Search

Background: previous studies have established that bacterial blood concentration is related with clinical outcome. Time to positivity of blood cultures (TTP) has relationship with bacterial blood concentration and could be related with prognosis. As there is scarce information about the usefulness of TTP, we study the relationship of TTP with clinical parameters in patients with Streptococcus pneumoniae bacteremia., Methods: TTP of all cases of Streptococcus pneumoniae bacteremia, detected between January 1995 and December 2004 using the BacT/Alert automated blood culture system in a teaching community hospital was analyzed. When multiple cultures were positive only the shortest TTP was selected for the analysis., Results: in the study period 105 patients with Streptococcus pneumoniae bacteremia were detected. Median TTP was 14.1 hours (range 1.2 h to 127 h). Immunosuppressed patients (n = 5), patients with confusion (n = 19), severe sepsis or shock at the time of blood culture extraction (n = 12), those with a diagnosis of meningitis (n = 7) and those admitted to the ICU (n = 14) had lower TTP. Patients with TTP in the first quartile were more frequently hospitalized, admitted to the ICU, had meningitis, a non-pneumonic origin of the bacteremia, and a higher number of positive blood cultures than patients with TTP in the fourth quartile. None of the patients with TTP in the 90th decile had any of these factors associated with shorter TTP, and eight out of ten patients with TTP in the 10th decile had at least one of these factors. The number of positive blood cultures had an inverse correlation with TTP, suggesting a relationship of TTP with bacterial blood concentration., Conclusion: Our data support the relationship of TTP with several clinical parameters in patients with Streptococcus pneumoniae bacteremia, and its potential usefulness as a surrogate marker of outcome.

We report the outcomes of patients who had in-stent restenosis (IRS) that was treated with intravascular brachytherapy (IVBT) or sirolimus-eluting stent (SES) implantation. The benefit of IVBT for treating ISR is well documented. SES implantation decreases first-time ISR and, in preliminary reports, has been used to treat ISR. Fifty consecutive patients who had ISR were treated; the first 25 patients underwent SES implantation and the next 25 patients were treated with IVBT using a beta-Cath System (a 40-mm strontium-90/yttrium-90 source). Quantitative angiographic and intravascular ultrasound follow-up were performed at 5.2 +/- 1.1 and 12.1 +/- 1.2 months; clinical follow-up was performed at 15 months. SES deployment and IVBT were successful in all patients. At 12-month follow-up, 8 patients who underwent IVBT had angiographic recurrence (4 in the stent and 4 at the stent edge); only 1 patient who underwent SES implantation developed recurrent ISR. At 12 months, in-stent late luminal loss was similar between the SES and IVBT groups (0.35 +/- 0.45 vs 0.34 +/- 0.46 mm, p = 0.9); however, in-stent net luminal gain was higher in the SES group than in the IVBT group (1.32 +/- 0.13 vs 0.57 +/- 0.19 mm, p <0.0001), and in-lesion late luminal loss was higher in the IVBT group (0.48 +/- 0.32 vs 0.16 +/- 0.42 mm, p = 0.004). At 12 months, intravascular ultrasound stent volume obstruction was higher after IVBT versus than after SES implantation (38.7% vs 6.7%, p <0.0001). At 15-month clinical follow-up, 64% and 96% (p <0.01) of patients who underwent IVBT and SES implantation, respectively, were free of major adverse cardiac events. In conclusion SES implantation for the treatment of ISR was effective and superior to catheter-based IVBT in preventing recurrent neointimal proliferation and angiographic restenosis at 1-year follow-up.

Guanine nucleotides behave as competitive antagonists at ionotropic glutamate receptors and show neuroprotective activity in different experimental excitotoxicity paradigms, both in vivo and in cultured cell preparations. Taking 5'-GMP as the reference nucleotide, we have tried to understand how these molecules interact with the agonist-binding site of the GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor. Using a crystallographic model of the ligand-binding core of the GluR2 receptor in complex with kainate, we have previously analyzed the structural changes associated to the binding of agonists to the receptor and suggested a mechanism for the coupling of agonist binding to channel gating. In the present investigation we used the structure of the apo form of the receptor to probe the primary interactions between GMP and GluR2 by means of an automated docking program. A targeted molecular dynamics (TMD) simulation procedure was subsequently used to force the closing of the protein and to study the rearrangement of the ligand and surrounding amino acids. The resulting structure provides a plausible model of the nucleotide-receptor complex. Indirect support for the validity of our approach was obtained when the same methodology was shown to yield structures of the kainate-GluR2 and 6,7-dinitroquinoxaline-2,3-dione (DNQX)-GluR2 complexes that were in very good agreement with the published crystallographic structures. Both the stacking interaction between the phenyl ring of Tyr73 and the purine ring of GMP and a salt bridge between the phosphate group of GMP and Arg108 in the S1 domain, together with several hydrogen bonds, are proposed to secure the anchoring of GMP to the agonist-binding site. Unlike conventional competitive antagonists, such as DNQX, occupancy of the site by GMP still allows receptor segments S1 and S2 to close tightly around GMP without interacting with the critical residue Glu209 that triggers channel opening. Thus, GMP appears to be rather a false agonist than a competitive antagonist. This fact and the nature of the energy barriers that stabilize GMP bound to the closed form of the receptor provide an explanation for the unusual behavior of some guanine nucleotides in ligand-displacement experiments.

