Metabolism of digoxin, digoxigenin digitoxosides and digoxigenin in human hepatocytes and liver microsomes

In vitro metabolism of digoxin and its cleavage-related compounds was investigated using hepatocytes in primary culture and microsomal fractions both isolated from human livers. On these models, digoxin (DG3) and digoxigenin bisdigitoxoside (DG2) were not shown to be significantly metabolized in vitro in man. Therefore, it appeared that the stepwise cleavage of DG3 and DG2 sugars was not cytochrome P450 dependent. This enzymatic system probably plays a minor role in humans for this particular reaction. However, digoxigenin monodigitoxoside (DG1) and digoxigenin (DG0) which are known to be formed after intra-gastric hydrolysis of DG3, were extensively converted to polar compounds (mainly glucuronides). In addition, using human liver microsomes, a wide variability in UDP-glucuronyl transferase (UDPGT) activities responsible for DG1 glucuronidation was demonstrated. These results suggest that two main factors may contribute to the overall interindividual variability of digoxin biotransformation: 1), the individual intra-gastric pH which influences the sugar cleavage leading to DG1 and DG0; ii), a variability in the level of the hepatic UDPGT specific for digitalis compounds conjugation.     

Fetal renal cystic disease: sonographic-pathologic correlation

Renal cystic disease encompasses a complex group of pathologic and clinical entities, with varied yet distinctive sonographic features. An accurate assessment of the fetal genitourinary tract and the amniotic fluid volume by sonography can lead to a specific prenatal diagnosis in most cases. This article emphasizes the usefulness of sonographic-pathologic correlation in understanding renal cystic disease. The entities discussed are infantile polycystic kidney disease (Osathanondh and Potter type I), multi-cystic renal dysplasia (type II), adult polycystic kidney disease (type III) and renal cystic dysplasia associated with obstructive uropathy (type IV). Sonograms of six correctly diagnosed cases between November 1982 and November 1984 were retrospectively reviewed and correlated with their pathologic findings. The differential diagnosis and possible pitfalls are discussed. In addition, the impact on perinatal management and the role of genetic counselling will be emphasized.     

Distal inferior mesenteric veins to renal vein shunt for treatment of bleeding anorectal varices: case report and review of literature

Isolated intractable bleeding from anorectal varices is a rare complication of portal hypertension. We report a case of a patient with cirrhosis and hepatofugal flow who had severe lower gastrointestinal bleeding from anorectal varices. This is the first case report of construction of a distal inferior mesenteric vein shunt to left renal vein as a selective shunt for treatment of bleeding anorectal varices in a patient with hepatofugal flow. The patient is a 39-year-old white man with a medical history significant for alcohol abuse who was seen with bright red blood per rectum requiring 10 units of packed red blood cells over the course of a year. The work-up revealed anorectal varices with no other colonic lesions. The patient underwent construction of a distal inferior mesenteric vein to left renal vein shunt.     

Force/velocity and power/velocity relationships in squat exercise

The purpose of this study was to describe the force/velocity and power/velocity relationships obtained during squat exercise. The maximal force (F ₀) was extrapolated from the force/velocity relationship and compared to the isometric force directly measured with the aid of a force platform placed under the subject's feet. Fifteen international downhill skiers [mean (SD) age 22.4 (2.6) years, height 178 (6.34) cm and body mass 81.3 (7.70) kg] performed maximal dynamic and isometric squat exercises on a guided barbell. The dynamic squats were performed with masses ranging from 60 to 180 kg, which were placed on the shoulders. The force produced during the squat exercise was linearly related to the velocity in each subject (r ²=0.83–0.98, P < 0.05–0.0001). The extrapolated F ₀ was 23% higher than the measured isometric force (P < 0.001), and the two measurements were not correlated. This may be attributed to the position of the subject, since the isometric force was obtained at a constant angle (90° of knee flexion), whereas the dynamic forces were measured through a range of movements (from 90° to 180°). The power/velocity relationship was parabolic in shape for each subject (r ²=0.94–0.99, P < 0.01–0.0001). However, the curve obtained exhibited only an ascending part. The highest power was produced against the lightest load (i.e., 60 kg). The maximal power (W˙ _max ) and optimal velocity were never reached. The failure to observe the descending part of the power/velocity curve may be attributed to the upper limitation of the velocities studied. Nevertheless, the extrapolation of W˙ _max from the power/velocity equation showed that it would be reached for a load close to body mass, or even under unloaded conditions. Accepted: 19 September 2000     

