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Head injury or hemorrhagic cortical infarction results in extravasation of blood and breakdown of red blood cells and hemoglobin. Iron liberated from hemoglobin, and hemoglobin itself, are associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS have been demonstrated to be involved in the mechanism of seizures induced by iron ions in the rat brain, an experimental animal model for posttraumatic epilepsy (PTE). ROS are responsible for the induction for peroxidation of neural lipids, i.e., an injury of neuronal membranes, and also could induce disorders in the excitatory and inhibitory neurotransmitters. Antioxidants, such as a phosphate diester of vitamin E and C (EPC-K1) and antiepileptic zonisamide, have been known to prevent the epileptogenic focus formation, or to attenuate seizure activities in the iron-injected rat brain. Natural antioxidants, such as alpha-tocopherol, and condensed tannins, including (-)-epigallocatechin and (-)-epigallocatechin-3-O-gallate, adenosine and its derivative, melatonin, uyaku (Lindera Strychnifolia), fermented papaya preparations, Gastrodia elata BI., and Guilingji, have been demonstrated to scavenge ROS and/or RNS and to be prophylactic for the occurrence of epileptic discharge in the iron-injected rat brain.

A total of 45 cases of multiple myeloma has been followed up clinically during the period from 7 to 80 months. Out of these, six patients (13.3%) were diagnosed to be the tumor-forming type; they developed discrete tumor formation at the disease onset or during clinical observation. Biological behavior of these cases is briefly outlined. Histologically, five cases presented with well or moderately well differentiated plasma cells according to the grading made by Pasmantier and Azar. The remaining one case was poorly differentiated in cell maturity, and with electron and immunofluorescence microscopies, proved to be of plasmacytic nature.

Spleen cells from tumor-bearing mice showed decreased natural killer (NK) activity and decreased binding to target cells with progression of the tumor. Treatment of spleen cells from tumor-bearing mice with vibrio cholerae neuraminidase (VCN) increased the cytotoxicity to a level twice or more as high as that of untreated cells, but the same treatment of spleen cells from normal mice had no or little effect. On the other hand, neither in spleen cells from tumor-bearing mice nor in those from normal mice, the VCN treatment had no effect on their binding to M-HeLa cells. The suppression of NK activity by preincubation with serum from tumor-bearing mice or prostaglandin E2 was completely abolished by VCN treatment. The above results indicate that VCN treatment of lymphocytes might augment NK activity by an antagonistic effect against an immune suppressive factor.

The influence of surgical stress on the natural killer (NK) activity of peripheral blood lymphocytes in patients with carcinoma of the lung or gastrointestinal system was studied. The peripheral blood lymphocytes of the patients showed a marked decrease in NK activity against K-562 cells as target cells 1-2 days after surgery. The activity remained lowered for 2 weeks after thoractomy and for 1 week after laparotomy. No appreciable suppression of NK activity was observed with normal human peripheral blood lymphocytes preincubated with postoperative patient sera. Peripheral blood mononuclear cells obtained postoperatively from patients lost NK activity after ultraviolet irradiation, without any detectable loss of viability. Such irradiated mononuclear cells showed inhibition of NK activity after a 24-hour preincubation with peripheral blood lymphocytes from normal subjects. Similar suppressive activity was demonstrable in a fraction of mononuclear cells with adhesiveness to plastic petri dishes, while non-adherent cells had no such activity. When added immediately to the cytotoxicity assay system without the 24-hour preincubation, patient mononuclear cells caused no inhibition of NK activity, whereas adherent cells from normal subjects enhanced NK activity. The findings seems to indicate that, following surgical stress, plastic dish-adherent peripheral blood mononuclear cells become deprived of NK helper activity and exert suppression, thus causing postoperative depression of NK activity.

The soluble protein, whole soluble protein, globulin and albumin fraction from human placenta, both normal and toxemic, have been introduced repeatedly into normal and pregnant rabbits and histological changes in the liver were observed. The striking changes in the liver have been induced by treating the animals with the globulin fraction and histologic pictures suggest that the toxemic liver damage is of allergic nature.

