual optical enantiomers.

YM-12617, 5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]- 2-methoxybenzenesulfonamide HCl is structurally novel, an extremely potent and highly selective alpha 1-adrenoceptor antagonist. An asymmetric center exists at the alpha-carbon atom in the phenethylamine portion of YM-12617, therefore two optical enantiomers exist. alpha-Adrenoceptor blocking properties and hypotensive activities of YM-12617 and its enantiomers have been compared in vitro and in vivo. 1. In the isolated rabbit aorta, R(-)- and S(+)-YM-12617 competitively antagonized phenylephrine-induced contraction with pA2 values of 9.95 and 7.69, respectively. Although R(-)- and S(+)-YM-12617 were also competitive antagonists toward UK-14,304 at prejunctional alpha 2-adrenoceptors in the isolated guinea-pig ileum, the affinities of R(-)-YM-12617 (pA2 = 6.18) and S(+)-YM-12617 (pA2 = 5.64) for these receptors were 5,900 and 110 times lower than those displayed for postjunctional alpha 1-adrenoceptors in the isolated rabbit aorta. 2. R(-)- and S(+)-YM-12617 displaced both 3H-prazosin and 3H-idazoxan binding to rat brain membranes; however, the affinities of the R(-)- and S(+)-enantiomers for alpha 1-adrenoceptors (pKi = 9.95 and 7.83, respectively) were 21,000 and 72 times higher than those for alpha 2-adrenoceptors (pKi = 5.62 and 5.97), respectively. 3. Based on pA2 values obtained in the isolated tissues and pKi values in the binding assays, R(-)-YM-12617 was 132-182 times more potent than S(+)-YM-12617 as an antagonist at alpha 1-adrenoceptors. In contrast, the R(-)- and S(+)-enantiomers were similar in potency at blocking alpha 2-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on YM-12617: a selective and potent antagonist of postsynaptic alpha 1-adrenoceptors.

YM-12617, 5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2 -methoxybenzenesulfonamide HCl is a structurally new type of extremely potent alpha 1-adrenoceptor antagonist. Its alpha-adrenoceptor blocking properties have been compared with those of prazosin, phentolamine and yohimbine using both pharmacological and 3H-ligand binding techniques in vitro and in vivo. In the isolated rabbit aorta, a tissue known to contain mainly alpha 1-adrenoceptors at postjunctional sites, YM-12617 competitively antagonized noradrenaline-induced contraction with a pA2 value of 10.11. Although YM-12617 was also a competitive antagonist toward clonidine at prejunctional alpha 2-adrenoceptors in the isolated rat vas deferens, its affinity for these receptors (pA2 = 6.41) was 5,000 times lower than that displayed for the postjunctional alpha 1-adrenoceptors in the isolated rabbit aorta. YM-12617 displaced both 3H-WB 4101 and 3H-clonidine binding to rat brain membranes; however, the affinity of YM-12617 for alpha 1-adrenoceptors (pKi = 9.64) was 3800 times higher than that for alpha 2-adrenoceptors (pKi = 6.06). Based on pA2 values obtained in the isolated tissues and pKi values in the binding assays, YM-12617 was 2-18, 36-117 and 1,740-5,750 times more potent than prazosin, phentolamine and yohimbine in antagonizing alpha 1-adrenoceptors, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombocytopenia: a risk factor for acute myocardial infarction during the acute phase of Kawasaki disease.

BACKGROUND: We report on 10 patients with Kawasaki disease and thrombocytopenia who were found to have a high incidence of coronary artery aneurysm and acute myocardial infarction. The clinical features of these patients, the cause of their thrombocytopenia and the relationship between cardiovascular pathology and thrombocytopenia were analyzed. METHODS: The clinical features of 10 patients with Kawasaki disease found to have thrombocytopenia (group A: mean age 8.0 +/- 7.0 months) and those of 293 patients with Kawasaki disease (group B, controls: mean age 13 +/- 20 months) were analyzed. Coagulation studies and bone marrow aspiration were performed to ascertain the cause of the thrombocytopenia in nine out of 10 subjects in group A. RESULTS: The minimum platelet count was 4-12 x 10(4)/mm3 (average day of illness, 10.3) and platelet counts were elevated to the baseline value within 1-2 weeks of onset of the illness. Low fibrinogen concentrations, high levels of fibrin degradation products, and low erythrocyte sedimentation rates with high C-reactive protein levels were observed in seven patients. In two other patients, immature megakaryocytes with normal coagulation values were observed. The differences in the incidence of coronary artery aneurysm and acute myocardial infarction between groups A and B were highly significant (coronary artery aneurysm: 60% in group A, 8.9% in group B; acute myocardial infarction: 40% in group A, 0.3% in group B). CONCLUSIONS: In many patients with Kawasaki disease and thrombocytopenia, the thrombocytopenia appears to be a result of intravascular coagulation, and to be one of the risk factors for acute myocardial infarction.

