[Clinical efficacy of sulbactam/ampicillin in comparison with cefotiam in the treatment of elderly patients with pneumonia].

Clinical efficacy and safety of pareteral sulbactam/ampicillin (SBT/ABPC) was compared with cefotiam (CTM) in a randomized clinical trial of pneumonia in the elderly at 13 National Hospitals of Kyushu island. 37 patients received SBT/ABPC 3 g i.v., b.i.d., and 31 patients received CTM 1 g i.v., b.i.d. for 7 to 14 days. 1. 68 patients (37 for SBT/ABPC and 31 for CTM) were evaluated for safety. No statistical differences were noted in the patients' backgrounds of either group. 2. The clinical efficacy of SBT/ABPC was 96.3% (26/27 cases) while CTM was 75.2% (17/23 cases). This was found to be statistically significant (Fisher's exact test: p < 0.05). 3. 100% of evaluated cases (10 for SBT/ABPC and 4 for CTM) showed bacterial elimination. 4. No side effects were observed in the study. 5. Abnormal laboratory findings were noted in 10.8% (4/37 cases) for SBT/ABPC and 3.2% (1/31 cases) for CTM. The major adverse events were mild elevation of GOT, GPT and A1-P for SBT/ABPC, and mild platelets overproduction for CTM. No statistical differences were noted in both groups. These results are consistent with SBT/ABPC as a highly effective antibiotic in the treatment of elderly patients with pneumonia.

[Isolation of vero-cytotoxin-producing Escherichia coli from cattle and serotyping and toxin-typing of the isolated strains].

Two hundred and sixty-six piglets with diarrhea (from 4 farms), 73 healthy pregnant pig (from 2 farms), 27 calves with diarrhea (from 9 farms) and 47 healthy milk cows (from 1 farm) were examined for Vero-cytotoxin-producing Escherichia coli (VTEC), and 52, 11, 15 and 67 strains of VTEC were isolated from 17 piglets, 11 pregnant pigs, 6 calves and 23 milk cows, respectively. All VTEC strains from the piglets produced only VT2vp, while the strains from the healthy pigs did not produce VT2vp, but did VT1 and/or VT2. Most VTEC strains from calves and cows produced VT2vhb and some produced VT2 and VT1. Serotyping of the isolated strains showed that many strains from the piglets belonged either O139:H1, O141:H4 or O141:HUT, but the strains from the pigs were either R-form or O-untypable. Many strains from the calves and cows were serotyped into O116 or O113, but there were several R-form and O-untypable. From these results, it is suggested that VTEC strains, especially from the pregnant pigs, calves with diarrhea and healthy milk cows, which produced the same type of Verotoxins to that produced by human isolates, may become sources of human infections.

Extended use of Fluosol emulsion in acute myocardial ischemia treatment.

An intravenous infusion of Fluosol enhanced significantly the t-PA thrombolysis of the arterio-venous shunt made by insertion of 125I-fibrin clot in rabbits. The plasma radioactivity released through thrombolysis increased in both time and dose-dependent manner after the administration of t-PA. Fluosol in combination with t-PA increased the plasma radioactivity, compared with the t-PA treatment alone at the corresponding dosage. The coronary blood flow was markedly reduced to almost zero after the thrombin injection into narrowed LCX with a clamp in open-chest dogs. An intravenous infusion of Fluosol or Pluronic F-68 solution at a dose of 15 ml/kg significantly shortened the thrombolysis time by intracoronary infusion of urokinase alone. While, little change in the QTc interval of ECG and the plasma CPK-MB activity was observed in the Fluosol group in combination with urokinase, suggesting a myocardial protective action of Fluosol possibly due to its oxygen carrying effect.

Immunological Survey of Planktonic Embryos and Larvae of the Starfish Asterina pectinifera, Obtained from the Sea, Using a Monoclonal Antibody Directed against Egg Polypeptides.

A monoclonal antibody, K1, specifically recognizes polypeptides with apparent molecular masses of 56 and 58 kDa, in the egg of the starfish Asterina pectinifera. The K1 antibody reacted with extracts prepared from ovaries, oocytes, morulae, blastulae, gastrulae, and bipinnariae. Brachiolariae, testes, pyloric ceca, body walls, and tubefeet did not contain K1-reactive antigenic molecules. Extracts of eggs of the starfish Asterias amurensis and several sea urchin species did not react with the K1 antibody. Among the members of the genus Asterina, extracts of brachiolariae of A. batheri and A. minor were not reactive, whereas blastulae and brachiolariae of A. pseudoexigua pacifica did contain an antigenic component. Unlike the antigenic peptides in A. pectinifera eggs, the apparent molecular mass of the antigen molecule in embryos and larvae of A. pseudoexigua pacifica was 41 kDa, which represents a remarkable phylogenetic variation of antigen molecules. Using the K1 antibody, we have developed an assay system that detects embryos and larvae of A. pectinifera in complex mixtures of biological specimens obtained from the sea.

