Search

Background: Human soluble recombinant thrombomodulin (TM alfa), a treatment for septic Disseminated intravascular coagulation (DIC), is recommended for patients with severe renal dysfunction in reduced doses. However, no studies have examined yet how dose reduction affects clinical efficacy. In this study, we investigated the significance of the TM alfa dose as a prognostic factor in clarifying the clinical background factors related to the clinical effect of TM alfa in patients with septic DIC.Methods: This study involved 102 patients with septic DIC admitted to a single-center intensive care unit between April 2013 and March 2020, receiving TM alfa. The following factors were retrospectively collected from the medical records of the target patients: (1) patient background, (2) sequential organ failure assessment (SOFA) score, (3) Japanese Association for Acute Medicine DIC diagnostic criteria score, (4) DIC treatment information, (5) TM alfa dose per bodyweight (normal dose: 0.06 mg/kg or reduced dose: 0.02 mg/kg), (6) DIC resolution within 7 days after the start of TM alfa administration (DIC resolution), (7) all deaths within 30 days after the start of TM alfa administration (30-days-all-cause mortality), (8) presence or absence of new hemorrhagic side effects after the start of TM alfa administration. Multiple logistic regression analysis was used to assess factors associated with DIC resolution and 30-days-all-cause mortality.Results: The SOFA score (odds ratio: 95% confidence interval, 0.76: 0.66–0.89), pneumonia (0.24: 0.08–0.75), and reduced dose administration of TM alfa (0.23: 0.08–0.66) were independent of and negatively related to the DIC resolution. For the 30-days-all-cause mortality, the SOFA score (1.66: 1.31–2.09), pneumonia (9.50: 2.49–36.25), and TM alfa dose reduction (3.52: 1.06–11.69) were independent, poor prognostic factors. We found no association between the hemorrhagic side effects and the TM alfa dose per bodyweight.Conclusions: The reduced dose of TM alfa for patients with severe renal dysfunction was observed to be an influential factor for DIC resolution and 30-day all-cause mortality in addition to SOFA score and pneumonia. Further studies are required in the future to verify this finding.

We present our findings in a case of central retinal artery occlusion (CRAO) that developed in a patient while being treatedwith intravenous cisplatin (CDDP) and etoposide (VP16) for small cell lung cancer. The patient was a 67-year-old womanwho had lung lobectomy for small cell lung cancer. She began adjuvant chemotherapy with CDDP and VP16 after thesurgery, and after 13 days of chemotherapy, she developed a sudden painless decrease of vision in her left eye. She wasreferred to Department of Ophthalmology, and our examination found that her decimal visual acuities were 1.0 OD andlight perception OS. Fluorescein angiography showed a CRAO in her left eye. Two months later, she had a sharp pain inthe left eye because of neovascular glaucoma, and cyclophotocoagulation was immediately performed. Although her visual function did not recover completely (light perception OS), the pain was alleviated after the cyclophotocoagulation. Physicalexaminations showed no additional abnormalities of the cardiovascular system. Although a CRAO during chemotherapyis extremely rare, ophthalmologists and internists should remember that a CRAO can develop in patients undergoing combined chemotherapy even though other cardiovascular events may not be present.

In order to evaluate the clinical efficacy of glycosaminoglycan polysulfate (GAGPS) in osteoarthrosis of the knee, a double blind comparative study was carried out at 26 orthopaedic clinics throughout Japan. A total of 120 patients was divided into two groups; one group was treated with 1 mg GAGPS (control group) and the other with 50 mg GAGPS (drug group). Five or more injections (average: 9.3) were given at about weekly intervals (average: 8.2 days). The score derived from the knee scoring scale improved significantly in both groups, either after the 5th and the 10th injections. The score that had improved after the 10th injection in drug group was statistically superior compared to the control (p less than 0.05), however, the difference in the two groups after the 5th injection did not reach a level of any statistical significance. Doctors' assessment of the usefulness of the drug based on the balance of effects and side effects was obtained in 71.2% and 41.1% in drug group and control group, respectively. The difference was statistically significant (p less than 0.01). In conclusion, the authors confirmed that the intraarticular injections of 50 mg GAGPS were useful for osteoarthrosis of the knee although the clinical symptoms were improved only gradually following the injections.

