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In the course of searching for new antifungal agents, a new pentanorlanostane derivative, cladosporide A (1), was isolated along with ergosterol, ergosterol peroxide and 23,24,25,26,27-pentanorlanost-8-ene-3beta,22-diol (2) from Cladosporium sp. as a characteristic antifungal agent against the human pathogenic filamentous fungus Aspergillus fumigatus. The structure of 1 was established as 3beta,22-dihydroxy-23,24,25,26,27-pentanorlanostane-29-al by spectroscopic and chemical investigation and X-ray crystallographic analysis. Inhibitory activity against A. fumigatus (IC80 0.5-4.0 microg/ml) was observed for cladosporide A (1), but no activity was observed against pathogenic yeasts, Candida albicans and Cryptococcus neoformans, and other pathogenic filamentous fungi, Aspergillus niger and A. flavus. The 4beta-aldehyde residue in 1 might be essential for the antifungal activity, since 23,24,25,26,27-pentanorlanost-8-ene-3beta,22-diol (2) showed no inhibition against the above four fungi.

Changes in immune function due to surgical injury have been well-documented. Immunosuppression is one of the causes of infectious complications leading to organ dysfunction in critical illness. It is not known what kind of surgery in the daily clinical practice causes immunosuppression. Stress response and immune function following surgery for esophageal carcinoma, assuming a highly-stressed operation, were studied and then compared with the stress response and immune function following gastric surgery, a moderately-stressed procedure. Forty patients who underwent esophagectomy and 39 patients receiving gastric operation were studied. The concentrations of serum interleukin-6 (IL-6) were measured preoperatively, at 1, 2, and 6 h, and at 1, 3, and 10 d after operation. Total protein, serum albumin, rapid turnover protein, serum CRP, and cortisol were measured before operation and at 1, 3, 7, and 21 d after operation. ConA- and PHA-stimulated lymphocyte proliferation, IgA, IgG, and IgM were also measured preoperatively, and on 7 and 21 d following surgery. The patients were fed exclusively by total parenteral nutrition (TPN). A striking rise of IL-6 was observed, with a peak in both groups at 1 to 6 h following operation. The peak values were 419+/-30 pg/mL, which was approximately twice as high in the esophagectomy patients as in the gastrectomy patients (195+/-40 pg/mL). CRP and cortisol also increased after operation, and these increases were also significantly greater in the esophagectomy patients. ConA- and PHA-stimulated lymphocyte proliferation decreased significantly 7 d after esophagectomy (P<0.05), but was unchanged in the patients receiving gastrectomy. Suppression of cellular immunity correlated significantly with serum cortisol, and was preceded by a rise in serum IL-6. The IgA, IgG, and IgM levels, however, remained unchanged from their preoperative values throughout the study in both groups. Nutritional status in terms of serum protein, albumin, and rapid turnover protein, decreased postoperatively, but there was no difference between the two groups. It is, therefore, concluded that cell-mediated immunosuppression, preceded by a hyperinflammatory response, is an observable reaction in patients following esophageal surgery, but not in patients undergoing gastric surgery.

Postburn endotoxin translocation has been well documented. However, the relationship between the secretion of catabolic hormones, degree of endotoxin translocation, and intestinal atrophy has not been previously demonstrated. In this experiment, modulation of the secretion of catabolic hormones according to the route of nutrient administration was examined in burned animals. A total of 55 rats, with and without a burn injury, were orally or parenterally fed. Urinary excretion of epinephrine and norepinephrine (U-EN) of each rat was measured for 48 h after burn injury as an indicator of the stress response. Evaluations of intestinal atrophy and endotoxin contents in the liver and spleen were also done 48 h after burn injury. U-EN after burn injury in rats administered total parenteral nutrition (TPN) was higher than in those fed orally. Endotoxin translocation and intestinal atrophy after thermal injury were also augmented by TPN. A significant positive correlation between U-EN and endotoxin content of the liver, and a negative correlation between U-EN and weight of the intestine, were observed. TPN enhances the stress response after burn injury. An increase in endotoxin translocation and intestinal atrophy by TPN are closely related to enhancement of the stress response.