Beta-lactam-induced neutropenia has been a well-recognized problem since the initiation of penicillin use. It generally develops following high-dose beta-lactam treatment lasting longer than 10 days, and its frequency rises with increases in the cumulative antibiotic dose. Beta-lactam-induced neutropenia is frequently preceded by fever or rash, which can be considered alarm signs. Unlike neutropenia induced by other nonchemotherapy drugs, beta-lactam-induced neutropenia usually lasts less than 10 days and infrequently causes infectious complications or death. Although any beta-lactam agent can cause neutropenia, recent studies have focused on cases of piperacillin-tazobactam- or cefepime-induced neutropenia; a high incidence of neutropenia has been demonstrated during prolonged treatment with these antibiotics. The apparent contradiction with the results of clinical trials that did not detect this complication is due to the fact that they involved treatments shorter than two weeks. The potential for the development of neutropenia during lengthy intravenous treatment should be borne in mind in the development of new beta-lactams.

We report one-year angiographic and intravascular ultrasound (IVUS) outcomes of in-stent restenosis (ISR) patients treated with intravascular brachytherapy (IVBT). The benefit of IVBT for treating ISR is well documented. However, few data exist on significant angiographic and intravascular ultrasonic in-stent lumen deterioration beyond the habitual 6-month analysis after the index radiation procedure or so-called late catch-up process in the treatment of ISR. Twenty-five consecutive patients with ISR were treated with IVBT using the Beta-Cath System (a 40 mm 90 Sr per 90 gamma source). Quantitative angiographic and IVUS analysis was performed in all of them at 6 and 12 months. IVBT was successful in all patients. Four patients (16%) developed recurrent angiographic binary restenosis at 6-month follow-up, all located within the adjacent reference segments, with 2 being associated with geographical miss. An additional 4 patients (16%) presented with recurrent ISR at 12-month follow-up, all within the stented segment. Significant in-stent lumen loss (0.16 +/- 0.42 mm to 0.34 +/- 0.46 mm; p = 0.008) and in-stent intimal hyperplasia growth (+11.2 +/- 0.48 mm3; p = 0.03) was observed between 6 and 12 months. Intracoronary beta-radiation for the treatment of ISR was associated with significant luminal deterioration (late catch-up) within the stents between 6 and 12 months due to an important late progression of in-stent intimal hyperplasia.

Radiocontrast administration is a common cause of hospital-acquired acute renal failure. It is associated with significant in-hospital and long-term morbidity and mortality and increases the costs of medical care by at least extending the hospital stay. A variety of therapeutic interventions, including saline hydration, diuretics, mannitol, calcium channel antagonists, theophylline, endothelin receptor antagonists, and dopamine, have been employed to prevent radiocontrast-induced acute renal failure. Recent advances have examined the impact of fenoldopam (dopamine-1 receptor agonist), N-acetylcysteine (antioxidant), iso-osmolar contrast agents, hemodialysis, and hemofiltration on ameliorating radiocontrast-induced acute renal failure. Although hydration with half-normal saline had remained the gold standard for the prevention of radiocontrast-induced nephropathy, recent data have revealed the superiority of hydration with normal saline over half-normal saline. This review focuses on the most recent studies of interventions to ameliorate radiocontrast-induced acute renal failure and provides a critical analysis of some of the recent studies conducted to prevent radiocontrast-induced nephropathy.

Preeclampsia is a common (approximately 7% of all pregnancies) disorder of pregnancy in which the normal hemodynamic response to pregnancy is compromised. Despite many years of intensive research, the pathogenesis of preeclampsia is still not fully understood. The objective of the present study was to investigate the levels of coenzyme Q(10) (CoQ(10)) in placental tissue compared to maternal and umbilical cord levels both during normal pregnancy and in those complicated with preeclampsia. Pregnant women (n = 30) and women with preeclampsia (n = 30) were included. Maternal, newborn cord blood levels and placental content of coenzyme Q(10) were measured by high performance liquid chromatography (HPLC). Plasma coenzyme Q(10) levels were significantly higher in normal pregnant women than in women with preeclampsia. CoQ(10) content in placenta from women with preeclampsia (mean 0.28 SEM 0.11 nmol/mg protein) was significantly higher compared to normal pregnancy (mean 0.09 SEM 0.01 nmol/mg protein; p = 0.05). Levels of CoQ(10) in cord blood from normal pregnant women (mean 0.30 SEM 0.05 micromol/l) were significantly lower than in preeclamptic women (mean 4.03 SEM 2.38 micromol/l). In conclusion, these data indicate a possible involvement of CoQ(10) in preeclampsia that might bear deep physiopathological significance and deserve to be further elucidated.

