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Es hat als ein groβer Fortschritt im Anaphylaxiestudium zu gelten, daβ in unserem Institute eine neue Methode entdeckt wurde, und zwar die Antikorperverdtinnungsmethode nach Ogafa bei der Prazipitinreaktion, die gleichzeitig einen ausschlaggebenden Anhaltspunkt fur die zum Zustandekommen der Anaphylaxie erforderliche Reiniektionsmenge gibt. Wenn man keine sichere Methode fur die Bestimmung der Reinjektionsmenge hat, so besteht der Nachteil, daβ die todliche Reinjektionsmenge naturlich vom Korpergewicht der Tiere abhangt ohne ihm aber propbrtional zu sem, was schon Doerr37) beklagte. Nach der Ogalaschen Methode kann man hingegen feststellen, daβ die todliche Reinjektionsmenge dem Korpergewachte in der Tat nicht proportional ist, indem die absolute Menge durch die Bindungszone des Prazipitins beelnfluβt wird. Diese Tatsache ist aus den obigen Tabellen klar erslchtlich. Nach Levi-Crailsheim10) und Reymann8) verandert sich das dem Orgamsmus injizierte heterologe Hamoglobin zuerst in Globin, dann in Fibnnogen von glelcher Art ; nach Herzfeld u. Klinger9) verwandelt sich das Fibnnogen wlederum in Globulin, schlieβlich in Albumin. Diese Substanzen zergen die Antigemtat in groβerem oder genngerem Maβe. Misao13) benchtete schon, daβ er oft bel Immunrslerung von Hamoglobin neben dem Hamoglobinopraztpitin Praziprtine gegen jede Art Plasmaerwelβ bekam und eme Umbildung des im Organismus injizierten Hamoglobins annahm. Inagaki38) meinte feststellen zu konnen, daβ die Albuminsteigerung nach groBerem Blutverlust vom Globin herruhre. Aus den Reymannschen Untersuchungen ging hervor, daβ bei 2 normalen Pferden sich ebenfalls ein Zusammenhang zwischen der Abnahme der Erythrozytenzahl und der Globulinsteigerung zeigte, eine Beobachtung, die eine Stutze durch die Untersuchungen von Howe39) findet, wenn man seme mteressante Beobachtung, daβ Kalber mlt einem sehr niedrigen Globulingehalt im Plasma geboren werden, und daβ dieser Globulingehalt in den ersten Lebenstagen zunimmmt (eine Zunahme, die durch Ernahrung mlt Kolostrum betrachtlich gefordert wird), mit der bekannten Tatsache kombimert, daβ Neugeborene in den ersten Lebenstagen einen stark vermehrten Bilirubingehalt im Plasma bezitzen (Icterus neonatorum). Nach theoretischen Uberlegungen, nach denen die Auffassung des Globins als eine der Quellen der Fibrinogen-, Globulin- und Albuminsteigerung wahrscheinlich ist, sind meine obenerwahnten Versuche uber die Anaphylaxie angestellt worden ; deren Hauptresultat ist, daβ bei positiver Prazipitinreaktion durch Injektion der geeigneten Menge jedes Antigens (1/2- 1/3 × Bindungszone) die Versuchstiere mit typischem anaphylaktischem Schocktod zugrunde gehen. Mehrere Arbeiten unseres Institutes lieβen erkennen, daβ bei aktiver Anaphylaxie die anaphylaktischen Meerschweinchen durch Reinjektion von 1/4 der der Bindungszone entsprechenden Antigenmenge durch typische Anaphylaxie mit Schocktod verenden. Die zum sicheren anaphylaktischen Tode mit chemisch reinem Antigen notige Dosis war 1/2 oder 1/3 der der Bindungszone entsprechenden Antigenmenge. Diese Tatsache ist vielleicht teilweise durch niedrigen Antikorperwert zu erklaren. Pfeiffer u. Mila40) berichteten, daβ die durch Rinderserum sensibilisierten Meerschweinchen nur durch die Reiniektion des Rinderserums, nicht aber durch die des Hamoglobins mit anaphylaktischen Symptomen reagierten, daβ dagegen die durch Rinderhamoglobin sensibilisierten Meerschweinchen nicht nur durch die Reinjektion des Hamogloins sondern auch durch die des Serums mit ziemlich groβem Temperaturabfall reagierten. Diese Angaben stimmen gut mit meinen Experimenten uberein.

