A case of liver cirrhosis with alpha-1-antitrypsin globules and hepatitis B surface antigen seropositivity

PAS staining, immunohistochemical examination and electron microscopy revealed presence of alpha-1-antitrypsin (AAT) globules in the hepatocytes of a HBsAg and anti-HBc seropositive female patient diseased of liver cirrhosis. The possible causes of cirrhosis are briefly analysed and the diagnostic importance of PAS-positive, amylase-resistant hepatocellular inclusions is discussed. Apart from the case reported, only two of 509 cirrhotic livers of adults, examined either by biopsy or post mortem, demonstrated similar characteristic PAS-positive globules. This indicates that in the population group (135,000 persons) referred for health care to the hospital where the examinations were done, AAT deficiency has played a negligible role in the development of liver cirrhosis in adults.     

Biochemical and antitumor activity of trimidox,a new inhibitor of ribonucleotide reductase

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of didox (N,3,4-trihydroxybenzamide) reduced the activity of ribonucleotide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% growth-inhibitory concentration, IC₅₀) at 5 M, whereas hydroxyurea, the only ribonucleotide reductase inhibitor in clinical use, exhibited an IC₅₀ of 500 M. Ribonucleotide reductase activity was also measured in situ by incubating L1210 cells for 24 h with trimidox at 7.5 M, a concentration that inhibits cell proliferation by 50% (IC₅₀) or at 100 M for 2 h; these concentrations resulted in a decrease in enzyme activity to 22% and 50% of the control value, respectively. Trimidox and hydroxyurea were cytotoxic to L1210 cells with IC₅₀ values of 7.5 and 50 M, respectively. Versus ribonucleotide reductase, trimidox and hydroxyurea yielded IC₅₀ values of 12 and 87 M, respectively. A dose-dependent increase in life span was observed in mice bearing intraperitoneally transplanted L1210 tumors. Trimidox treatment (200 mg/kg; q1dx9) significantly increased the life span of mice bearing L1210 leukemia (by 82 in male mice and 112% in female mice). The antitumor activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that trimidox is a new and potent inhibitor of ribonucleotide reductase and that it is a promising candidate for the chemotherapy of cancer in humans.Abbreviations Didox N,3,4-trihydroxybenzamide - MTT {3-[4,5-dimethyl-thiazo-2yl]}-2,5-diphenyl tetrazolium bromide - PBS phosphate-buffered saline - trimidox 3,4,5-trihydroxybenzamidoxime HCl     

Indocyanine green angiography of choroidal tumors

Background: Fluorescein angiography (FA) has been widely used in the diagnostic evaluation of cboroidal tumors. Indocyanine green angiography (ICG-A), which permits better visualization of choroidal vasculature than FA, has been recently introduced into clinical practice. Only few reports exist on the ICG-A characteristics of choroidal tumors. Methods: The fluorescein and indocyanine green angiograms of 61 patients were assessed. These included 14 patients with choroidal nevi, 30 with malignant melanomas, 7 with suspected melanomas or atypical nevi, 5 with hemangiomas and 5 with metastases. Results: The outline of pigmented tumors was more accurate on ICG-A than on FA. Characteristic patterns were seen in all intra-ocular tumors with ICG-A, so it was possible to distinguish hemangiomas from malignant lesions. Characteristic features of malignant melanomas include abnormal vascular pattern and marginal late dye leakage. None of the benign lesions showed these features. In suspected melanomas, the presence of abnormal choroidal vascular patterns and/or late dye leakage on ICG-A may indicate malignancy. Conclusion: The study suggests that ICG-A can yield additional information that is useful in differentiating amongst choroidal tumors. Better delineation of pigmented lesions with ICG-A allows more accurate treatment planning and follow-up.     

Effects of RSR13, a synthetic allosteric modifier of hemoglobin, alone and in combination with dizocilpine, on outcome from transient focal cerebral ischemia in the rat

This study examined the effect of a pharmacologically induced rightward shift in the partial pressure of oxygen at which 50% of hemoglobin is saturated (P50) on outcome from transient focal cerebral ischemia in the rat. Halothane anesthetized rats (n=20 per group) were given saline or a single 15-min infusion of 150 mg/kg RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylproprionic acid) intravenously before or 30 min after onset of 75 min of middle cerebral artery filament occlusion (MCAO). Seven days later, severity of hemiparesis and cerebral infarct size were examined. RSR13 alone did not significantly improve outcome. Conscious normothermic rats (n=12 per group) were also given RSR13 (150 mg/kg) or 0.9% NaCl intravenously and subjected to 75 min of MCAO with 7 days of recovery. Again, RSR13 alone did not significantly reduce infarct size or improve neurologic score. A dose-response curve for dizocilpine (MK-801) was then constructed in conscious normothermic rats subjected to 75 min of MCAO. Dizocilpine (0.5 mg/kg i.v.) caused a 90% reduction in mean infarct size while 0.25 mg/kg reduced infarct size by 48%. Other rats were then subjected to 75 min of MCAO after being given dizocilpine (0.25 mg/kg i.v.; n=18) or RSR13 (150 mg/kg i.v. )+dizocilpine (0.25 mg/kg i.v.; n=15). RSR13+dizocilpine resulted in smaller cortical infarct volume (8+/-14 mm3 vs. 34+/-37 mm3, p<0.02) and total cerebral infarct volume (46+/-28 mm3 vs. 81+/-60 mm3, p<0. 05) compared to dizocilpine alone, respectively. We conclude that a pre-ischemic peak increase in P50 of approximately 25 mmHg alone is insufficient to reduce focal ischemic injury, but may be advantageous when used in conjunction with other neuroprotective agents.     