In mammals, D-aspartate is present in various neuroendocrine cells, being especially abundant in pinealocytes. Although D-aspartate is suggested to be involved in some neuroendocrine function, little is known about its origins as well as its physiological roles. In the present study, we found that an appreciable amount of D-aspartate (50.8 pmol/1 x 10(6) cells) is present in clonal human retinoblastoma Y79 cells. The amount of D-aspartate corresponds to 28% of that in rat pinealocytes. The D-aspartate concentration did not change with the culture duration or passage, suggesting de novo biosynthesis of it. Thus, Y79 cells may constitute a suitable experimental system for studies on the biogenesis and signal transduction of D-aspartate in mammalian cells.

A 79-year-old male was admitted to our hospital for further examination on gastric carcinoma (1' type) in the cardia. The histology of biopsied tissue was moderately differentiated adenocarcinoma (tub2). The patient refused a gastrectomy and received three cycles of local injection therapy with OK-432 + Beriplast into the tumor. However, the tumor showed no decrease in size. Considering the quality of life, the patient was given out patient treatment with 5'-DFUR (Furtulon, 800 mg/day). Three months later, the patient showed a partial response (PR) on the basis of gastric X-ray and endoscopic findings. No adverse reactions to the drug were seen. The patient has been receiving the same drug since then, and has continued to show PR for 15 months. Biopsied tissues were checked immunohistochemically for expression of thymidine phosphorylase (TdRPase), and changes in tissue TdRPase level were examined by ELISA. The TdRPase level decreased with shrinking of the tumor. These results suggest that the shrinking of tumor following 5'-DFUR therapy is closely related to TdRPase.

Objective: To investigate the effects of soybean oil emulsion and oral or enteral administration of eicosapentaenoic acid (EPA) on stress response, cytokine production, protein metabolism, and immune function after surgery for esophageal cancer., Summary Background Data: It has been reported that safflower oil, rich in n-6 polyunsaturated fatty acid (n-6 PUFA), affects the survival rate of septic animals and decreases the immune function. It has also been reported that the administration of fish oil, in contrast, reduces these stress responses and stress-induced immunosuppression. In humans, the effects of soybean oil emulsion and the administration of EPA on stress response and immune function after surgery have not been established., Methods: Patients who underwent esophagectomy with thoracotomy were divided into three groups. Seven patients were fed by total parenteral nutrition (TPN) with soybean oil emulsion, which accounted for 20% of total calories. Seven patients were given oral or enteral administration of 1.8 g/day EPA, in addition to TPN with soybean oil emulsion. Nine patients served as the control group; these patients received fat-free TPN. Serum interleukin-6 (IL-6), C-reactive protein, concanavalin A (con A)- or phytohemagglutinin (PHA)-stimulated lymphocyte proliferation, natural killer cell activity, and stress hormones were measured., Results: The postoperative level of serum IL-6 was significantly higher in the group receiving soybean oil emulsion than in the fat-free group. Oral or enteral supplementation of EPA with soybean oil emulsion significantly reduced the level of serum IL-6 compared with the patients receiving soybean oil emulsion. Con A- or PHA-stimulated lymphocyte proliferation decreased significantly on postoperative day 7 in all groups of patients. The supplementation of EPA with soybean oil emulsion significantly improved the lymphocyte proliferation and natural killer cell activity on postoperative day 21 compared with the group receiving soybean oil emulsion., Conclusions: Soybean oil emulsion amplifies, and the supplementation of EPA reduces, the stress response and stress-induced immunosuppression.

Aldehyde dehydrogenase (ALDH) isozyme 2 genes were determined in 15 students. Of these subjects, five healthy male students were administered 0.4 kg/kg ethanol. One subject was defective in aldehyde dehydrogenase 2 (ALDH2), two had normal ALDH2, and the other two were hetero type. After the intake of alcohol, the concentration of ethanol, acetaldehyde, and C4 compounds in blood and urine were determined. The student with the inactive form of ALDH2 was flushed and his levels of 2,3-butanediol and acetaldehyde in blood and urine were found to be the highest.