Die Gegenwart des die Glyko- sowie Taurocholsauren spaltenden Fermentes (Cholase) als Organpulver oder Glyzerinextrakt in verschiedenen Organen und Geweben, sowie ihre physikalisch-che-mischen Eigenschaften wurden untersucht und dabei folgende Ergebnisse gewonnen : 1. Die Cholase kommt in abnehmender Reihe in Niere, Leber, Skelettmuskel in ziemlich groβer Menge vor, in nur geringer Menge in absteigender Reihe in Herzmuskel, Milz, Lunge und Hoden. Die meiste Cholase wurde in der Hundeniere vorgefunden. Dann folgen der Wirksamkeit nach in absteigender Reihe : Rattenleber Kanlnchenniere und Kaninchenleber. 2. Die Wirkung der Cholase tritt am starksten nach 72 Stunden Digestion auf und ihr optimaler pH-Wert liegt bei 7.0 und 9.0. 3. Durch dieses Ferment wird die Glykocholsaure leichter zerlegt als die Taurocholsaure. 4. Die Cholase ist gegen Saure und Alkali bei pH-Wert zwischen 3.0-11.0 ziemlich bestandig, und noch wirksam bei Halten auf 650℃. 5. Das Ferment als Glyzerinextrakt ist an Kieselgur, Tierkohle, Kaolin und Tonerde adsorbierbar und zwar an die letztere am starksten und bei pH=3.7-4.5. Das Tonerdeadsorbat wird mittelst der Ammonphosphatlosung leicht eluiert und das Eluat, verglichen mit dem ursprunglichen Glyzerinextrakt, hundertfach an Cholase angereichert. 6. Bestdndigkeit der Cholase gegen Saure und Alkali, ihr Verhalten gegen Temperatur und Adsorptionsbedingungen an Tonerde u.s.w. erinnern wohl an das Histozym, aber es laβt sich nicht entscheiden, ob die Cholase mit dem Histozym identrsch rst.

A 34-year-old woman infected with human T cell leukemia virus type-I(HTLV-I) with recurrent thrombocytopenia and various autoantibodies is described. The platelet counts fluctuated between 1.3 x 10(4)/microliters and 14.8 x 10(4)/microliters without any medical treatment, and thrombocytopenia improved with a decrease of platelet-associated IgG (PA-IgG). Autoantibodies such as rheumatoid factor, antinuclear factor, anti-Sm, anti-RNP and anti-SSA antibodies were also recognized. Marker analysis of peripheral mononuclear cells showed an increase in the proportion of CD 25+ cells, CD 3+ HLA-DR+ cells, CD4+ HLA-DR+ cells and CD8+ HLA-DR+ cells. The recurrent thrombocytopenia and development of various autoantibodies in this HTLV-I carrier are speculated to be due to the alteration of B cell functions by T cells infected with HTLV-I.

Serum levels of total IgE, specific IgE, IgG and IgG4 against house dust mite were measured in mite-sensitive asthma patients receiving immunotherapy with house dust. Serum levels of total IgE, mite specific IgE and IgG did not significantly change during the course of hyposensitization. Increased levels of mite specific IgG4 were observed in patients during immunotherapy. The increase in specific IgG4 was dependent on the total dose of house dust administered in both children (r = 0.636, p less than 0.001) and adults (r = 0.629, p less than 0.01). However, the increase of specific IgG4 in adults was not as apparent as in children. These results might suggest that mite specific IgG4 is a useful immunological marker in the immunotherapy for allergic asthma, and that IgG4 antibody acts as a blocking antibody in atopic bronchial asthma.

Cellular stimulating factors on cell proliferation in the supernatants of chick embryo carcases and adult muscles were studied. There were plural stimulating factors in embryonic and adult muscular supernatants that promoted cell proliferation without any supplement of sera and other materials. Salting-out methods with ammonium sulfate, ethanol fractionation, and isoelectric precipitation were used to isolate the stimulating factors, and these three methods proved the presence of plural stimulants on cell proliferation in the supernatants of chick embryo and adult muscles. The stimulants had altered physico-chemical properties and biological activities due to embryological development. The embryonic stimulants enhanced the synthesis of DNA and protein remarkably, and RNA synthesis in whole cell systems slightly. The muscular stimulants enhanced protein synthesis without any stimulation of DNA and RNA synthesis. Partial purification of the stimulants from the ethanol fractions was performed by DEAE-cellulose chromatography and Sephadex gel chromatography.

The tubular basement membrane (TBM) (i.e. tubular basal lamina) of rat kidney was shown to be a fine meshwork by electron microscopy after negative staining. Strands of the meshwork formed a regular three dimensional lattice work. The pores of the meshwork were polygonal. There were two main pore sizes: one approximately 30 A in diameter, the other 42--60 A. In view of our previous observation that glomerular and alveolar basement membranes were made up fine meshwork, it is quite possible that the basement membranes of other organs are also made up such fine meshwork.