We reported the experience of high-dose chemotherapy (HDC) combined with peripheral stem cell transplantation (PBSCT) in 29 years-old man with advanced retroperitoneal germ cell tumor accompanied with left supraclavicular lymph node metastases, who obtained complete remission after comprehensive treatment. The initial levels of serum AFP, hCG and beta-hCG were high at 30.2 ng/ml, 14,000 mIU/ml and 66 ng/ml, respectively. After 3 courses of chemotherapy (BEP regimen), while left supraclavicular lymph node swelling was disappeared, the retroperitoneal mass lesion persisted on CT scan. Not all of 3 markers fell to the normal range. After myelosuppressive chemotherapy (etoposide 500 mg/m2 Day 1-3), PBSCs were collected by two consecutive apheresises on Day 17 and 18. In total, 19.5 x 10(6)/kg CD 34 positive cells were obtained. The patient underwent PBSCT (all CD 34 positive cells were infused) on Day 0 following HDC (CBDCA 250 mg/m2/day, etoposide 300 mg/m2/day, IFM 1.5 g/m2/day, Day-7(-)-3, respectively). He became severely leukopenic and thrombopenic with nadir of 200/microliter on Day 6 and 2 x 10(4)/microliter on Day 2, respectively. By administration of platelet transfusion and G-CSF, the white blood cell counts and thrombocyte counts recovered to 6,400/microliter and 4.1 x 10(4)/microliter on Day 10, respectively. Microbiologically enterocolic and respiratory tract infections occurred with elevated body temperature (> 40 degrees C). Antibiotic and antimycotic treatments were continued until disappearance of all clinical and microbiological evidence. He was kept for 10 days in clean room. After HDC, all markers fell to the normal range, but the retroperitoneal residual mass still persisted. Resection of the residual mass and retroperitoneal lymph node dissection were performed with pathological examination revealing tissue necrosis without viable cell. The patient has survived with no sign of the disease for 9 months.

Background The concentration of ECP in serum has been proposed as a marker of airway inflammation in asthma. However, its clinical significance is still to be determined. Objectives This study was performed to determine whether concentration of ECP in serum reflects clinical status in asthma and can serve as a predictive parameter. Methods Cross-sectional analysis was performed in 28 children with asthma. A total of 91 blood samples was obtained to determine levels of ECP in serum and eosinophil counts. Forced expiratory volume in 1 s was also determined at the time of the sampling. Data were analysed on the basis of asthma symptoms in the 4 weeks before and the 4 weeks after sampling. Results Serum levels of ECP were significantly lower in patients who had been asymptomatic for 3 or 4 weeks before sampling than in patients who had been symptomatic or asymptomatic for only 1 or 2 weeks. In the former group, serum levels of ECP were higher when patients became symptomatic after sampling than when they remained stable, a finding that suggests that serum levels of ECP may have a predictive value in certain situations. Although the concentration of ECP in serum was not proved to be predictive in the latter symptomatic group, the concentration of ECP was significantly lower when measured again 4 weeks later when the patients' symptoms had resolved. In contrast, levels of ECP were unchanged when patients remained symptomatic, a finding that suggests serum levels of ECP may reflect the clinical response to therapy. Conclusions Serum ECP may be a useful marker for monitoring and predicting the clinical course in asthma.

An 86-year-old was admitted to our hospital with the complaint of urinary retension. Ultrasonography and CT scan revealed a large cystic intrapelvic mass which was palpated on the bilateral inguinal portion. When the needle aspiration was performed, we aspirated serous fluid which a concentration of prostate-specific antigen (PSA) was remarkably elevated to 6200 ng/ml. Following hormonal therapy with diethylstilbestrol diphosphate, maximum androgen blockade with Flutaminde and LH-RH analog was performed. But no reduction in the size of the cyst was observed, he died from dyspnea caused by carcinomatosa 91 days later. Autopsy revealed a papillary cystadenocarcinoma of the prostate. Furthermore, we revealed that the cyst is primary and neoplastic changes supervened in this case. Seven cases of papillary cystadenocarcinoma of the prostate in the Japanese literature are reviewed briefly.

