Cirrhosis caused by amiodarone

A woman who had been taking amiodarone--400 mg/day--for over nine years, developed cirrhosis. Electron microscopy showed phospholipid-laden lysosomal lamellar bodies containing myelin figures. A review is made about the reported cases of amiodarone-induced cirrhosis, including detailed histological findings. We conclude that periodical clinical and biochemical monitoring must be made in patients receiving treatment with amiodarone, and that the pathophysiologic mechanism responsible for the amiodarone toxicity still remains unclear.     

Adrenomedullary secretion of epinephrine is increased in mild essential hypertension

To assess whether patients with mild essential hypertension have excessive activities of the sympathoneuronal and adrenomedullary systems, we examined total body and forearm spillovers and norepinephrine and epinephrine clearances in 47 subjects with mild essential hypertension (25 men, 22 women, aged 38.1 +/- 6.7 years) and 43 normotensive subjects (19 men, 24 women, aged 36.5 +/- 5.9 years). The isotope dilution method with infusions of tritiated norepinephrine and epinephrine was used at rest and during sympathetic stimulation by lower body negative pressure at -15 and -40 mm Hg. Hypertensive subjects had a higher arterial plasma epinephrine concentration (0.20 +/- 0.01 nmol.L-1: mean +/- SE) than normotensive subjects (0.15 +/- 0.01) (P < .01). The increased arterial plasma epinephrine levels appeared to be due to a higher total body epinephrine spillover rate in the hypertensive subjects (0.23 +/- 0.02 nmol.min-1.m-2) than the normotensive subjects (0.18 +/- 0.01) (P < .05) and not to a decreased plasma clearance of epinephrine. The arterial plasma norepinephrine level, total body and forearm norepinephrine spillover rates, and plasma norepinephrine clearance were not altered in the hypertensive subjects. The responses of the catecholamine kinetic variables to lower body negative pressure were not consistently different between normotensive and hypertensive individuals. These data indicate that individuals with mild essential hypertension (1) have elevated arterial plasma epinephrine concentrations that are due to an increased total body epinephrine spillover rate, indicating an increased adrenomedullary secretion of epinephrine; (2) have no increased generalized sympathoneuronal activity and no increased forearm norepinephrine spillover; and (3) have similar responses of both the sympathoneuronal and adrenomedullary systems to sympathetic stimulation by lower body negative pressure.     

Platelet transfusions are associated with the development of anti-major histocompatibility complex class I antibodies in patients with left ventricular assist support

BACKGROUND: Preformed anti-human leukocyte antigen (HLA) antibodies delay heart transplantation in patients with left ventricular assist devices (LVAD) because of difficulty in finding crossmatch-negative donors. These antibodies may also be associated with adverse outcome after transplantation. METHODS: In a retrospective analysis of 40 patients with LVAD at Columbia-Presbyterian Medical Center between 1990 to 1996, age, sex, diagnosis, race, duration of support, transfusions, and infections were studied by univariate and multivariate analysis as predictors for development of either anti-HLA class I (anti-I) or anti-HLA class II (anti-II) immunoglobulin G (IgG) or M (IgM) antibodies. RESULTS: Eighteen (45%) patients had development of anti-I and 20 (50%) had development of anti-II antibodies over the study period. Median time for LVAD support was 142 days (range 35 to 439). Only total number of perioperative platelet transfusions predicted the development of anti-I IgG antibodies (p = .04). No other associations were found for development of anti-I IgM or anti-II antibodies of either IgG or IgM specificity. Patients who had development of anti-I IgG received a mean of 13.9 (SE +/- 2.6) units of platelets compared with a mean of 7.7 (SE +/- 2.3) units in those who did not (p = .01). By Kaplan-Meier analysis, at the median duration of follow-up, 8% of patients receiving < 6 units were predicted to have development of anti-I antibodies compared with 63% receiving > 6 units (p = .002). In the last 7 patients, leukocyte filters were used to decrease the antigenic load during platelet and red blood cell transfusions. Only 1 of 7 (14%) patients had development of anti-HLA antibodies compared with 31 of 33 (94%) in whom filters were not used (p < .005). CONCLUSIONS: These results indicate that platelet transfusion during LVAD implantation is a risk factor associated with development of HLA class I IgG antibodies. Use of leukocyte filters during platelet transfusion may decrease the risk of development of anti-HLA antibodies.     

Interrelationship between the Na+/glucose cotransporter and CFTR in Caco-2 cells: relevance to cystic fibrosis

Both the Na+-dependent glucose cotransporter (SGLT1) and the cystic fibrosis transmembrane conductance regulator (CFTR) modulate Na+ and fluid movement, although in opposite directions. Yet few studies have investigated a possible interrelationship between these two transporters. By using the Caco-2 human colon carcinoma cell line, we confirmed that the activities of these transporters increased with spontaneous differentiation to the enterocytic phenotype. We showed that SGLT1 was positively regulated by Cl- and that optimal activity of CFTR was dependent on the presence of glucose. We also demonstrated that inhibition of CFTR by glibenclamide or diphenylamine-2-carboxylate did not modify the activity of SGLT1 and inhibition of SGLT1 by phlorizin did not modify the activity of CFTR, although it resulted in inhibition of glycoconjugate synthesis. These results point to positive substrate-cross regulation of SGLT1 and CFTR and suggest that NaCl and glucose are important for not only Na+ absorption and fluid movement, but also for cAMP-dependent Cl- efflux, and glycoconjugate synthesis, functions that are known to be anomalous in cystic fibrosis.     

