Ouabain attenuates cardiotoxicity induced by other cardiac steroids.

BACKGROUND AND PURPOSE: All cardiac steroids have a similar structure, bind to and inhibit the ubiquitous transmembrane protein Na(+), K(+)-ATPase and increase the force of contraction of heart muscle. However, there are diverse biological responses to different cardiac steroids both at the cellular and at the molecular level. Moreover, we have recently shown that ouabain inhibits digoxin- and bufalin-induced changes in membrane traffic. The present study was designed to test the hypothesis that ouabain also has an inhibitory effect on cardiotoxicity induced by other cardiac steroids. EXPERIMENTAL APPROACH: The hypothesis was tested in isolated heart muscle preparations and in an in vivo model of cardiotoxicity in guinea pigs. KEY RESULTS: Ouabain at a low dose attenuated the toxicity induced by bufalin and digoxin in heart muscle preparations. In addition, ouabain at the low dose (91 ng.kg(-1).h(-1)), but not at a higher dose (182 ng.kg(-1).h(-1)), delayed the development of digoxin-induced (500 microg.kg(-1).h(-1)) cardiotoxicity in anaesthetized guinea pigs, as manifested by delayed arrhythmia and terminal ventricular fibrillation, as well as a reduced heart rate. In addition, as observed with ouabain, the phosphoinositide 3-kinase inhibitor wortmannin (100 microg.kg(-1).h(-1)) delayed the digoxin-induced arrhythmia in anaesthetized guinea pigs. CONCLUSIONS AND IMPLICATIONS: The present study demonstrates the inhibitory effect, probably through signal transduction pathways, of ouabain on digoxin- and bufalin-induced cardiotoxicity in guinea pigs. Further understanding of this phenomenon could be beneficial for increasing the therapeutic window for cardiac steroids in the treatment of chronic heart failure.

A common mechanism underlies vertebrate calcium signaling and Drosophila phototransduction.

Drosophila phototransduction is an important model system for studies of inositol lipid signaling. Light excitation in Drosophila photoreceptors depends on phospholipase C, because null mutants of this enzyme do not respond to light. Surprisingly, genetic elimination of the apparently single inositol trisphosphate receptor (InsP(3)R) of Drosophila has no effect on phototransduction. This led to the proposal that Drosophila photoreceptors do not use the InsP(3) branch of phospholipase C (PLC)-mediated signaling for phototransduction, unlike most other inositol lipid-signaling systems. To examine this hypothesis we applied the membrane-permeant InsP(3)R antagonist 2-aminoethoxydiphenyl borate (2-APB), which has proved to be an important probe for assessing InsP(3)R involvement in various signaling systems. We first examined the effects of 2-APB on Xenopus oocytes. We found that 2-APB is efficient at reversibly blocking the robust InsP(3)-mediated Ca(2+) release and store-operated Ca(2+) entry in Xenopus oocytes at a stage operating after production of InsP(3) but before the opening of the surface membrane Cl(-) channels by Ca(2+). We next demonstrated that 2-APB is effective at reversibly blocking the response to light of Drosophila photoreceptors in a light-dependent manner at a concentration range similar to that effective in Xenopus oocytes and other cells. We show furthermore that 2-APB does not directly block the light-sensitive channels, indicating that it operates upstream in the activation of these channels. The results indicate an important link in the coupling mechanism of vertebrate store-operated channels and Drosophila TRP channels, which involves the InsP(3) branch of the inositol lipid-signaling pathway.

Left hydronephrosis caused by Crohn disease successfully treated conservatively.

We report the case of a 35-year-old man who presented with fever, diarrhea, and a left abdominal mass. Diagnostic studies confirmed Crohn disease and revealed an abdominal mass obstructing the left ureter with hydroureter and hydronephrosis. The patient was successfully treated conservatively, with corticosteroids and mesalamine, A review of the literature indicates a predominance of right ureteral involvement in Crohn disease, associated with a high incidence of ileocecal disease. Most of these patients were treated surgically, with resection of ileocecal lesion and/or ureterolysis. Ureteral obstruction as a complication of Crohn disease is discussed, with emphasis on conservative treatment.