Six nuclear parameters (number of focus layers, pixel count, three-dimensional luminance coefficient variation (3D-CV), roundness, intranuclear inclusion, and nuclear groove) were measured to examine the usefulness of discriminant analysis between papillary carcinoma of the thyroid (Papillary ca) or adenomatous nodule/goiter (A. nodule) using Mahalanobis distance. Forty-two of 442 indeterminate specimens were histologically diagnosed with Papillary ca or A. nodule. Six nuclear parameters for each specimen were examined to conduct discriminant analysis between papillary ca and A. nodule using Mahalanobis distance. The number of nuclear focus layers, pixel count, and intranuclear inclusion [×10-1] of Papillary ca were higher than those of A. nodule (3.91 ± 0.44, 888 ± 257, and 2.2 ± 4.2 vs. 3.59 ± 0.54, 785 ± 111, and 1.3 ± 3.5). The 3DCV [×10-3], roundness [×10-1], and nuclear groove [×10-1] of Papillary ca were lower than those of A. nodule (12.1 ± 5.7, 8.464 ± 0.144, and 2.2 ± 4.2 vs. 15.1 ± 5.2, 8.602 ± 0.078, and 3.3 ± 4.9). Positive discrimination rates of each specimen were 96.3% and 73.3% for Papillary ca and A. nodule, respectively. The discriminant analysis for each specimen is reasonable and useful for providing high discrimination rates.

Ornithine decarboxylase (ODC) activity was markedly induced in the spleen of mice infected with Plasmodium berghei, showing maximal activity at 8 days after the infection. The increase of spleen weight, on the other hand, reached its peak after 14 days of infection. In the blood of P. berghei-infected mice, no increase of ODC activity was observed. This indicated that ODC was induced in the spleen cells, but not in the parasites themselves which existed in the blood. Polyamines (putrescine, spermadine and spermine) were also elevated in the spleen following induction of the ODC activity. On the other hand, increases of ODC activity and spleen weight were observed in the spleen of mice with hemolytic anemia induced by acetylphenylhydrazine, but the extent of these increases were smaller than those in the spleen of mice infected with P. berghei. The present results suggest that increases in ODC activity and polyamine levels in the spleen of P. berghei-infected mice are related to hyperplasia of the spleen (splenomegaly) where the formation of leukocytes and erythrocytes (hematopoiesis) was dramatically stimulated by the infection.

We report a case of leiomyosarcoma in the bladder which occurred in an 18-year-old boy who had been treated with cyclophosphamide over a period of 6 years for retinoblastoma diagnosed 50 days postpartum. Total cystectomy and formation of an ileal conduit were performed. Three years after the operation, he was tumor-free.

A case of recurrent eosinophilic cystitis with peripheral eosinophilia and hyperimmunoglobulinemia E, which responded successfully to initial and secondary steroid therapies is reported.

Primary pulmonary hypertension (PPH) is associated with specific structural alterations, including cellular intimal thickening, intimal fibrosis, and plexiform lesions.To determine the phenotypes of smooth muscle cells (SMCs) in such lesions, the authors conducted an immunohistochemical analysis of lung tissues from two patients with PPH, using two antimuscle actin antibodies, HHF35 and CGA7, and two anti-SMC myosin heavy chain markers, anti-SM1 and anti-SM2 antibodies and related antibodies. Cells that stained positive (+) with HHF35, CGA7, anti-SM1, and anti-SM2 were considered to be SMCs of a mature state. Conversely, those that stained positive with HHF35 and anti-SM1, but weakly positive (+/−) or negative (−) with CGA7 and anti-SM2, were considered to be SMCs exhibiting an immature state.Cellular intimal thickening was composed of SMCs of an immature phenotype (HHF35+, CGA7+/−, SM1+, SM2+/−), accompanied by the expression of fibronectin and the presence of macrophages; intimal fibrosis contained mature SMCs (HHF35+, CGA7+, SM1+, SM2+); and plexiform lesion consisted of proliferative endothelial cells (von Willebrand factor-positive cells, proliferating cell nuclear antigen-positive cells) and underlying immature SMCs (HHF35+, CGA7−, SM1+, SM2−) associated with fibronectin expression and macrophage infiltration.These findings suggest that smooth muscle cells with specific phenotypes may contribute to the development of specific vascular lesions in primary pulmonary hypertension.