The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells

Interactions between the novel benzamide histone deacetylase (HDAC) inhibitor MS-275 and fludarabine were examined in lymphoid and myeloid human leukemia cells in relation to mitochondrial injury, signal transduction events, and apoptosis. Prior exposure of Jurkat lymphoblastic leukemia cells to a marginally toxic concentration of MS-275 (e.g., 500 nM) for 24 h sharply increased mitochondrial injury, caspase activation, and apoptosis in response to a minimally toxic concentration of fludarabine (500 nM), resulting in highly synergistic antileukemic interactions and loss of clonogenic survival. Simultaneous exposure to MS-275 and fludarabine also led to synergistic effects, but these were not as pronounced as observed with sequential treatment. Similar interactions were noted in the case of (a) other human leukemia cell lines (e.g., U937, CCRF-CEM); (b) other HDAC inhibitors (e.g., sodium butyrate); and (c) other nucleoside analogues (e.g., 1-beta-D-arabinofuranosylcytosine, gemcitabine). Potentiation of fludarabine lethality by MS-275 was associated with acetylation of histones H3 and H4, down-regulation of the antiapoptotic proteins XIAP and Mcl-1, enhanced cytosolic release of proapoptotic mitochondrial proteins (e.g., cytochrome c, Smac/DIABLO, and apoptosis-inducing factor), and caspase activation. It was also accompanied by the caspase-dependent down-regulation of p27(KIP1), cyclins A, E, and D(1), and cleavage and diminished phosphorylation of retinoblastoma protein. However, increased lethality of the combination was not associated with enhanced fludarabine triphosphate formation or DNA incorporation and occurred despite a slight reduction in the S-phase fraction. Prior exposure to MS-275 attenuated fludarabine-mediated activation of MEK1/2, extracellular signal-regulated kinase, and Akt, and enhanced c-Jun NH(2)-terminal kinase phosphorylation; furthermore, inducible expression of constitutively active MEK1/2 or Akt significantly diminished MS-275/fludarabine-induced lethality. Combined exposure of cells to MS-275 and fludarabine was associated with a significant increase in generation of reactive oxygen species; moreover, both the increase in reactive oxygen species and apoptosis were largely attenuated by coadministration of the free radical scavenger L-N-acetylcysteine. Finally, prior administration of MS-275 markedly potentiated fludarabine-mediated generation of the proapoptotic lipid second messenger ceramide. Taken together, these findings indicate that the HDAC inhibitor MS-275 induces multiple perturbations in signal transduction, survival, and cell cycle regulatory pathways that lower the threshold for fludarabine-mediated mitochondrial injury and apoptosis in human leukemia cells. They also provide insights into possible mechanisms by which novel, clinically relevant HDAC inhibitors might be used to enhance the antileukemic activity of established nucleoside analogues such as fludarabine.     

Cardiovascular risk factors in males with hypertriglycemic waist (Tehran Lipid and Glucose Study)

BACKGROUND: Many studies performed on nontraditional risk factors have proposed a metabolic triad including increased serum level of apolipoprotein B, hyperinsulinemia and high small, dense LDL-C as a risk factor of cardiovascular diseases. Hypertriglycemic waist (increased waist circumference as well as high fasting triglyceride level) can be used as a simple criterion to predict the metabolic triad. The aim of this study was to investigate the prevalence of hypertriglycemic waist and the frequency of cardiovascular risk factors in the affected population. MATERIALS AND METHODS: The study was performed on 4169, 18-70 y-old male subjects of the population of Tehran Lipid and Glucose Study (TLGS). The subjects fell into four groups with respect to serum level of fasting triglycerides (Tg) and waist circumference (WC). Subjects of group 1 had serum Tg > or =1.8 mmol/l as well as WC > or =95 cm, while those of group 2 had Tg > or =1.8 mmol/l and WC <95 cm. The triglycerides level was less than 1.8 mmol/l in groups 3 and 4, whereas WC was > or =95 cm and lower than 95 cm, respectively. Cardiovascular risk factors, anthropometric and laboratory variables were compared between the groups. RESULTS: In total, 784 subjects had high serum levels of Tg as well as increased WC. The mean age of subjects was significantly higher in groups 1 and 3 compared to others (37+/-15, 48+/-14, 41+13 and 46+/-13 y of age in groups 4, 3, 2 and 1, respectively, P<0.001). The prevalence of cardiovascular risk factors was significantly higher in group 1 as compared with others. Systolic and diastolic blood pressure, body mass index and WC were significantly higher in group 1 than in the others. Serum total cholesterol, Tg and LDL-C were significantly higher in group 1 compared to others, whereas HDL-C was significantly lower in this group. The prevalence of subjects who had at least four risk factors was 75 and 8% in groups 1 and 4, respectively. CONCLUSION: Hypertriglycemic waist can be used as a simple criterion to predict cardiovascular risk factors.     

Subretinal neovascularization in angioid streaks

Angoid streaks are linear crack-line dehiscences of Bruch's membrane. Choroidal neovascularization is the most serious complication of angioid streaks. The authors try to determine the incidence of neovascular macular degeneration in angioid streaks, their detection and treatment. A retrospective study of 26 eyes of 13 patients with angioid streaks was performed, 6 of whom had macular complications and 3 had subretinal neovascular membranes. Indocyanine green angiography is an adjunctive diagnostic tool in the detection of subretinal neovascular membranes in angioid streaks. Laser photocoagulation of choroidal neovascularization in angioid streaks may end the choroidal neovascularization and help stabilize visual acuity.