Metabolic stress reversibly activates the Drosophila light-sensitive channels TRP and TRPL in vivo.

Drosophila transient receptor potential (TRP) is a prototypical member of a novel family of channel proteins underlying phosphoinositide-mediated Ca(2+) entry. Although the initial stages of this signaling cascade are well known, downstream events leading to the opening of the TRP channels are still obscure. In the present study we applied patch-clamp whole-cell recordings and measurements of Ca(2+) concentration by ion-selective microelectrodes in eyes of normal and mutant Drosophila to isolate the TRP and TRP-like (TRPL)-dependent currents. We report that anoxia rapidly and reversibly depolarizes the photoreceptors and induces Ca(2+) influx into these cells in the dark. We further show that openings of the light-sensitive channels, which mediate these effects, can be obtained by mitochondrial uncouplers or by depletion of ATP in photoreceptor cells, whereas the effects of illumination and all forms of metabolic stress were additive. Effects similar to those found in wild-type flies were also found in mutants with strong defects in rhodopsin, Gq-protein, or phospholipase C, thus indicating that the metabolic stress operates at a late stage of the phototransduction cascade. Genetic elimination of both TRP and TRPL channels prevented the effects of anoxia, mitochondrial uncouplers, and depletion of ATP, thus demonstrating that the TRP and TRPL channels are specific targets of metabolic stress. These results shed new light on the properties of the TRP and TRPL channels by showing that a constitutive ATP-dependent process is required to keep these channels closed in the dark, a requirement that would make them sensitive to metabolic stress.

Long-term prognosis of acute pulmonary oedema--an ominous outcome.

BACKGROUND: Acute pulmonary oedema (APOE) is a major health problem, leading to poor hospital and long-term outcomes. There is a relative paucity of studies describing prognosis of consecutive unsolicited patients diagnosed with APOE and hospitalized in internal medicine departments. AIMS: To describe the clinical profile and outcome (in hospital and 1-year prognosis) of successive unselected patients with APOE, in a prospective observational study. METHODS AND RESULTS: The study population included 150 consecutive unsolicited patients (90 men, 60 women; median age 75 years) with APOE all hospitalized in an internal medicine department, in a 900-bed care centre. Ischaemic heart disease (IHD), hypertension and diabetes were present in 85%, 70% and 52% of patients, respectively. The most common precipitating factors for APOE included high blood pressure (29%), rapid atrial fibrillation (29%), unstable angina pectoris (25%), infection (18%) and acute myocardial infarction (MI; 15%). Eighteen patients (12%) died in hospital, with 82% of these deaths attributed to cardiac pump failure. Predictors for an increased in-hospital mortality included: diabetes (P<0.05), orthopnoea (P<0. 05), echocardiographic finding of depressed global left ventricular systolic function (P<0.001), acute MI during hospital stay (P<0.001), hypotension/shock (P<0.05), and the need for mechanical ventilation (P<0.001). After a median hospital stay of 10 days, 132 patients were discharged home. The 1-year mortality was 40%. Only the presence of pleural effusion was found as a predictor for 1-year mortality. CONCLUSION: Most patients with APOE in this study are elderly, and have IHD, hypertension, diabetes and a previous history of APOE. The overall mortality is high (in-hospital, 12%: 1-year, 40%). Left ventricular dysfunction was associated with high in-hospital mortality, but not with long-term prognosis.

Transient chylous ascites following a distal splenorenal shunt.

The development of chylous ascites following abdominal surgery is an infrequent yet alarming complication. We present a patient in whom chylous ascites was diagnosed 6 days after a distal splenorenal shunt. Ten days following bed rest, sodium restriction, and a low-fat diet with medium-chain triglyceride supplementation the ascites resolved.

Phospholipase C and termination of G-protein-mediated signalling in vivo.

In Drosophila photoreceptors, phospholipase C (PLC) and other signalling components form multiprotein structures through the PDZ scaffold protein INAD. Association between PLC and INAD is important for termination of responses to light; the underlying mechanism is, however, unclear. Here we report that the maintenance of large amounts of PLC in the signalling membranes by association with INAD facilitates response termination, and show that PLC functions as a GTPase-activating protein (GAP). The inactivation of the G protein by its target, the PLC, is crucial for reliable production of single-photon responses and for the high temporal and intensity resolution of the response to light.