Telomerase is a specialized type of reverse transcriptase that catalyzes the synthesis and extension of telomeric DNA. High levels of telomerase activity have been detected in most hepatocellular carcinoma (HCC) tissues; very weak telomerase activity is, however, detected in approximately half of nontumorous chronic liver disease tissues. The purpose of this study was to investigate the possible source of this weak telomerase activity in these tissues using quantitative competitive reverse transcription (RT)-polymerase chain reaction (PCR) and in situ RT-PCR. Competitive RT-PCR indicated that the relative amount of human telomerase RNA (hTR) was significantly higher in chronic hepatitis or liver cirrhosis compared with the normal liver (p0.005), and in HCC compared with the normal liver (p0.001) and with chronic hepatitis or liver cirrhosis (p0.0001). In the normal liver tissue, hTR was detected by in situ RT-PCR in occasional sinusoidal cells and nuclei of occasional hepatocytes. In tumor-free liver or tumor-bearing liver, hTR was detected in sinusoidal cells, infiltrating lymphocytes, occasional proliferative bile ductal epithelial cells, and the nuclei of occasional hepatocytes. In HCC, hTR was detected in nuclei of all HCC cells as an intense signal and in sinusoidal cells. These results indicate that the amount of hTR increases in the nuclei of hepatocytes during hepatocarcinogenesis, and that the cells associated with the weak telomerase activity in approximately half of the nontumorous chronic liver lesions are mainly migrating lymphocytes and sinusoidal cells.

The response to interferon in chronic hepatitis C is believed to be affected by hepatic iron content. We histopathologically examined liver biopsy specimens from patients with chronic hepatitis C to determine whether the presence or absence of hepatic iron deposits correlated with the response to interferon.Sixty-three patients with hepatitis C treated with interferon-alpha were examined. Liver biopsy specimens obtained just before treatment were sliced and stained with Perls' Prussian blue. Twenty patients had complete responses, 24 patients had transient responses, and 19 patients had no response.Iron deposits stained by Prussian blue were seen in hepatocytes, sinusoidal cells, and portal mesenchymal cells. The degree of hepatocytic and sinusoidal iron deposits did not correlate with the response to interferon. However, the degree of portal iron deposits did correlate with hepatic inflammation activity (tau = 0.55, p0.001) and the severity of liver fibrosis (tau = 0.60, p0.001), and it correlated negatively to the response to interferon (tau = -0.49, p0.001).The results suggest that portal iron deposits are a factor in the response to interferon. The presence of portal iron deposits seems to be related to a poor response.

OBJECTIVES--To investigate whether interstitial collagenase (MMP-1) concentration in synovial fluid can be useful as a marker for disease activity in rheumatoid arthritis (RA), to determine the main route by which collagenase degrades the matrix of articular cartilage, and to investigate if an imbalance between metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP) is responsible for the activity of MMPs in RA. METHODS--Collagenase concentrations were measured in synovial fluid and paired serum samples using a specific sandwich enzyme linked immunosorbent assay. Collagenase activities were also assayed in synovial fluid samples. Synovial tissues obtained from the same patient were examined by immunohistochemical staining and the numbers of cells expressing collagenase were counted. RESULTS--Collagenase concentrations in synovial fluid did not correlate with C reactive protein and collagenase levels in serum, but did correlate positively with the degree of synovial inflammation, and increased with increasing numbers of cells identified as expressing collagenase in synovial tissue. Collagenase activities did not correlate with TIMP-1 concentrations, but did correlate strongly with the ratios of collagenase concentration to TIMP-1 (r = 0.73). CONCLUSION--The collagenase concentration in synovial fluid cannot be used as a marker for systemic disease activity, but can be used as a marker for the degree of synovial inflammation in the joint from which the sample is aspirated. In advanced RA, most of the collagenase is probably produced in synovial lining cells and released into synovial fluid, where it degrades the matrix of articular cartilage. An imbalance between MMP and TIMP may be of importance in the degradation of extracellular matrix of articular cartilage in RA.

99mTc-DMSA renal scintigraphy was utilized to investigate the influence of ESWL on renal function in comparison with that of PNL. In the beginning, the reproducibility of renal uptake rate by the scintigraphy was examined in eleven healthy volunteers under both non-diuretic and diuretic states. The renal uptake rate was shown to be sufficiently reproducible in the same person in the two different trials. However, the differences and the standard deviations were shown to be a few percentages, which were not statistically significant. Changes in the repeated renal uptake rate seem to indicate not only changes of renal function with the treatment but also some technical errors. Herein, to investigate changes in renal function of the therapeutic side, the uptake ratio rate (rate of uptake rate in the therapeutic side/uptake rate in the contral lateral side) was utilized instead of uptake rate. Renal scintigraphy was carried out in 48 patients with unilateral renal stones before and after ESWL or PNL monotherapy or the combined ESWL and PNL therapies. Within one week of treatment, the uptake ratio rate significantly decreased in patients with PNL or the combined ESWL and PNL, although DMSA uptake rate in the therapeutic side did not significantly changes. Neither renal uptake rate nor uptake ratio rate significantly changed after ESWL treatment. There was no significant difference in changes of uptake ratio rate between Siemens Lithostars Plus and the improved Dornier HM-3 lithotriptors. This study indicated that ESWL monotherapy did not affect the uptake ratio rate, although PNL monotherapy and the combined ESWL and PNL therapies may affect the uptake ratio rate to some extent.

