GALLSTONE CIRRHOSIS: ARE WE ONLY SEEING THE TIP OF THE ICEBERG?

Gallstones are common and their incidence increases with age.¹ Fifty per cent of these stones are in the common bile duct (CBD) in the elderly.² Most of them are silent but with time there is an increasing chance of developing symptoms which are more likely to be serious in the elderly.³ Failure to relieve mechanical obstruction of bile flow may lead to secondary biliary cirrhosis.⁴ It has been estimated that on average secondary biliary cirrhosis develops some seven years after the onset of obstruction from a stricture, four and half years after gallstone obstruction and 10 months after the onset of malignant stricture.⁵ The characteristic features are the pathological findings of portal-portal linkages, with a pattern of monolobular cirrhosis and the preservation of normal vascular relationships.⁶ Secondary biliary cirrhosis may lead to hepatic insufficiency and portal hypertension with the resultant complications, such as bleeding oesophageal varices, hypersplenism with pancytopenia, ascites and encephalopathy. We describe a patient in whom the diagnosis was not suspected until laparotomy and confirmed only at autopsy.     

Expression of alpha-melanocyte stimulating hormone and the invasive ability of the B16 murine melanoma.

The expression of alpha melanocyte stimulating hormone (MSH) has been investigated in two variants of the B16 murine melanoma. The presence of MSH was demonstrated by immunohistochemical methods using anti-MSH antibodies. The low metastasis variant B16-F1, which grows as an encapsulated non-invasive tumour, showed no alpha-MSH immunoreactivity. In contrast, the high metastasis variant BL6 was found to be alpha-MSH positive and the immunoreactivity was found predominantly in the peripheral invading zones of the tumour.     

Pharmacokinetics of Anandron in patients with advanced carcinoma of the prostate

Summary The pharmacokinetics of total radioactivity and unchanged drug were studied in patients receiving Anandron (Nilutamide, RU 23908) after a single dose of [¹⁴C] Anandron and after q12 h dosings of unlabelled drug for 2–7 weeks. The results indicate that the radioactivity in plasma consists of unchanged drug and metabolites. The plasma decay of Anandron after the absorption phase was biexponential in all patients, with the terminal phase half-life ranging from 23.3–87.2 h. The plasma decay of total radioactivity after the absorption phase was biexponential in 3/12 and monoexponential in 9/12 patients. The calculated terminal phase half-lives for total radioactivity after [¹⁴C] Anandron were 34.5–137.3 h. The AUC_0– of the unchanged drug in plasma represented 23%–38% of the AUC_0– of total radioactivity. Urinary radioactivity consisted primarily of metabolites, the majority of which were chloroform-nonextractable. Urinary excretion of radioactivity at 120 h ranged from 49%–78% of the administered dose; the unchanged Anandron (at 72 h) was 0.6%–1.3% of the dose. In three patients studied, the fecal excretion of Anandron was 1.4%–7.0%. Steady-state plasma levels (4.4–8.5 g/ml) were attained within approximately 2 weeks from the initiation of twice daily dosing of Anandron. When the plasma pharmacokinetics of radioactivity and unchanged drug after the first single dose were compared with that during steady state, AUC_{0–12 h} of unchanged Anandron during steady state was significantly higher than the AUC_0– after the first single dose, suggesting that the plasma clearance of Anandron is lowered upon chronic administration of the drug, assuming that the bioavailability is constant.     

Induction of heme oxygenase-1 expression inhibits platelet-dependent thrombosis

Heme oxygenase-1 (HO-1) plays a key role in protecting tissue from oxidative stress. Although some studies implicate HO-1 in modulating thrombosis after vascular injury, the impact of HO-1 on the rate of clot formation in vivo is poorly defined. This study examined the potential function of HO-1 in regulating platelet-dependent arterial thrombosis. Platelet-rich thrombi were induced in C57BL/6J mice by applying 10% ferric chloride to the exposed carotid artery. Mean occlusion time of wild-type mice (n = 10) was 14.6 +/- 1.0 min versus 12.9 +/- 0.6 min for HO-1-/- mice (n = 11, p = 0.17). However, after challenge with hemin, mean occlusion time was significantly longer in wild-type mice (16.3 +/- 1.2 min, n = 15) than HO-1-/- mice (12.0 +/- 1.0 min, n = 9; p = 0.021). Hemin administration induced an approximately twofold increase in oxidative stress, measured as plasma thiobarbituric acid reactive substances. Immunohistochemical analysis revealed that hemin induced a robust increase in HO-1 expression within the carotid arterial wall. Ex vivo blood clotting within a collagen-coated perfusion chamber was studied to determine whether the accelerated thrombosis observed in HO-1-/- mice was contributed to by effects on the blood itself. Under basal conditions, mean clot formation during perfusion of blood over collagen did not differ between wild-type mice and HO-1-/- mice. However, after hemin challenge, mean clot formation was significantly increased in HO-1-/- mice compared with wild-type controls. These results suggest that, under basal conditions, HO-1 does not exert a significant effect on platelet-dependent clot formation in vivo. However, under conditions that stimulate HO-1 production, platelet-dependent thrombus formation is inhibited by HO-1. Enhanced HO-1 expression in response to oxidative stress may represent an adaptive response mechanism to down-regulate platelet activation under prothrombotic conditions.     