1. In the bile of rabbits, the metabolisms of biliverdin and bilirubin are in a solucible state, and which have a ratio of 2: 1 in normal animals. 2. In the production of biliverdin, the liver, especially the parenchyma of the liver has a very important role, while that of the reticulo-endothelial system is rather minor. However, in the case of glucose administration, the reduction of bilirubin from biliverdin is performed in the reticulo-endothelial system, thus conferring an important part of this system. 3. The production of bilirubin is performed primarily extrahepatically, and the participation of the extrahepatical reticuloendothelial system is of a conservative nature, thus denying us any willingness to agree to the theory of bilirubin production in the reticulo-endothelial system. 4. On administration of hemolysed blood, bile pigments in bile demonstrate a remarkable increase, while as compared when injected into the auricle veins in cases of administration through the portal vein a decline in the functions of the liver reticulo-endothelial system is seen, causing a decrease in biliverdin amount. In the former modus of administration, an occasional stimulation of the liver reticulo- endothelial system is seen, causing reduction of biliverdin to bilirubin. 5. Concluding from these facts, biliverdin in rabbit bile occupies the role of an intermediate product in the production and metabolism of bilirubin.

The cytostatic and cytotoxic effects of highly purified natural human tumor necrosis factor (HuTNF-alpha) and natural human interferon-alpha (HuIFN-alpha) on 23 cell lines were studied in vitro. Natural HuTNF-alpha showed cytostatic and cytotoxic effects on PC-9, KHG-2, HT-1197, KG-1 and L-929 cells, and HuIFN-alpha showed both effects on KHG-2 and Daudi cells. A mixture of HuTNF-alpha and HuIFN-alpha (1:1, by unit) showed cytostatic and cytotoxic effects on HuTNF-alpha- or HuIFN-alpha-resistant cell lines such as KB, KATO-III, HEp-2, P-4788, as well as on HuTNF-alpha- or HuIFN-alpha-susceptible cells. Thus, the combined preparation of HuTNF-alpha and HuIFN-alpha expanded the spectrum of sensitive cells. The dosage of the mixed preparation required to produce 50% inhibition of cell growth was less than 20% of that of HuTNF-alpha or HuIFN-alpha alone. These results indicate that the cytostatic and cytotoxic effects of HuTNF-alpha and HuIFN-alpha are synergistically enhanced when they are administered together.

Leu-7 positive lymphocytes, including natural killer cells, play an important role in the immune system's surveillance function to prevent the development of cancer. The incidence of lung cancer is significantly high in patients with end-stage pulmonary fibrosis. We hypothesized that the number of Leu-7 positive cells may be decreased in areas of severe pulmonary fibrosis. To demonstrate this, Leu-7 positive cells were immunohistochemically stained in 41 lung specimens obtained from patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders. The number of Leu-7 positive cells was evaluated according to the pathological findings. In pathologically normal lung, Leu-7 positive cells were mostly found within the capillaries of the septa and rarely in the alveolar space or the stroma. The number of Leu-7 positive cells was 0.69 +/- 0.15 in areas of advanced fibrosis (n = 41), 2.39 +/- 0.60 in areas that had newly developeing fibrosis (n = 41), 1.14 +/- 0.57 in bronchiolitis obliterans organizing pneumonia (n = 9), and 1.35 +/- 0.87 in diffuse alveolar damage (DAD) (n = 11). The number of Leu-7 positive cells in areas of newly developing fibrosis (2.39 +/- 0.60) was significantly higher than that in areas of established fibrosis (0.69 +/- 0.15, P < 0.05). Our present study demonstrates a significant decrease in the number of Leu-7 positive cells in areas of advanced fibrosis. This evidence may partly explain the high incidence of lung cancer associated with pulmonary fibrosis.