Drug resistant variant cell lines were selected in vitro for resistance to adriamycin or vincristine, P388/ADR and P388/VCR-600, respectively, from P388 murine leukemia cells. These cells were demonstrated by immunoblot studies with P-glycoprotein specific monoclonal antibody (C219) to overexpress not only P-glycoprotein but also approximately 65 kDa protein, and the expression levels were found to correlate with the degree of resistance. Furthermore, in Northern blot analysis with an MDR1 cDNA as a probe, an overexpressed transcript with the length of about 2.4 kilobases which might encode this previously uncharacterized protein was also detected in the multidrug resistant cell line. Thus, it is suggested that this protein might be associated with multidrug resistant phenotype and be related to P-glycoprotein.

Aging is of utmost importance in the pathogenesis of the prostate gland (i.e., benign prostate hyperplasia or prostatic carcinoma). The object of this study was to examine the morphological and histological changes of the aging prostate of the so-called senescence-accelerated mouse (SAM). Ventral and dorsolateral lobes of prostate glands of SAM were microdissected into two-dimensional ductal arrays. Gross morphology, ductal branching patterns, and histology were examined in these microdissected specimens. Wet weight and numbers of ductal tips in ventral and dorsolateral prostate glands in senescence accelerated-prone (SA-P) mice were significantly smaller than those of senescence accelerated-resistant (SA-R) mice, although the changes of patterns of gross ductal morphology were virtually identical in these groups. High incidence of stromal hyperplasia with fibrosis and inflammation was observed in the dorsal lobe of the aged SA-P mouse. Atypical glandular epithelial cells and cribriform glandular deformity were observed in the dorsal and lateral lobe of aged SA-P mice. Marked heterogeneity in age-related pathological changes was observed between prostatic lobes. These data suggest that the aging process occurs heterogeneously within the prostate gland, and that SA-P mice may be an important model for the study of age-related changes in the prostate gland. © 1994 Wiley-Liss, Inc.

Panipenem/betamipron (PAPM/BP), a mixture of a newly synthesized carbapenem antibiotic panipenem (PAPM) and N-benzoyl-beta-alanine, betamipron (BP), was evaluated for pharmacokinetics, in vivo and in vitro antimicrobial effect, and clinical efficacy in pediatric patients. Intravenous drip infusion of either 10 mg/10 mg/kg or 20 mg/20 mg/kg of PAPM/BP for 30 minutes resulted in maximum plasma concentrations of 36.6 micrograms/ml and 92.5 micrograms/ml, half lives (T 1/2 beta) of 1.17 hours and 0.88 hours, and urinary excretion until 6 hours of 29% and 17.7%, respectively. Antibacterial activities of PAPM against Gram-positive cocci and Gram-negative rods isolated from pediatric patients were equal to or slightly stronger than those of imipenem, ceftazidime, cefoperazone, and piperacillin. Clinical effects of PAPM/BP evaluated in 17 patients were as follows; excellent in 8 cases, good in 8 cases, and fair in 1 case. The overall efficacy rate was 94.1%. Elevations of GOT and/or GPT were observed in 2 patients and transient eosinophilia was observed in 1 patient.