Eleven inoperable patients with advanced esophageal carcinoma were treated with chemotherapy (carboplatin, 5-FU, vindesine) and concomitant radiotherapy. Two patients (T2) received this treatment due to their poor general condition and refusal of operation, and 9 patients for infiltration of tumor into the adjacent organs (T4). Administration of carboplatin (30 mg/body) and 5-FU (250 mg/body) together with radiotherapy (1.8 Gy/d) for 5 days a week was performed. This chemoradiation therapy was carried out for 5 consecutive weeks. In addition, vindesine (1-3 mg/body) was administered in the 1st and 4th week. After evaluation, endoscopic balloon dilatation was performed in 6 patients with stenosis of the esophagus. The general response rate was 80%. CR was noted in 2 patients of T2 but 1 patient of T4 developed severe leucopenia and immunosuppression, and died of septic MOF. All but the MOF case could take enough food orally following the endoscopic dilatation. The 1-year survival rate in the T4 group (45%) was significantly better than the non-treatment group (0%). In conclusion, this treatment is beneficial for patients with inoperable esophageal carcinoma to obtain a satisfactory QOL and survival rate.

Study Design: A case of cervical myelopathy caused by an anomalous vertebral artery is reported., Objectives: To report a case of high cervical myelopathy resulting from spinal cord compression by an anomalous vertebral artery. Authors believe that this is the first reported case in which the nutrient artery to the abnormal artery originated from the posterior inferior cerebellar artery., Summary of Background Data: Although fenestration of the vertebral artery is net an unusual anomaly to the best of the authors knowledge, three cases of high cervical myelopathy resulting from the anomaly were reported. There is no reported case in which an abnormal artery originated from the posterior inferior cerebellar artery., Methods: The clinical features of the case are reported and discussed with a review of the previously documented cases., Results: The cord compression war relieved surgically, and the patient's symptoms improved postoperatively., Conclusions: A fenestrated vertebral artery should be included in the differential diagnosis of the upper cervical or the craniovertebral junctional lesions of unknown origin. Magnetic resonance imaging is useful for the diagnosis. In the present case, there was an anomalous branch entered as a nutrient artery from the posterior inferior cerebellar artery. Careful management for similar abnormal arteries includes surgery.

Polaprezinc, an insoluble zinc complex of L-carnosine, exhibits anti-ulcer effects by acting directly on mucosal lesions. The disposition of polaprezinc in the stomach was studied to clarify the usefulness of its structure as an insoluble complex. The time courses of 14C-radioactivity in the gastric contents and gastric tissues were parallel to those of 65Zn after oral administration of a mixture of 14C-polaprezinc and 65Zn-polaprezinc (14C-, 65Zn-polaprezinc) to rats. The gastric contents of 14C-polaprezinc and 65Zn-polaprezinc were greater than those of 14C-L-carnosine and 65ZnSO4. Mean residence times (MRT) of 14C-polaprezinc and 65Zn-polaprezinc in the stomach were almost the same (ca. 2 hr), and they were double those of 14C-L-carnosine and 65ZnSO4. In gastric tissues, the area under the concentration curves (AUC0-8 hr) of 14C-polaprezinc and 65Zn-polaprezinc were 1.7 times greater than those of 14C-L-carnosine and 65ZnSO4, respectively. After administration of 14C-, 65Zn-polaprezinc to rats with acetic acid-induced ulcers, 14C and 65Zn-radioactivities in the ulcerous sites were very similar and greater than those of 14C-, 65Zn-polaprezinc dissolved in acid. In conclusion, polaprezinc is retained in the stomach longer and adheres to the ulcerous sites more than zinc or L-carnosine. The characteristics of this compound may arise from its insolubility and contribute to its strong pharmacological action.

The author has performed quantitative studies of cerebrospinal fluid (CSF) pulsations in the cervical region in 10 normal subjects and in 13 cases of syringomyelia using a superconducting MRI system. In the normal subjects, the caudally directed CSF flow in the anterior subarachnoid space reached its maximum velocity at 100-200 msec after the R-wave of the ECG. Measured velocities were 26-44 mm/sec at upper cervical levels and 44-124 mm/sec at lower cervical levels. Further small peaks in the caudal direction were seen at approximately 500 msec after the R-wave. Cases of syringomyelia showed lower velocities in the syrinx than in the anterior subarachnoid space, and the movements varied greatly between the cases and levels examined. CSF pulsations in the subarachnoid space were observed in all cases with Chiari malformation. These results suggest that CSF pulsations in the subarachnoid space are transmitted to the syrinx fluid, and that the movements of the syrinx fluid are influenced by various factors.