Tremendous excitement has been generated by the use of botulinum toxin for the treatment of various types of urethral and bladder dysfunction over the past several years. Botulinum toxin is the most lethal naturally occurring toxin known to mankind. Why, then, would an urologist want to use this agent to poison the bladder or urethral sphincter? In this review article we will examine the mechanisms underlying the effects of botulinum toxin treatment. We will discuss the current use of this agent within the urologic community and will provide perspectives on future targets of botulinum toxin.

Transforming growth factor-beta1 (TGF-beta1) exerts potent immunosuppressive effects. In this study, we investigated the potential role of TGF-beta1 produced by hepatocellular carcinoma (HCC) cell lines in immunosuppression mechanisms. Using the Mv1Lu cell-growth inhibition assay and an enzyme-linked immunosorbent assay (ELISA), we detected optimal levels of TGF-beta1 in the culture supernatants conditioned by the HCC cell lines PLC/PRF/5, Hep3B, and HepG2. To determine the biological activity of TGF-beta1 in the supernatants, we examined the effects of the culture supernatants on the production of interferon (IFN)-gamma induced during the culture of peripheral blood mononuclear cells (PBMCs) stimulated with interleukin (IL)-12. IFN-gamma production of IL-12-stimulated PBMCs in the 1:1 dilution of the acid-activated conditioned medium of PLC/PRF/5, Hep3B, and HepG2 reduced to 14.7 +/- 0.8, 17.3 +/- 9.0, and 35.9 +/- 14.6%, respectively, compared with the value in the culture with control medium (complete culture medium). These results suggest that HCC cells producing TGF-beta1 may reduce the generation or activation of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, and thus could enhance their ability to escape immune-mediated surveillance.

The preS2 region of the hepatitis B virus (HBV) has been reported to have human polymerized albumin receptor (PAR) activity, which correlates with viral replication. Here, we studied the genomic sequence of the preS region from rare patients lacking PAR activity, despite active viral replication. PAR and DNA polymerase activity was identified in 178 HBe antigen-positive HBV carriers, and a significant correlation between 2 markers was shown, except in 2 hepatitis patients lacking PAR activity. Nucleotide sequences of the preS region of HBV from both patients were examined by direct sequencing of PCR products. In one patient, a 45-base deletion was found to overlap half of the putative polymerized human albumin binding site in the preS2 region. In the other patient, a point mutation at the first nucleotide of the start codon of the preS2 region of HBV was found. There was no such genomic change in the 3 control HBV sequences. These results indicate that the preS2 region is necessary for binding of polymerized human albumin, and this is the first report of naturally existing mutant virus with no or low PAR activity.

The analgesic effects of morphine and some related compounds, such as meperidine, observed by the conventional method, are supplemented by the release of epinephrine from the adrenal medulla. It is assumed that this action of epinephrine is not due to an additive synergy in the analgesic effect but to the face that the action of epinephrine on a definite higher center or centers effects synergistically in the reflex depressant action of these analgesic agants. This assumption is based on the following evidences. Prolongation of reaction time in mice by morphine and meperidine (but not by ohton), determined by the hot-plate method, was significantly reduced by adrenalectomy and this reduction was normalized by the concurrent use of epinephrine, in a small dose which in itself cannot prolong the reaction time. No such action was found in cortisone and DOCA. The effects of morphine and meperidine in prolonging the reaction time were reduced by priscol and dibenamine, as well as by tetraethylammonium salt. A large dose of pyrazolone derivatives causes, not the prolongation of reaction time but a jumping reflex response in the early stages, indicating central excitation, in part of the mice. The ratio of mice exhibiting such an early reflex increases with adrenalectomy or the administration of dibenamine, and is markedly decreased by epinephrine, insufficient to show any analgesic response by itself, and by cortisone. This action of cortisone indicates some difference in the natures of central excitation by pyrazolones and by morphine. Judging from the work of SCHAYER18, the distribution in the brain of epinephrine injected in the dose to normalize the reduced effect of morphine in the adrenalectomized mice, may also be anticipated by the epinephrine which might be released from the adrenal medulla by morphine in an amount much smaller than the "near·lethal doses9 ".