99mTc-DMSA renal scintigraphy was carried out in 54 patients with unilateral renal stones before and after PNL. Four to 8 weeks after PNL the DMSA renal uptake significantly decreased to 17.2 +/- 6.0% from 18.2 +/- 6.7% before PNL. DMSA renal uptake did not change in the contralateral side. Since in some patients changes in the DMSA renal uptake of 5-7% were observed after PNL not only in the PNL side but also in the contralateral side, the renal function was assessed by the formula: DMSA renal uptake in the PNL side/DMSA renal uptake in the contralateral side, and the change of this ratio was evaluated in 44 patients, in whom the renal DMSA uptake in the PNL side was less than two times that in the contralateral side. The DMSA renal uptake ratio decreased to 95.6 +/- 8.7% from the base line 4-8 weeks after PNL. This change was statistically significant. Some functional risks such as massive bleeding with PNL, the fever after PNL and the number of nephrostomy tract did not affect the decrease in the renal function. In 29 patients in whom renal function was reevaluated one year after PNL, the DMSA renal uptake ratio significantly decreased to 94.2 +/- 9.6% from the base line 4-8 weeks after PNL. But the ratio significantly improved to 99.6 +/- 11.6% about one year after PNL. In two patients with a cold area on the renal image, the renal function of the operated side still remained at about 80% levels from the base line even one year after PNL.(ABSTRACT TRUNCATED AT 250 WORDS)

We took cultures of many human renal cell cancers and established two cell lines in vitro which were derived from the spindle cell carcinoma of a 67-year-old woman (MR-1) and from the dark cell carcinoma of a 74-year-old woman (MR-2). Using a nude mouse, we established the cell line in vivo (MRV) which was derived from the same patient as that for MR-1. MR-2 was maintained through 140 passages and MR-2 110 passages. MRV was maintained through 7 passages. With passaging, the characteristics, the doubling times and the chromosomal numbers of these cell lines changed, these changes were caused by the transformation, the mutation and the selection of the passaging cells. The study of the sensitivity test of the anti-cancer drugs to the established cell lines was done using the radioisotope uptake assay in vitro and the tumor volume changes in nude mice in vivo. We considered there were differences between the effective drugs used in vitro assay and in vivo assay. As to radioisotope uptake assay, it is difficult to judge the exact effect of the plant alkaloids, which inhibit the cell division and are dependent on the contact time, and we may overestimate the effect of the cytotoxic antibiotics. Further investigation on the methodology of the sensitivity test of the anti-cancer drugs would be necessary for the clinical application.

Phenotypic profile of human neuroblastoma cell lines: Association with morphological characteristics

Difluoro-phenyl-ethyl(4-aminopropylamidinohydrazone) (DFPA) was synthesized as an irreversible inhibitor of ornithine and S-adenosylmethionine decarboxylases and analyzed for antiproliferative effects on leukemia cells. The compound irreversibly inhibited ornithine and S-adenosylmethione decarboxylases. This inhibition could not be reversed by dialysis or chromatography on Sephadex G-50. When human lymphoid leukemia Molt 4B cells were cultured in the presence of the inhibitor, the intracellular levels of polyamines (putrescine, spermidine and spermine) and the rate of cell proliferation were markedly depressed. In these polyamine-depleted and growth-retarded cells, the synthesis of protein, but not of DNA or RNA, was observed to be significantly inhibited.

A rare case of urethral metastasis from prostatic adenocarcinoma is reported. Ordinary histological examination by hematoxylin and eosin staining could not determine whether the primary site was the prostate or the urethra. However, with an immunoperoxidase technique using prostate-specific acid phosphatase and prostate-specific antigen as markers for prostatic cells, we obtained a precise diagnosis of the primary sites. As a result, the patient could be successfully treated with hormonal therapy.

Methylglyoxal bis(3-aminopropylamidinohydrazone (MGBA) inhibited S-adenosylmethionine decarboxylase (AdoMetDC) activity competitively with S-adenosylmethionine (AdoMet), showing a Ki value of 2.60 x 10(-5) M. It also inhibited ornithine decarboxylase competitively with ornithine, showing a Ki value of 3.80 x 10(-5) M. MGBA inhibited the growth of human erythroid leukemia K562 cells. Putrescine, spermidine, and spermine concentrations in MGBA-treated cells were depressed to 19%, 36%, and 66% of the values of control cells, respectively.

Effects of methylglyoxal bis(butylamidinohydrazone) (MGBB), a reversible inhibitor of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases of ODC and AdoMetDC activities, ODC and mRNA level and polyamine contents in mouse skin were investigated in connection with tumor formation. Formation of papillomas by applications of TPA to 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin was effectively inhibited by simultaneous topical applications of MGBB, MGBB also dose-dependently inhibited the ability of TPA to induce increases of ODC activity, ODC mRNA level and the accumulation of putrescine and spermidine in mouse skin. Induction of AdoMetDC activity was not affected by the drug. These inhibitory effects of MGBB on ODC induction and tumor promotion were more evident in multiple application experiments than with a single application of the drug.