The effect of treatment with bacterial preparations on blood flow in normal and malignant tissues was investigated, clinically and experimentally. The time course of the local effect of the preparations was recorded by Laser Doppler Velocimetry (LDV) via a probe on the surface of normal and malignant tissues directly over the injection site. Experimentally, no definite enhancement of blood flow with OK-432, a streptococcal preparation, was observed in nude mice. Clinically, intradermal administration of OK-432 or tuberculin (PPD) resulted in an approximate 11-or 4-fold increase in blood flow, respectively. The injection of OK-432 into malignant tissues, such as dermal cancer and breast cancer with direct extension to the skin, resulted in an approximate 3.5-fold increase. The results suggested that bacterial preparations can act as an adjuvant to enhance drug delivery to tumor tissue in cancer chemotherapy, and that the enhancement of blood supply is induced by immune response.

The effect of treatment with intravenously administered Angiotensin II (AT II) on blood flow in normal and malignant tissues was investigated clinically. The time course of the effect of AT II was directly recorded by laser doppler velocimetry (LDV) via a probe placed on the surface of normal and malignant tissues. Intravenous administration of AT II resulted in an approximate 3.5 (1.3-14.0)-fold increase in blood flow in eleven malignant tissues, such as breast cancer with direct extension to the skin and abdominal skin metastasis of gastric adenocarcinoma. On the other hand, the blood flow in normal skin was decreased under AT II-induced hypertension, but a reactive hyperemia-like increase was observed soon after the withdrawal of AT II. These results strongly suggested that intravenously administered AT II can act as an adjuvant to enhance, by varying degrees, drug delivery to tumor tissue in cancer chemotherapy and that the administration of chemotherapeutic agents is undesirable soon after the withdrawal of AT II.

We studied the concentration of ampicillin (ABPC) into middle ear effusions after administration of bacampicillin (BAPC). Nine patients with acute purulent otitis media were given orally single doses of the drug at a level of 10 mg/kg, and concentrations of ABPC which is the active antibiotic metabolite of BAPC were determined in middle ear effusions periodically after the administration. Bacteria present in effusions were identified, and their ability to produce beta-lactamase was also determined. ABPC concentrations in middle ear effusions were inversely related to the ability of bacteria detected from the intratympanic cavity to produce beta-lactamase. ABPC concentrations in middle ear effusions from which only beta-lactamase negative organisms were detected were higher by 5.2- and 2.3- fold at 60 and 120 minutes after the administration of BAPC, respectively, than those in effusions from which beta-lactamase positive organisms were detected. ABPC concentrations achieved in middle ear effusions in cases where only beta-lactamase negative organisms were detected exceeded MIC80's of the drug against main causative bacteria of acute purulent otitis media such as Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae. Because only 10% or less of these species produces beta-lactamase, BAPC appears to be one of the highly effective drugs in the treatment of this disease.

The number and topographic localization of spontaneously occurring mitotic figures were studied in 22 elevated dysplasias of the stomach. The lesions were divided into 3 equally thick zones. Mitoses occurred in 5 of 7 slight dysplasias, in 7 of 8 moderate dysplasias, and in all 7 severe dysplasias. When present, mitoses were localized to the superficial zone in slight, moderate and severe dysplasias, in the middle zone in some moderate dysplasias, and in almost all severe dysplasias. In the deeper zone, mitoses were seen in one of the moderate dysplasias and in as much as 5 of the severe dysplasias. The number of mitoses were significantly higher in moderate and severe dysplasia, when compared to slight dysplasia. The percentage of atypical mitoses increased gradually from 27% in slight dysplasia to 41% in moderate, and 52% in severe dysplasias. In the adjacent, non-dysplastic gastric mucosa, a 1.5% of atypical mitoses was found. Significantly higher amounts of atypical mitoses were recorded in severe dysplasias, as compared to slight and moderate dysplasias. The results suggest that the various types of elevated dysplasias (slight, moderate and severe) of the stomach may be distinguished, not only by the characteristics of the atypical cells in interphase--as is the case today--but also by the topographic distribution of mitoses and by the difference in percentage of atypical mitoses occurring in these lesions. The possible significance of the mitosis as a biohistological marker of the behaviour of elevated dysplasias of the stomach is discussed.