A 26-year-old female with Bartter's syndrome associated with Graves' disease is reported. This patient had a history of Graves' disease from the age of 22 and anti-thyroid drug (Methimazole) had been administered for 2 years. Thyroid function returned to normal but general fatigue and polyuria continued. Hypokalemia was diagnosed at 25 years of age and she was referred to our hospital for evaluation. Blood pressure was normal and laboratory data revealed normal thyroid function, hypokalemic alkalosis, high plasma renin activity and high plasma aldosterone concentration. She showed normal pressor sensitivity to norepinephrine infusion, grossly diminished pressor sensitivity to exogenous angiotensin II infusion compared with the normal. A renal biopsy specimen showed juxtaglomerular cell hyperplasia. Electron microscopy confirmed lacis cell (agranular cell) proliferation.

CD14 is a pattern recognition receptor on myeloid cells and plays a pivotal role in an innate immune system that is responsible for Gram-negative and Gram-positive bacteria infection. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, can induce production of a large quantity of proinflammatory cytokines into the circulation mediated by CD14-mediated macrophages and monocytes. These cytokines eventually cause septic shock. Several in vitro and in vivo studies have shown that suppression of a CD14 function by a CD14 antibody led to an inhibition of the production of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-8. In the present study, we found that CD14 antisense oligonucleotide (ODN) can prevent lethal LPS shock in D-galactosamine-sensitized mice. This ODN inhibited CD14 expression in a mouse macrophage cell line, RAW264.7, and suppressed production of TNF-alpha in LPS-stimulated RAW264.7 cells. Furthermore, we designed a consensus antisense ODN that could hybridize human and mouse CD14 RNA, and we evaluated its efficacy. The consensus antisense ODN rescued mice primed with Mycobacterium bovis bacillus Calmette-Guerin (BCG) from the LPS-induced lethal shock. In this model, the CD14 antisense ODN down-regulated LPS-elicited CD14 expression in the liver, resulting in a decrease in LPS-induced TNF-alpha production. These findings suggest that the CD14 antisense ODN is distributed in the liver and efficiently suppresses LPS-induced TNF-alpha production by reducing CD14 expression on Kupffer cells. This CD14 antisense ODN may be useful for the development of a therapeutic agent against sepsis and septic shock.

Changes in brain vascularity in adult rats during adaptation to chronic normobaric hypoxia with or without elevated CO(2) were morphometrically investigated. Immunohistochemistry with anti-rat endothelial cell antigen (RECA-1) antibody was carried out for the vascular analysis. After the rats were subjected to hypoxia for 2 to 8 weeks (wks)(10 percent O(2) in N(2)), the total area of blood vessels was measured in 6 brain regions. After 2 wks of hypoxia, the blood vessel area was found to be significantly increased in the frontal cortex, striatum, hippocampus, thalamus, cerebellum, and medulla oblongata, by 44% , 96% , 65% , 50% , 102% and 97% , respectively. The ratio of large vessels with an area > 500 micro m(2) was also increased in all brain regions. Hypoxic adaptation in brain vascularity did not change during 8 wks of hypoxia, and the hypoxia-induced levels measured in the vasculature returned to control levels 2 wks after the termination of hypoxia in areas of the brain other than the cortex and thalamus. In addition, hypoxia-induced changes in terms of the total vascular area and vessel size distribution were significantly inhibited by the elevation in CO(2), whereas chronic hypercapnia without hypoxia had no effect on brain vascularity. These findings suggested that adaptations in brain vascularity in response to hypoxia are rapidly induced, and there are regional differences in the reversibility of such vascular changes. Carbon dioxide is a potent suppressor of hypoxia-induced vascular changes, and may play an important role in vascular remodeling during the process of adaptation to chronic hypoxia.

There is little information available concerning the influence of right bundle branch block (RBBB) on the prognosis of patients with inferior myocardial infarction (MI). In this study we evaluated the influence of RBBB on the short-term prognosis of patients with inferior MI. Our study subjects were 1,265 hospitalized patients with Q wave MI. Patients were divided into 4 groups based on the presence or absence of RBBB and on the location of the infarction. RBBB was classified into 4 categories according to the timing of its appearance and its duration as new permanent, transient, old and age indeterminate. In-hospital death and pulmonary congestion were observed more frequently in patients with RBBB than in those without RBBB. Moreover, in inferior MI as in anterior MI, in-hospital death and pulmonary congestion occurred more frequently in new permanent RBBB patients than in patients with other types of RBBB. Multivariate regression analysis reveals that new permanent RBBB was a strong independent predictor for an adverse short-term prognosis in patients with inferior MI, as well as in patients with anterior MI. New permanent RBBB during inferior MI is a strong independent predictor for increased in-hospital mortality, regardless of the infarction location.