The sequence-dependency of the antitumor effect of etoposide (VP-16) and 1-beta-D-arabinofuranosylcytosine (ara-C) and its mechanisms were investigated in L1210 ascites tumor. Treatment with VP-16 (15 mg/kg) and ara-C (25 mg/kg) was administered intraperitoneally on days 1, 4, and 7 after tumor inoculation. Three-hour pretreatment with VP-16 followed by ara-C produced 70% of cure rate, but only 20% of cure rate was obtained with the reverse sequence. Simultaneous administration led to the worst therapeutic result. To clarify this sequence-dependent interaction of the both drugs, the effect of VP-16 on incorporation of ara-C into DNA was investigated in vivo. On day 3 after intraperitoneal transplantation of 1 x 10(6) L1210 cells, 15 mg/kg of VP-16 and 1 microCi of (3H)ara-C was administered intraperitoneally with or without time interval. The effect of VP-16 on ara-C incorporation was also strikingly schedule-dependent and compatible with the schedule dependency of the antitumor effect. At 1 hr after injection of ara-C, simultaneous administration of 15 mg/kg of VP-16 reduced ara-C incorporation by 67% of ara-C injection alone. But in sharp contrast to simultaneous-administration, 3 hour preadministration of VP-16 increased ara-C incorporation up to 247%. From 1 to 6 hour after intraperitoneal administration of 15 mg/kg of VP-16, the sedimentation rate of L1210 DNA was increasing on alkaline sucrose gradients. This repairing period from VP-16 induced DNA damage might be the vulnerable time to ara-C through an increase in ara-C incorporation into DNA.

A variant P388 murine leukemic cell resistant to 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene)-beta-D-glucopyr anoside (etoposide) (VP-16-213) was cloned. The variant P388/VP-16 cell line was 159-fold resistant to 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene)-beta-D- glucopyranoside and showed cross-resistance to vincristine (18.9-fold) and Adriamycin (522.9-fold), determined by comparing the 50% inhibitory concentrations in a 48-h growth inhibition assay. To identify the possible role of Ca2+-phospholipid-dependent protein kinase (protein kinase C) in this drug resistance, we studied the specific phorbol ester binding component and protein kinase C in the parent and drug-resistant sublines of P388 cells. The phorbol ester receptor, as expressed by the numbers of sites per cell, significantly decreased in P388/VP-16 (57.6% of control). Scatchard analysis revealed that the variant contained a single class of binding sites. However, no difference was observed in the dissociation constants (Kd), thereby suggesting much the same affinity of receptors between the two lines. Phorbol diester analogues inhibited [20-3H]phorbol-12,13-dibutyrate binding of both the variant and control cell lines, in a stereospecific manner and consistent with their binding potency. The activity of protein kinase C, which is related to the phorbol ester receptor, significantly decreased in the variant cell. The enzyme activity, particularly in the membrane fraction of P388/VP-16 cells, was remarkably decreased. These data suggest that the decrease in the specific phorbol diester receptor and protein kinase C in the variant cells might correlate with the pleiotropic drug resistance.

Ornithine decarboxylase (ODC) was induced in the liver, lung and brain of the mouse injected intraperitoneally with 12- 0 -tetradecanoyl-phorbol 13-acetate (TPA), showing maximal enzyme activity four hours after the injection. The increase of ODC activity was due to the enhanced syntheses of mRNA and protein. The induction of ODC activity by TPA was specifically blocked by methylglyoxal bis(butylamidino-hydrazone) (MGBB), a competitive inhibitor of ODC and S -adenosyl-methionine decarboxylase, but not by the analog methylglyoxal bis(guanylhydrazone) (MGBG).

The authors report a case of needle tract implantation of hepatocellular carcinoma following percutaneous biopsy of the liver. The patient, a 62-year-old Japanese male, was found to have a small hepatocellular carcinoma diagnosed by needle biopsy; this was followed by transcatheter chemoembolization, a combination of transcatheter arterial infusion of adriamycin and transcatheter arterial embolization of Gelfoam, and right lobectomy. Eight months after the biopsy and the lobectomy, a nodule of hepatocellular carcinoma, measuring 3.5 cm in diameter, was found at the site of the previous biopsy and excised. The patient is doing well without further recurrence of tumor 23 months after the lobectomy and 15 months after the excision of the implanted tumor in the subcutis.