Synthesis and biological evaluation of novel prodrugs of anthracyclines for selective activation by the tumor-associated protease plasmin

New prodrugs of daunorubicin and doxorubicin designed for selective activation by the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are converted to the corresponding cytotoxic drugs upon proteolysis by the tumor-associated protease plasmin. Application of a self-eliminating spacer was essential for enzyme activation. A prodrug containing a chloro-substituted spacer was synthesized with the aim of enhancing the rate of conversion by plasmin. All prodrugs were highly stable in buffer solution and in serum and on the average 15-fold less cytotoxic than the parent drugs in seven human tumor cell lines. A marked in vitro selectivity was demonstrated by incubation of the doxorubicin prodrugs with a plasmin generating MCF-7 breast cancer cell line transfected with urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic effect as the free parent drug doxorubicin in the u-PA transfected cells, indicating complete conversion of the prodrug by plasmin. Addition of the plasmin inhibitor Trasylol drastically increased the ID(50) values in the u-PA transfected MCF-7 cells for both prodrugs 4 and 5.     

Postsurgical, chronic, nonprogressive, cutaneous ulcers: a possible variant of pyoderma gangrenosum associated with diabetes mellitus

Two patients developed persistent ulcers on the trunk after cutaneous surgery. Both had "chemical" diabetes mellitus. Bacteriologic and histopathologic studies of the ulcers were not revealing of cause. The characteristics of the ulcers are described, and are contrasted with typical lesions of pyoderma gangrenosum and Meleney's postoperative progressive synergistic bacterial gangrene. We believe these patients had variant lesions of pyoderma gangrenosum.     

Inhibition of growth of B16 murine malignant melanoma by exogenous interferon

We previously reported that polyinosinic-polycytidylic acid, a potent interferon inducer, inhibits the growth of B16 malignant melanoma in the C57BL/6 mouse. Two experiments were done to evaluate the effectiveness of interferon in tumor inhibition in vivo. In the first, mice were implanted with melanoma and divided into four groups, according to treatment: interferon preparation; interferon control preparation ("breakthrough fraction"); phosphate-buffered saline control; and murine serum albumin control. Daily, each mouse was given i.p. injections of 200,000 NIH reference units (hereafter called units) of interferon or of one of the control substances. The second experiment was similar to the first, except that bovine serum albumin was an additional control. In both experiments, the average tumor volume in interferon-treated mice was statistically significantly smaller than that of each control group. Mouse interferon preparations also inhibited the multiplication of B16 malignant melanoma cells in culture. This inhibition was statistically significant from interferon levels as low as 5 to as high as 5000 units/ml. The degree of inhibition markedly increased from 5 up to 500 units, the inhibition reaching its maximum at this concentration. The inhibitory effect of interferon was abrogated by anti-murine interferon serum produced in a rabbit. These findings suggest that the in vivo inhibition of the growth of B16 melanoma demonstrated with polyinosinicpolycytidylic acid and with exogenous interferon probably results, at least in part, from a direct effect of interferon on the tumor cells themselves.     

Stress-Doppler echocardiography in the diagnosis of ischemic heart disease in an ambulatory setting]

Coronary arteriography, bicycle ergometry and transesophageal atrial pacing (TAP) in combination with Doppler echocardiography (stress-Doppler echocardiography) were used to evaluate cardialgias in 30 outpatients. Stress-Doppler echocardiography showed a high (94%) sensitivity and a high (86%) specificity to detect coronary heart disease (CHD). There was a high correlation (r = 0.79, p less than 0.001) between the wall motion values obtained by echocardiography during TAP and coronary rating. The left ventricular (LV) diastolic filling (DF) was studied by pulsed wave Doppler echocardiography in the postpacing period. The Doppler-derived parameters of LV DF obtained in that period appeared to be moderately sensitive (75%) and specific (64%) in detecting CHD. In post-pacing ischemia, the "pseudonormalized" LV filling pattern was observed in 5 of 6 patients (sensitivity 80%) having three-vessel disease and major left (or equivalent) coronary stenosis.     

Combination of dacarbazine and mitomycin in advanced colorectal cancer

Summary Twenty evaluable patients with advanced measurable colorectal cancer received 3-week courses of a combination of IV dacarbazine 300 mg/m²/day from day 1 to day 5 and IV mitomycin 2 mg/m²/day from day 1 to day 5. Fourteen of these patients had had no prior chemotherapy and received two or more courses of this two-drug regimen. None of the patients achieved complete or partial response. Severe to life-threatening myelosuppression, was encountered in patients with prior radiotherapy and or prior chemotherapy, and/or in patients with a Karnofsky score 70. Hematologic toxicity was mild in the other patients. Nonhematologic toxic effects were generally mild to moderate and consisted essentially in nausea and vomiting. It is concluded that in our hands the regimen selected for this trial has no significant antitumor activity in advanced colorectal cancer.