Angiographical and computed tomographic findings in diffuse pulmonary arteriovenous fistulas.

We reported two rare cases of diffuse pulmonary arteriovenous fistulas in infants and children. Both pulmonary angiography and chest computed tomography were obtained and revealed fine network formations clearly, from which the final diagnosis was made.

Isolated tissue and binding studies of YM-17690, a novel and non-analogous leukotriene agonist.

YM-17690, 3-[4-carboxymethoxy-3-[p-(4-phenylbutoxy) benzamido]phenyl]propionic acid, produced a dose-dependent contraction of guinea-pig ileum and its EC50 value was 1.6 X 10(-8) M. The response was not affected by pretreatment with atropine, mepyramine, indomethacin, dazoxiben and AA-861 (a 5-lipoxygenase inhibitor), but was inhibited by FPL-55712 (an LTD4 and LTE4 antagonist). YM-17690 induced dose-dependent contractions of guinea-pig lung parenchyma and trachea with EC50 values of 3.9 X 10(-9) and 2.2 X 10(-8) M, respectively. Pretreatment of these tissues with FPL-55712 resulted in a parallel shift of the YM-17690 dose-response curves to the right. The pA2 values for FPL-55712 in lung parenchyma and trachea were 7.41 and 8.21, respectively, and the slopes of the regression lines of Schild plots were 1.00 and 1.02, respectively. YM-17690 produced a dose-dependent inhibition of [3H]LTD4 binding to guinea-pig lung membranes and its pKi value was 9.28. However, the compound showed only 25% inhibition of [3H]TLC4 binding to guinea-pig hippocampus membranes, even at 10(-5) M. These results suggest that YM-17690 is a selective leukotriene (LTD4 and LTE4) agonist and that it will therefore be a valuable tool in the study of actions of leukotrienes and for the characterization of their receptors.

Doppler flow patterns through the ductus arteriosus in patients with congenital diaphragmatic hernia.

We investigated Doppler flow patterns through the ductus arteriosus (DA) of 13 newborn infants with congenital diaphragmatic hernia (CDH) using color Doppler ultrasonography (CDUS). Patterns were classified into 3 types: left-to-right (L-R), bidirectional (BD) and right-to-left (R-L) shunting. Among the 13 patients examined, 3 showed L-R shunting, 5 BD shunting and 5 R-L shunting. Patients with L-R shunting showed significantly better levels of PaO2 and AaDO2 than those with other Doppler flow patterns. However, there were no differences in clinical findings between patients with BD and R-L shunting. All patients with L-R shunting survived after CDH repair without pre-operative stabilization including Lipo-PGE1 (LPE) administration. Four of the 5 patients with BD shunting survived, but only one of the 5 patients with R-L shunting survived after CDH repair following administration of LPE. It was suggested that Doppler flow patterns through the DA may be useful for predicting prognoses and selecting suitable treatment for CDH.

A study of biohazard protection for farming modules of lunar base CELSS.

For the Closed Ecological Life Support System (CELSS) of a manned lunar base which is planned to be built on the moon early in the 21st century, several proposed programs exist to grow vegetables inside a farming module. At the 40th IAF (Malaga, 1989) the author et al presented a proposal for supplying food and nutrients to a crew of eight members, a basic concept which is based on growing four kinds of vegetables. This paper describes measures for biohazard protection in farming modules. In this study, biohazard protection means prevention of the dispersion of plant diseases to other plant species or other portions of farming beds.

Distribution of trace elements in the human body determined by neutron activation analysis.

Neutron activation analysis and instrumental semiconductor gamma-ray spectrometry were used for analysis of 20 trace elements in 10 autopsied human organs and tissues (liver, kidney, cerebrum, cerebellum, heart, muscle, pancreas, spleen, lung, and aorta) from 63 Japanese persons, whose ages ranged from 15 days to 85 yr. Distributions of aluminum, bromine, magnesium, manganese, rubidium, selenium, and vanadium in human body were almost uniform. High concentrations of cadmium were found in kidney and liver samples. There was a high mercury concentration in the liver, kidney, and brain samples. Concentrations of other elements (arsenic, gold, cobalt, chromium, copper, iron, indium, antimony, selenium, titanium, and zinc) in each organ or tissue are also presented in this paper.

The basic health care system for the lunar base crew.

A plan of the health care system for the crew on the lunar base is described in this study. The health care system consists of two subsystems. The first is the daily health care system. The system contains health care menus, similar to those on Earth, and some biochemical and ordinary medical examinations. The second system is a periodic medical inspection for the crew's bones and the determination of natural radioisotopes in the body. These care systems are automatically treated with the examination and data filing. Usually these examinations are carried out without the presence of a medical doctor. Examinations and files of the whole results are controlled by a computer. The daily results of examinations are compared with data in the file. If any abnormal values are found in the results, an appropriate message is sent advising whether he must receive an in-depth examination by a medical doctor, or be reexamined by the same submenu. The automatic health care system also records transactions with the life support monitoring system.