Pharmacokinetics, in vitro, and in vivo effect of aztreonam (SQ 26,776, AZT), a newly synthesized monobactam antibiotic, were investigated in pediatric patients. The pharmacokinetics were studied in 12 children without renal or hepatic impairment, each of whom received single 10, 20 and 40 mg/kg intravenous doses of drug. Serial samples of serum and urine were assayed for AZT. Serum pharmacokinetics of AZT were described by an open, linear, two-compartment kinetic model. After intravenous administration, AZT was eliminated primarily by urinary excretion of unchanged drug (60.4%). The average biological half-lives of AZT in serum were 1.33 (10 mg/kg, n = 1), 1.69 +/- 0.40 (20 mg/kg, n = 8), and 1.51 +/- 0.61 (40 mg/kg, n = 3) hours. The antibacterial activity of AZT against E. coli and P. aeruginosa was equal or slightly stronger than that of CPZ, LMOX, and CTX. It had no antimicrobial activity against Gram-positive cocci. In vivo effect of AZT was evaluated in 13 children with various infections. The result was excellent in 7 cases, good in 1 case, fair in 3 cases and poor in 1 case, with effective ratio of 66.7%. Exanthema or elevation of GOT and GPT were noticed in 3 patients.

Pharmacokinetic and clinical studies of ceftizoxime suppository (CZX-S) were performed in 10 children with the following results. CZX-S attained a peak serum concentration of 6.85 micrograms/ml 30 minutes after dosing with the drug 5.6 mg/kg (one suppository of CZX-S contains 250 mg of CZX in potency). The mean 6-hour urinary excretion rate in 4 children was 18.9%. The subjects consisted of 8 patients comprising 1 with pharyngitis, 3 with tonsillitis, 1 with gingivitis and 3 with urinary tract infection. The overall effect of CZX-S was "excellent" in 5 patients and "good" in 3, with an effectiveness rate of 100%. No side effects ascribable to CZX-S were encountered in any of the patients. A few patients complained of discomfort after the first or second insertion of the drug. However, the discharge of the suppository was as infrequent as 1.5% of the total 133 insertions. CZX-S is therefore well tolerated for clinical use in children. It is concluded that the unique suppository formulation of CZX-S is useful in the treatment of infections in children with heavy psychophysiologic disorders and in children who cannot take oral drugs because of severe vomiting.

Intracranial mixed germ-cell tumors are rare. We describe the findings from six autopsies of patients with these tumors. The patients were all young at presentation (mean age, 16 years), and five of the six were male. Headache, vomiting, polyuria and diplopia were common symptoms. Radiographic evaluation demonstrated a mass on the midline of the brain. The patients were treated mainly with radiation, but survival (mean, 3.7 years) was not as long as predicted. At autopsy, the tumors occupied most of the ventricular spaces, and ranged from being well-circumscribed to invasive. All tumors contained both germinoma components and nongerminomatous germ-cell tumor components. Because the distribution of these components was not homogenous, at least two sections were necessary for the diagnosis. Immunoreactivity for placental alkaline phosphatase was found in all tumors. Immunostaining for human chorional gonadotropin, alpha-fetoprotein and carcinoembryonic antigen was usually associated with abnormally high serum levels of these tumors markers in life. A number of the cells in both kinds of tumor components expressed proliferating cell nuclear antigen, probably reflecting the intense malignant potential.

An 8-year-old boy with combined IgG1 deficiency and neutropenia underwent allogeneic BMT from his HLA-identical, MLC-negative sister, because immunoglobulin (Ig) infusions and prophylactic antibiotics failed to prevent life-threatening infections. Conditioning was with busulfan and cyclophosphamide, MTX and CYA were given for the prophylaxis of GVHD. For 16 months after BMT no serious infections have occurred and serum IgG1 levels have returned to the normal range without Ig replacement. BMT may be appropriate treatment for patients with IgG subclass deficiency who rarely respond to conservative therapy.

Massive rhabdomyolysis followed by myocardial necrosis was observed in a 14-year-old patient undergoing allogeneic bone marrow transplantation for severe aplastic anemia. Rhabdomyolysis was preceded by the administration of cyclophosphamide as part of a preparative regimen for transplantation Although the specific etiology of this rhabdomyolysis is still unknown, an association with high-dose cyclophosphamide should be noted.