By prepariug over 100 thin slices from 77 cases of urinary calculi mainly consisted of vesical calculi and immersing them in various solvents, the solubility of these calculi has been examined by polarization microscopy from the standpoints of the composition and structure of urinary calculi. (1) MgNH4P04·6H20 (struvite) has been found to be most soluble and it is the best example in the dissolution of urinary calculi; and as for the solvents, Versene proved to be the best solvent. (2) The alkaline pH seems to have an intimate relationship with the dissolution of uric acid calculi. (3) Calcium oxalate proved to be insoluble in any solvent. In addition, no difference in its stability against solvents could be recognized in its monohydrate or dihydrate: (4) Cystine dissolved in the 10% Versene solution. (5) Amorphous-like substance apparently was dissolved slightly in 0.5% urease solution at 37°C, however, it is not possible to dissolve this substance completely, From these results calcium oxalate and amorphous-like substance seem to be the most difficult substances to dissolve, and therefore, the bearing they have on the dissolution of urinary calculi seems to most significant. In the present stage where little is known of real etiologic factors concerning the formation of urinary calculi, in the clinical application of the dissolution of stones further studies need to be carried on, but from the very nature of construction of urinary calculi, the local dissolution methods seem to be rather difficult at present, and rather somatic dissolution in connection with prophylaxis against recurrent stones seems to be the direction in which future studies need to be carried out.

Gamma-Glutamylpropargylglycylglycine (gamma-Glu-PPG-Gly) was isolated as a metabolite of propargylglycine (2-amino-4-pentynoic acid, a natural and synthetic inhibitor of cystathionine gamma-lyase) from human blood incubated with D,L-propargylglycine in the presence of L-glutamate and glycine, and identified by fast-atom-bombardment mass spectrometry, indicating that human blood can metabolize propargylglycine to gamma-Glu-PPG-Gly. When whole blood was incubated with 2 mM D,L-propargylglycine in the presence of 10 mM L-glutamate and 10 mM glycine at 37 degrees C for 16h, 0.094+/-0.013 micromol of gamma-Glu-PPG-Gly was formed per ml of whole blood. When erythrocytes were incubated under the same conditions for 16h, 0.323+/-0.060 micromol of gamma-Glu-PPG-Gly was formed per ml of erythrocytes, suggesting a large contribution of erythrocytes to gamma-Glu-PPG-Gly formation in whole blood. The apparent Km value of gamma-Glu-PPG-Gly formation in human erythrocytes for D,L-propargylglycine was 0.32 mM. The observed rate of gamma-Glu-PPG-Gly formation and the Km value for D,L-propargylglycine suggest that metabolism of propargylglycine to gamma-Glu-PPG-Gly can play a definite biological role in human subjects who are loaded with propargylglycine.

Our purpose was to investigate developmental alterations of human alpha-fetoprotein (AFP) oligosaccharides in maternal serum by lectin affinity electrophoresis and to compare the AFP glycoforms in maternal serum with those in umbilical cord serum and amniotic fluid. AFP glycoforms were separated by affinity electrophoresis with concanavalin A (Con A), lentil lectin (LCA), erythroagglutinating phytohemagglutinin (E-PHA) and Allomyrina dichotoma lectin (allo A) and detected by sensitive antibody affinity blotting. In maternal serum, increased proportions of Con A-nonreactive AFP (AFP-C1), LCA strongly-reactive AFP (AFP-L3) and E-PHA-reactive AFP (AFP-P4 and AFP-P5) decreased gradually during the early gestational weeks. Allo A-nonreactive AFP (AFP-A1 and asialo-AFP) were found only in amniotic fluids during early gestational weeks. The percentages of these glycoforms at full term were almost the same among those body fluids. Since the glycoforms of maternal serum AFP were close to those of umbilical cord serum AFP, lectin-affinity electrophoretic analysis of maternal serum AFP may be useful for evaluating the developmental state of fetus by examining the nature of AFP sugar chain.