Angiogenesis involves complex processes mediated by several factors and is associated with inflammation and wound healing. High mobility group box 1 (HMGB1) is released from necrotic cells as well as macrophages and plays proinflammatory roles. In the present study, we examined whether HMGB1 would exhibit angiogenic activity in a matrigel plug assay in mice. HMGB1 in combination with heparin strongly induced angiogenesis, whereas neither HMGB1 nor heparin alone showed such angiogenic activity. The heparin-dependent induction of angiogenesis by HMGB1 was accompanied by increases in the expression of tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor-A120 (VEGF-A120). It is likely that the dependence of the angiogenic activity of HMGB1 on heparin was due to the efficiency of the diffusion of the HMGB1-heparin complex from matrigel to the surrounding areas. VEGF-A165 possessing a heparin-binding domain showed a pattern of heparin-dependent angiogenic activity similar to that of HMGB1. The presence of heparin also inhibited the degradation of HMGB1 by plasmin in vitro. Taken together, these results suggested that HMGB1 in complex with heparin possesses remarkable angiogenic activity, probably through the induction of TNF-alpha and VEGF-A120.

We report 2 cases of small cell carcinoma (SmCC) of the stomach with distant metastasis that were treated with the same chemotherapeutic regimens as used to treat small cell lung cancer. Although the mean survival of patients with SmCC of the stomach is reported to be only 7 months, our patients survived for 15 and 14 months, respectively. In our experience, these chemotherapeutic regimens might provide a survival benefit for patients with SmCC of the stomach, although they demonstrated no remarkable antitumor effects.

Interaction between the receptor for advanced glycation end products (RAGE) and its ligands has been implicated in the pathogenesis of various inflammatory disorders. In this study, we establish an in vitro binding assay in which recombinant human high-mobility group box 1 (rhHMGB1) or recombinant human S100A12 (rhS100A12) immobilized on the microplate binds to recombinant soluble RAGE (rsRAGE). The rsRAGE binding to both rhHMGB1 and rhS100A12 was saturable and dependent on the immobilized ligands. The binding of rsRAGE to rhS100A12 depended on Ca2 and Zn2, whereas that to rhHMGB1 was not. Scatchard plot analysis showed that rsRAGE had higher affinity for rhHMGB1 than for rhS100A12. rsRAGE was demonstrated to bind to heparin, and rhS100A12, in the presence of Ca2, was also found to bind to heparin. We examined the effects of heparin preparations with different molecular sizesunfractionated native heparin (UFH), low molecular weight heparin (LMWH) 5000Da, and LMWH 3000Da on the binding of rsRAGE to rhHMGB1 and rhS100A12. All 3 preparations concentration-dependently inhibited the binding of rsRAGE to rhHMGB1 to a greater extent than did rhS100A12. These results suggested that heparin's anti-inflammatory effects can be partly explained by its blocking of the interaction between HMGB1 or S100A12 and RAGE. On the other hand, heparin would be a promising effective remedy against RAGE-related inflammatory disorders.

The involvement of macrophages in the induction of metallothionein (MT) synthesis by bacterial endotoxin was studied in vitro. Rat peritoneal macrophages were incubated with endotoxin. The incubation medium from endotoxin-activated macrophages accelerated MT synthesis by human hepatic Chang cells. However, the incubation medium from non-activated macrophages did not. Endotoxin added to the culture medium of Chang cells was ineffective in inducing MT synthesis. The contents of zinc, copper and cadmium, which are primary inducers of MT, in the incubation medium of macrophages in the presence of endotoxin were not different from those in the absence of endotoxin. These results suggest that MT synthesis is induced by endotoxin-treated macrophages.

Metaplastic bony tissue along with hyperplastic mucosal epithelium showing no atypism was detected in biopsy materials from a Yamada type I gastric polyp. The tissue was metaplastic woven bone associated with calcification. Histogenesis of the bone formation is as yet unknown. This is the first reported case of the presence of metaplastic bone accompanied by hyperplastic gastric mucosa so far.

A significant amount of anticoagulant substance was released along with histamine, when human lung mast cells were stimulated with anti-IgE and Ca-ionophore A23187. Its activity was lost by heparinase, not by chondroitin-ABC lyase or chondroitin-AC lyase, and also inhibited by Polybrene, suggesting it would be heparin.

Rat kidney glomerular basement membrane (GBM) was isolated and digested with alpha-amylase and elastase. Electron microscopy revealed a meshwork structure composed of fibrils 3 nm in width. They appeared to be type IV collagen fibrils. We succeeded in clarifying a significant ultrastructural aspect of the GBM which had been unclear until now. The findings are consistent with our previously proposed GBM molecular sieve theory.