Relative contribution of low-density lipoprotein receptor and lipoprotein lipase gene mutations to angiographically assessed coronary artery disease among French Canadians

A possible future clinical application of NMDA receptor antagonists is the control of the development of opiate analgesic tolerance. Therefore, the ability of NMDA receptor antagonists to modify the acute analgesic effects of opiates becomes increasingly important. The present study sought to evaluate the analgesic potency of combined administration of morphine (5-20 mg/kg) and a competitive NMDA receptor antagonist D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; 0.3-5.6 mg/kg) in the tail-flick and tail-pinch tests with rats. It was found that D-CPPene significantly increased the duration of morphine analgesia, but there was hardly any evidence for potentiation of morphine analgesia shortly after morphine administration. This effect could only in part be attributed to the D-CPPene-induced disruption of the development of 'learned hyperresponsiveness' (i.e., acquisition of decreased latencies to escape from repeated exposures to noxious stimulation). In addition, the plasma concentration of morphine was not affected by concurrent treatment with D-CPPene.     

GTPase activity of Rab5 acts as a timer for endocytic membrane fusion

The GTPase cycle is a versatile regulatory mechanism directing many cell functions, and Rab family members use it to regulate intracellular transport. Current models propose that GTP hydrolysis by Rab proteins is either required for membrane fusion or occurs afterwards to allow recycling of the protein. To measure the GTPase activity of Rab5 in endocytic membrane fusion, we engineered a mutant that preferentially binds xanthosine 5'-triphosphate (XTP),Rab5(D136N) and monitored the kinetics of [alpha(32)P]-XTP hydrolysis in situ during endosome fusion in vitro. Surprisingly, nucleotide hydrolysis occurred even in the absence of membrane fusion, indicating that membrane-bound Rab5 undergoes futile cycles of GTP(XTP) binding and hydrolysis. Nucleotide triphosphate hydrolysis by Rab5 is not conditional on membrane fusion and is reduced by its effector Rabaptin-5. Our data reveal that the GTP cycle of Rab proteins differs from that of other GTPases (for example, EF-Tu) and indicate that GTP hydrolysis acts as a timer that determines the frequency of membrane docking/fusion events.     

Anti-C1q receptor/calreticulin autoantibodies in patients with systemic lupus erythematosus (SLE)

We report a case of acute glomerulonephritis associated with acute Q fever. An abattoir worker with a nonspecific febrile illness and pneumonia and abnormal liver function test results developed hematuria, proteinuria, and acute renal failure that resolved with appropriate antimicrobial therapy. Renal biopsy demonstrated diffuse proliferative and exudative glomerulonephritis. Serological tests confirmed recent infection with Coxiella burnetii, with a fourfold rise in the titer of phase II antibody, positive phase II IgM antibody, and negative phase I antibody. Other known causes of glomerulonephritis were excluded. Most reports of renal complications of C. burnetii infection describe glomerulonephritis associated with endocarditis due to chronic Q fever. Renal involvement in patients with acute C. burnetii infection has been rarely described. Glomerulonephritis should be recognized as a complication of acute C. burnetii infection and endocarditis due to chronic Q fever.     

Oscillatory-sensitization model of repeated drug exposure: cocaine's effects on shock-induced hypoalgesia

1. The authors have recently proposed that the sensitization produced by repeated exposure to drugs or stress may give way to an alternating pattern of increases and decreases in the response to each subsequent exposure (i.e., oscillate), as the limits of the physiological system are approached. 2. Evidence for oscillation has been obtained for 6 drug/non-drug stressors and 9 neurochemical or endocrine endpoints. This paper extends the model to a behavioral outcome. 3. In the first experiment, rats were given 0, 1, 2 or 3 pretreatments with cocaine hydrochloride (COC; 12 mg/kg i.p.), separated by 1-week intervals, and then were tested for footshock-induced hypoalgesia (5-sec, 2-mA), as measured by withdrawal latencies from a hot-plate. 4. The second experiment replicated the first and extended the pretreatment sequence to 5 COC injections. 5. In both experiments, shock significantly increased latencies over the no-shock controls. COC enhanced shock-induced hypoalgesia and this sensitization reached its maximum after 2 COC pretreatments. Thereafter, oscillation developed such that the sensitization was attenuated by 3 as compared to 2 COC injections, enhanced by 4 injections, and reattenuated after 5 COC pretreatments. 6. These data complement other findings by demonstrating that the oscillation model extends to a stress-induced behavioral outcome.