[New quantitative parameters for CT evaluation of orbitopathy in dysthyroid ophthalmopathy].

The new index (c/o ratio) is defined as the content of the orbit divided by the capacity of the bony orbit on the mid-orbital axial CT slice showing the medial and the lateral rectus muscles and optic nerve. Other quantitative parameters such as for exophthalmos and the capacity of bony orbit were also obtained on CT films. These parameters were measured in 474 eyes of patients with dysthyroid ophthalmopathy. The capacity of bony orbit showed large variations among all patients. The average for males was 17.8cm3 and that for females was 16.1cm3. Exophthalmos measurement on CT is more reliable than that by the Hertel exophthalmometer. The new index (c/o ratio) is a very reliable parameter for evaluating orbitopathy in dysthyroid ophthalmopathy. A large c/o ratio (greater than 1.6) was of clinical significance, because approximately 70% of the enlargement of the extraocular muscle observed in older patients (greater than 40 yrs old) was associated with a large c/o ratio (greater than 1.6).

Tumoricidal activity of lymphotoxin (tumor necrosis factor beta) in vivo: its effects on macrophages.

We investigated the cytotoxic activity of recombinant human lymphotoxin (rHuLT) against Meth A sarcoma in vitro and in vivo. In direct cytotoxic assay, Meth A cells showed very low, if any, sensitivity to rHuLT. However, rHuLT was found to be strongly cytotoxic for subcutaneously implanted Meth A cells. In order to explain this discrepancy, we examined the indirect effects of rHuLT on Meth A cells particularly through macrophages. rHuLT showed macrophage chemotactic activity in vitro and also in vivo. Thus, injection of rHuLT into the mouse peritoneal cavity caused migration of macrophages to the peritoneal cavity. In addition, histologic analysis revealed that 6 h after intratumor injection of rHuLT, nonspecific esterase-positive cells started to migrate into Meth A tumor tissues, and after a further 24 h, a larger number of nonspecific esterase-positive cells had migrated into the Meth A tumor tissues. Moreover, peritoneal exudate cells induced by rHuLT showed considerably higher cytotoxic activity against Meth A cells than proteose peptone- or phosphate-buffered saline-induced peritoneal exudate cells. Furthermore, the cytotoxic activity of peritoneal exudate cells was found to reside in macrophages. Investigation of the mechanism of macrophage activation by rHuLT revealed that rHuLT can activate macrophages for cytotoxicity synergistically with mouse interferon-gamma. These results strongly suggest that rHuLT, when injected into the tumor, can induce the migration of macrophages into the tumor and activate macrophages in situ to kill tumor cells.

Recent studies on perfluorochemical (PFC) emulsion as an oxygen carrier in Japan.

In summary, we have discussed PFC emulsions as oxygen carriers, and concluded as follows: PFC emulsions which are clinically usable at present, such as Fluosol-DA, have some negative points. For instance, there is the requirement of relatively high FiO2 level, short retention time in the blood stream, slow excretion rate from the organs, limited dosage for infusion, and so on. However, in the clinical cases of moderate acute anemia, the consumed oxygen in the PFC phase was nearly 30% of that in the hemoglobin phase in the administration of only 1,000 ml of Fluosol-DA. It strongly suggests that PFC emulsion can carry a considerable amount of oxygen to the tissues and play an important role in improving the tissue hypoxia. Moreover, we surgeons wish to say that there is a great difference for the surgeons' mental state during a surgical operation between the cases where no blood transfusion is allowed for a religious or other reason, and the cases where we may use Fluosol-DA depending on the patients' condition. In the former cases, surgeons will be under stress such that he or she might cause the patients to lose blood excessively. On the other hand, when the surgeon has something in reserve, that is, when he or she may use Fluosol-DA if needed, a good result will usually be obtained in the operation, even without actually using Fluosol-DA. One might be led to say that a key point for the success of operations is the surgeon's mental condition, freedom from anxiety.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of a mouse serum protein increased by administration of an antitumor polysaccharide, PSK, as a variant of mouse transferrin and some of its biological activities.