Cardiovascular adverse drug reaction associated with combined beta-adrenergic and calcium entry-blocking agents.

Numerous studies have shown a beneficial effect of combination therapy with beta-blockers and calcium antagonists in patients with anginal syndrome and/or hypertension. However, because both agents exert a negative chronotropic effect, their combined use may cause bradyarrhythmias with resultant symptoms of cerebral, coronary, and systemic hypoperfusion. We describe our clinical experience with patients who had cardiovascular adverse drug reactions (CVADRs) with combination therapy. This prospective study included 26 patients who had CVADRs among 2,574 admissions during a 2-year period. The study group included 14 men and 12 women with a median age of 73 years. Various combinations of calcium antagonists and beta-blockers were associated with the CVADRs. The most frequent pharmacologic combination was diltiazem plus propranolol. The CVADRs were the cause for hospital admission in 10 patients, an associated cause in nine patients, and developed during hospitalization in seven patients. Cardiac bradyarrhythmias were found in 22 patients. These rhythm abnormalities resolved within 24 h after discontinuation of the offending drugs. Temporary transvenous pacemaker insertion was necessary in only one patient with complete atrioventricular block. Twenty-two patients recovered, two patients died of pump failure not associated with CVADRs, and in two patients, the CVADRs contributed to the patients' death. CVADRs are not uncommon in elderly patients with ischemic heart disease and/or hypertension treated with the concomitant use of calcium antagonist and beta-adrenergic blocking drugs. Use of calcium antagonist plus beta-blocker may unpredictably cause serious hemodynamic events, marked suppression of sinus node activity, and prolongation of atrioventricular conduction in some patients. Enhanced therapeutic monitoring may be warranted when calcium antagonists are combined with beta-blockers.

Novel mechanism of massive photoreceptor degeneration caused by mutations in the trp gene of Drosophila.

The Drosophila trp gene encodes a light-activated Ca(2+) channel subunit, which is a prototypical member of a novel class of channel proteins. Previously identified trp mutants are all recessive, loss-of-function mutants characterized by a transient receptor potential and the total or near-total loss of functional TRP protein. Although retinal degeneration does occur in these mutants, it is relatively mild and slow in onset. We report herein a new mutant, Trp(P365), that does not display the transient receptor potential phenotype and is characterized by a substantial level of the TRP protein and rapid, semi-dominant degeneration of photoreceptors. We show that, in spite of its unusual phenotypes, Trp(P365) is a trp allele because a Trp(P365) transgene induces the mutant phenotype in a wild-type background, and a wild-type trp transgene in a Trp(P365) background suppresses the mutant phenotype. Moreover, amino acid alterations that could cause the Trp(P365) phenotype are found in the transmembrane segment region of the mutant channel protein. Whole-cell recordings clarified the mechanism underlying the retinal degeneration by showing that the TRP channels of Trp(P365) are constitutively active. Although several genes, when mutated, have been shown to cause retinal degeneration in Drosophila, the underlying mechanism has not been identified for any of them. The present studies provide evidence for a specific mechanism for massive degeneration of photoreceptors in Drosophila. Insofar as some human homologs of TRP are highly expressed in the brain, a similar mechanism could be a major contributor to degenerative disorders of the brain.

Reversible pancreatitis, hepatitis, and peripheral polyneuropathy associated with parenteral gold therapy.

A 63-year-old man with seronegative rheumatoid arthritis developed acute pancreatitis, severe hepatitis, and sensorimotor polyneuropathy after receiving 150 mg of intramuscular aurothioglucose (gold). Positive lymphocyte transformation test to gold indicated a cell mediated hypersensitivity to the drug, while multiple investigations ruled out other underlying causes for his illness. After cessation of gold therapy a complete recovery occurred.

Acute transient chylous ascites associated with acute biliary pancreatitis.

We report a case of acute chylous ascites secondary to acute biliary pancreatitis, the first such case reported in the literature. Surprisingly, chylous ascites was detected during elective cholecystectomy. The pathogenesis and management of this problem is discussed.