Serum adenosine deaminase activity in bacillary or paucibacillary pulmonary tuberculosis.

Serum Adenosine Deaminase (ADA) enzyme levels were estimated in 61 patients with symptoms and signs suggestive of Pulmonary Tuberculosis and correlated with "Gold standards" such as smear positivity of sputum for Acid Fast bacilli, Tuberculin skin testing and Radiological evidence. The mean ADA levels in smear and Tuberculin negative patients was 13.13 +/- 5.97 u/L, while in those with smear and/or strongly positive Tuberculin reaction, the mean levels of ADA were 33.52 +/- 15.22 u/L. The mean serum ADA levels in 25 healthy voluntary donors with no evidence of active or old Tuberculous lesion, were found to be 16.5 +/- 3.18 u/L. The specificity, sensitivity, positive predictive value and negative predictive value of the test was found to be 87%, 71%, 90% and 66.5% respectively. The results conclude that the serum ADA value is sufficiently useful in identifying those patients in whom the diagnosis of Pulmonary Tuberculosis should be actively considered.     

Evaluation of the nephrotoxicity of iproplatin (CHIP) in comparison to cisplatin by the measurement of urinary enzymes

Summary Levels of three enzymes, leucine aminopeptidase (LAP), N-acetyl--D-glucosaminidase (NAG), and -glucuronidase (BGA) were measured in the urine of patients receiving hematologically toxic doses of iproplatin (a) with or (b) without pretreatment hydration. The maximum post-treatment increases in the levels of each of the enzymes were compared between these two groups of patients. In addition, the maximum increases in urinary enzyme levels in iproplatin-treated patients were compared with those in patients treated with 40 mg/m² cisplatin, a known nephrotoxic agent.Increases in LAP levels after cisplatin treatment in the periods studied are significantly higher than those after iproplatin treatment (P0.05). No differences were found in the increases in BGA and NAG levels between iproplatin treatment and cisplatin treatment. No differences were found in the increases in levels of any of the enzymes between patients receiving iproplatin with pretreatment hydration and no prior hydration.The work reported in this paper was supported in part by grant CA-21071 from USPHS NCI and by Bristol Myers Co.     

Metabolism of aromatic and heterocyclic amine bladder carcinogens: bioanalytical considerations

Aromatic and heterocyclic amines are environmental chemicals which can cause bladder cancer in man. Because these chemicals cause carcinomas at a site distal to their portals of entry, metabolic processes are involved in initiation of their carcinogenic effects. N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and its deformylated analogue, ANFT, were used as model compounds to assess metabolism. Electrochemical properties of ANFT made liquid chromatography with electrochemical detection a specific and sensitive method for analysis. Peroxidatic metabolism of ANFT by prostaglandin H synthase (PHS) in the presence of N-acetylcysteine resulted in the formation of 2-amino-4-(5-nitro-2-furyl)-5-(N-acetylcystein-S-yl)thiazole (ANFT-MA). This thioether product has an oxidation potential significantly lower than ANFT. Rat urinary excretion of ANFT-MA was significantly decreased with peroxidase inhibitors, 6-n-propyl-2-thiouracil and methimazole. Inhibitors did not alter excretion of ANFT or prostaglandin E2, a PHS product of arachidonic acid metabolism. 1H and 13C-NMR were selected to explore potential structural differences between ANFT and FANFT which might explain preferential PHS metabolism of ANFT. Evidence for a "zwitterion" configuration for ANFT but not FANFT was observed. ANFT in the "zwitterion" configuration would be a better reducing co-substrate. Chemical synthesis and GC-MS fragmentation patterns identified 3-(2,3-dihydro-1-methyl-2-pyrrolyl)pyridine as a peroxidatic product of nicotine metabolism. This peroxidatic product was found in urine from a cigarette smoker in an amount approximately 6% that observed for continine. Thus, a potential r?le for peroxidative metabolism was demonstrated in man.     

Primary liposarcoma of the orbit: a clinicopathological study

Primary liposarcoma of the orbit is a rare tumour. There are very few cases of orbital liposarcoma reported in the literature, mostly of the myxoid variety. In this paper, the authors report the clinical presentation, histopathological features, results of diagnostic studies and management of a case of orbital low grade myxoliposarcoma with local recurrence, together with a review of the literature.