One of the so-called LC components, the content of which is increased in the serum of PSK (antitumor polysaccharide) treated mice, was purified by repeated ion-exchange column chromatography on DEAE-Sephadex A-50. The purified protein, designated as LC-2, was identified as a variant of mouse transferrin, which is a serum beta 1-globulin having an iron-binding capacity. The absorption spectrum and ultraviolet circular dichroism (CD) curve of LC-2 were identical with those of mouse transferrin. The molecular weight, isoelectric point and amino acid composition of LC-2 were in good agreement with the results obtained previously for mouse transferrin. However, the carbohydrate content of LC-2 was different from that of mouse transferrin. This protein restored the depressed spleen cell response of tumor-bearing mice to concanavalin A (Con A) and promoted the metabolism of proteose-peptone induced peritoneal macrophages obtained from tumor-bearing mice. Furthermore, it had weak but definite antitumor activity against Sarcoma 180 cells in vivo.

Immunological effects of mouse ceruloplasmin.

Mouse ceruloplasmin, the level of which in serum increases on administration of antitumor polysaccharides, was shown to have enhancing effects on the antibody production of mouse spleen cells toward sheep red blood cells and restorative effects on the suppressed mixed lymphocyte reaction of spleen cells of tumor-bearing mice. The proliferation of interleukin-2 dependent cytotoxic T cells and the suppressed concanavalin A response of the tumor bearing mice spleen cells were also enhanced by this serum glycoprotein, weakly but reproducibly. Furthermore, this serum glycoprotein was found to enhance glucose consumption and interleukin-1 production and cytotoxic activities of mouse peritoneal macrophages. These results suggest that mouse ceruloplasmin plays some roles in the natural resistance surveillance against tumors.

Natural killer (NK) cell activating factor released from murine thymocytes stimulated with an anti-tumor streptococcal preparation, OK-432.

Natural killer (NK) activity of mouse splenocytes was significantly augmented when the splenocytes were incubated for 3 to 4 hr with culture supernatants of mouse thymocytes stimulated by OK-432, an antitumor preparation from the Streptococcus pyogenes SU-strain. Antiviral activity was also detected in the culture supernatants, but IL 2 activity was not. When the culture supernatants of thymocytes stimulated by OK-432 were fractionated on a column of Blue Sepharose CL-6B, NK enhancing activity and antiviral activity were observed in partly overlapping fractions that bound to the column. However, the antiviral activity in the Blue Sepharose-bound fraction was neutralized completely by treatment with anti-IFN (alpha, beta) antiserum, whereas significant NK cell enhancing activity was still observed after treatment with anti-IFN (alpha, beta) antiserum. When the Blue Sepharose-bound fraction was subjected to gel filtration, the NK cell enhancing activity was detected in the 25,000 to 35,000 and 40,000 to 67,000 m.w. regions, but antiviral activity was observed in the over 67,000 m.w. region. These results indicate that a new kind of lymphokine, called natural killer cell activating factor (NKAF), distinct from IFN and IL 2, was found. The NKAF was found to have the following properties: its pI value is between pH 5.5 and 6.5, it binds to concanavalin A- and lentil agglutinin-Sepharose, and it is stable with pH 2-24 hr treatment. In addition, NKAF-producing cells were peanut agglutinin (PNA)-thymocytes when thymocytes were fractionated by the agglutination-sedimentation method with the use of PNA.

Present status of clinical studies of Fluosol-DA (20%) in Japan.

Fluosol-DA (20%) is a fine-particle stable emulsion with low toxicity and rapid elimination from the body. Based on comprehensive animal experiments and phase one human studies, Fluosol-DA (20%) has been given clinically to 401 patients in Japan. In 270 of these patients, it was given to treat severe hemorrhage, and in 131, it was given to improve impaired cerebral circulation or for other nonhemorrhagic indications. In these studies, Fluosol-DA (20%) was effective as a blood gas carrier as well as a plasma expander. After infusion of 20 ml of Fluosol-DA (20%) per kilogram of body weight, while maintaining the FIO2 at or near 0.5 or 0.6, PFCs transport an amount of oxygen equivalent to approximately 6.3 +/- 1.4% of the oxygen transported by the hemoglobin phase and approximately 100% of the oxygen transported by plasma. The arteriovenous oxygen difference in the PFC phase was approximately 25 to 30% of that in the hemoglobin phase. Of the oxygen consumed by the tissues, approximately 17% was provided by the PFC phase after treatment with Fluosol-DA (20%). Hemodynamic parameters of patients with hemorrhage were either maintained or recovered to normal levels after Fluosol-DA (20%) infusion. No acute or chronic untoward reactions were observed either early or late after infusion of Fluosol-DA (20%), except for a transient decrease in neutrophils and platelets after the initial administration of a test dose of 1 ml, and these parameters recovered spontaneously in 30 minutes. No abnormal findings that could be attributed to Fluosol-DA (20%) were found in the heart, lungs, liver, spleen, kidneys, bone marrow, endocrine system, or other organs. Organ retention of PFC particles was evaluated in 6 autopsy cases in Japan. Although PFCs were detected in many organs several months after a single Fluosol-DA (20%) injection of 20 ml per kilogram of body weight, PFCs were not found in body tissues of those who were autopsied more than 7 months after its infusion. RES function was slightly depressed for a few days in patients receiving 20 ml of Fluosol-DA (20%) per kilogram of body weight. It was also depressed for several days in rats given 40 ml per kilogram of body weight. Compared with that of control patients, recovery to preoperative levels was slightly delayed in patients receiving Fluosol-DA (20%). Despite this, administration of up to 20 ml of Fluosol-DA (20%) per kilogram of body weight should be safe with respect to the RES function.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of a perfluorochemical emulsion as a blood gas carrier.