To better understand the nature of the symptoms of depression in the early stages of Pick's disease, we performed a retrospective study of the medical records of eight patients who were originally treated for major depressive disorders before being clinically diagnosed with Pick's disease. Six of the eight manifested psychomotor retardation and social withdrawal, seven of the eight were agitated and five of the eight showed hyperbulia too. However, only two of the eight showed melancholia or physical symptoms such as insomnia or loss of appetite. All patients were treated with antidepressants but these were not effective in relieving the symptoms of depression. The data we gathered in this study will be useful in the future for distinguishing between Pick's disease-related depression (in the early stages of the disease) and major depression.

Cellular immunocompetence was investigated in 17 cases of aortitis syndrome (3 active, 14 inactive stage). Both the active and inactive groups demonstrated significantly lower interleukin-2 (IL-2) production than healthy volunteers. The active aortitis syndrome group produced significantly more interleukin-1 beta (IL-1 beta) than the inactive group. The proportion of CD11b+ CD8+ cells was significantly lower in the active aortitis syndrome group. Further, the proportions of CD11b- CD8+ cells and CD57+ CD16- cells in the aortitis syndrome patients were significantly higher than the healthy volunteers. These results suggest that there are intrinsic qualitative abnormalities in the T cells that produce IL-2 in aortitis syndrome. Pathogenesis of aortitis syndrome is considered as follows: during the active stage, diminished IL-2 production impairs differentiation and proliferation of suppressor T cells, thus creating abnormalities in the inhibitory functions of immunoregulation and promoting the proliferation of cytotoxic T and natural killer (NK) cells. This presumably initiates inflammation of the aorta and/or artery.

The results obtained in this investigation may be summarized as follows : 1. The CO2-output of the male muscle and other tissues is greater than that of the female. 2. The female muscle contains larger amount of water than the female muscle. 3. The muscle immersed 1/2 Ringer solution (or 1/2.5 R.) gave out smaller amount of CO2 per minute than the muscle in 2-Ringer's solution (or 2.5 R.). In spite of the difference in the water content of tissue between different sex, the salt content of the tissue liquid seems to be the same. In other words, larger the water content means larger content of tissue liquid in the tissue. Artificial introduction of water in the tissue or reduction of water content by immersing the tissue in 1/2 or 2-Ringer's solution is quite different from the natural condition occurring between different sex. However both of these conditions influence the gaseous metabolism in the same manner. On an assumption that the gas diffusion in liquid is proportional to the solubility of that gas, the above mentioned difference of CO2-output should be just reversed. Therefore it is not possible to interpret how the water content influences the gaseous metabolism. It may only be stated that the muscle which has a small amount of water to an extent which does not abolish excitability, gives out much CO2 and vice versa.

1. The properdin levels in sera from mice bearing Ehrlich ascitic carcinoma and from rabbits with Brown-Pearce carcinoma decrease inversely with the increase of the ascites or the tumors. In the incipient period of tumor transplantation, the level rather rises. When the tumor is proliferating or large, the level keeps falling or is low. On the contrary, when the tumor is regressing or disappears, the level elevates or reverts to that before transplantation. Strong A and R III mice with spontaneous mammary cancer have markedly low serum properdin levels as compared with those of healthy mice. 2. The properdin levels are less than 2 units per milliliter of the serum in 44.4 per cent of patients with gastric cancer, in 18.2 per cent of ones with non-malignant tumor and in 18.2 per cent of ones with gastric or duodenal ulcer. The abnormal low level has been found in 33.3 per cent of patients without recurrence, who had undergone extended radical gastrectomy combined with radical lymphadenectomy for gastric cancer. 3. Some correlation can be seen between the serum properdin levels and the degree of progress of gastric cancer. 4. The cancer patients with low total serum protein have lower serum properdin levels than those having nomal protein. 5. As for influence of surgical operation on the serum properdin levels, there is observed a tendency that a minor operation causes the levels to increase and a major operation causes the levels to fall. 6. It has been inferred that the properdin system could be one of the host natural resistance against cancer.