Over 10 years of research has led to the development of a perfluorochemical (PFC) emulsion that can be utilized clinically as a blood gas carrier. The physiochemical properties of this PFC emulsion and their biophysiological effects on animals meet the minimum requirements of an oxygen transport medium. As PFC is chemically and biochemically inert, its toxicity is extremely low. Acute toxicity was related chiefly to the particle size of the emulsion. PFC particles injected intravenously are phagocytized in the reticuloendothelial system as foreign bodies and are excreted from the lungs. The excretion rate was roughly proportional to the vapor pressure of each PFC. An emulsion consisting of 7 parts perfluorodecalin and 3 parts perfluorotripropylamine, 20% (wt/vol) PFC final, Fluosol-DA 20%, was selected as the best formulation in view of efficacy, stability, and excretion rate. No untoward reactions were observed after administration of this emulsion. More than 400 patients have received intravenous Fluosol-DA 20% in Japan.

Elevation of colony stimulating factors in mouse serum after injection of PSK, an antitumor polysaccharide.

The level of colony stimulating factors (CSF) in mouse serum was elevated by a single intraperitoneal injection of PSK, a host-mediated antitumor protein-bound polysaccharide obtained from Basidiomycetes. The assay for CSF activity was performed by employing a semisolid methylcellulose culture method using mouse bone marrow cells, and the activity was estimated by an equation well matched with the dose response curve obtained in the CSF assay. A temporary increase of CSF activity within 10 h after the injection of an antitumor polysaccharide, Krestin (PSK) (250-1000 mg/kg) was followed by a fast decline in the activity, but no significant increases were detected in the cases of 62.5 and 125 mg/kg PSK injections. The CSF activity in PSK (500 mg/kg)-treated mouse serum was separated into two active fractions by DEAE ion-exchange chromatography, and both fractions were found to induce colonies comprised of cells with the properties of macrophage in regard to morphology, cytochemistry of non-specific esterase, phagocytic function and expression of Fc receptors on the cell surface. The elevation of the serum CSF level due to administration of so-called host-mediated antitumor agents might be one of the tumor-defense mechanisms in vivo.

Clinical studies of a perfluorochemical whole blood substitute (Fluosol-DA) Summary of 186 cases.

After the experimental and phase one studies of our so-called "artificial blood," Fluosol-DA (20%), an emulsified mixture of perfluorodecalin and perfluorotripropylamine, were successfully completed, phase two and three clinical studies were carried out on 186 patients in Japan. The initial dose was 20 ml/Kg body weight (BW), and additional 10 ml/Kg BW doses were applied as needed. Oxygen-supplying and plasma-extending effects were established. No untoward reaction was observed in any of the 186 cases except in a case that involved long-term repeated administration. Initial studies on FLuosol-DA suggest reasonable safety; however, additional clinical trials appear warranted.

Success in the radical resection of esophageal cancer with artificial blood infusion: case report.

Using the oxygen-carrying, so-called "artificial blood", Fluosol-DA, developed by us, we successfully performed a radical resection for esophageal cancer and a one-stage reconstruction, without any blood transfusion. The operation was performed quite safely despite a large blood loss, a stable condition was performed quite safely despite a large blood loss, a stable condition being maintained during and after the operation. Fluosol-DA has no relation to blood type and is stable in a frozen state for one year or more and can, therefore, be used conveniently and safely for treating severe and intraoperative hemorrhages. Furthermore, this preparation may well have at wide application because it greatly reduces the risk of postoperative hepatitis.