Prophylactic intravenous (i.v.) injections of a selective agonist of ORL1 receptors nociceptin (orphanin FQ) in a dose of 0.4 mg/kg prevented the development of aconitine-induced arrhythmia in rats narcotized with diethyl ether or chloralose. Pretreatment with L-NAME (50 mg/kg) completely abolished this effect of orphanin FQ, while the pretreatment with indomethacin (10 mg/kg) only attenuated the agonist effect, rather than abolished it completely. At the same time, pretreatment with hexamethonium (10 mg/kg) or glibenclamide (3 mg/kg) had no effect on the nociceptin-dependent cardiac tolerance to the arrhythmogenic action of aconitine. Intracerebroventricular (i.c.v.) infusion of orphanin FQ (36 microg) also prevented the onset of aconitine-induced arrhythmia, but this effect was completely abolished by hexamethonium. It is concluded that the antiarrhythmic action of nociceptin with respect to aconitine-induced arrhythmia upon i.v. and i.c.v. administration is explained by different mechanisms. In the former case, the effect of orphanin FQ is related to the activation of NO synthase and cyclooxygenase, while the central action involves the vegetative nervous system.

Background: In diabetic patients in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, abciximab reduced target vessel revascularization by approximately 50% compared with placebo. Whether this is a result of a lower restenosis rate caused by inhibition of intimal hyperplasia remains to be defined., Methods and Results: The purpose of this study was to determine whether abciximab at the time of stent implantation would reduce in-stent intimal hyperplasia measured by intravascular ultrasound at 6-month follow-up in type 2 diabetics. Ninety-six diabetic patients (96 lesions) who underwent elective stent implantation for a de novo lesion in a native coronary artery were randomly assigned to receive abciximab or no abciximab. In-stent intimal hyperplasia volume, expressed as percentage of stent volume, did not differ between groups: 41.3+/-21.0% for those treated with abciximab versus 40.5+/-18.3% for those treated without abciximab (P=0.9). There were also no significant differences in angiographic minimal luminal diameter at follow-up (1.74+/-0.69 versus 1.66+/-0.63 mm; P=0.5), late loss (1.03+/-0.63 versus 1.07+/-0.58 mm; P=0.7), restenosis rate (17.8% versus 22.9%; P=0.5), or cumulative incidence of major adverse cardiac events at 12 months (19.1% versus 20.4%; P=0.9)., Conclusions: Six-month intravascular ultrasound volumetric analysis showed that abciximab, at the time of coronary stent implantation, was not associated with a reduction of in-stent intimal hyperplasia in diabetic patients.

Purpose: To electrophysiologically characterize alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors in chick retinal membrane fragments, incorporated into Xenopus oocytes by direct microinjection., Methods: A 6-day retinal membrane suspension was injected into Xenopus oocytes by use of an electronic nanoliter injector. Fifteen to 40 hours after injection, the oocytes were assayed for kainate-elicited inward currents, under voltage-clamp conditions (membrane potential held at -70 mV). The structural incorporation of the retinal membrane fragments into the oocyte membrane was verified by specific immunofluorescent staining., Results: Chick retinal membrane fragments were efficiently grafted onto Xenopus oocytes after microinjection, with 22.9% +/- 7.6% of the oocyte membrane being stained with anti-chick retina antibody. Part of the retinal material was seen as patches of relatively uniform size (292.1 +/- 72.3 microm(2)). Bath-applied kainate induced dose-dependent (EC(50): 64 +/- 7 microM), nondesensitizing inward currents (15-90 nA) in the chimeric Xenopus oocytes. Sham-injected oocytes did not respond to kainate. Kainate-driven currents were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 1-(4-aminopropyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466), but not by gamma-D-glutamylaminomethyl sulfonic acid (GAMS) or aminophosphonoheptanoate (AP7), suggesting the involvement of AMPA receptors in the observed responses. Guanine nucleotides (GNs) also blocked kainate currents in a concentration-dependent manner., Conclusions: An alternative oocyte microinjection technique to analyze the electrophysiological properties of glutamate receptors in chick retinal membranes is described. The results show the functional activity of putative AMPA-preferring receptors from chick retina and confirm, in the chick retinal model, the antagonistic behavior of guanine nucleotides toward glutamate receptors and their potential role as neuroprotective agents under excitotoxic conditions.

Terminology used to refer to necrotizing infections is extensive because of the absence of clear definitions and the use of classification systems based on a variety of criteria, including etiologic, microbiologic, anatomic, and clinical aspects. This situation has led to some confusion. In the attempt to unify terminology, it might be more appropriate to use only the terms necrotizing fasciitis and myonecrosis, in which differentiation is mainly anatomical. Another option would be to use only the expression necrotizing soft tissue infections, a non-specific term, since these constitute a group of clinical processes having similar pathophysiologic characteristics and therapeutic principles.

It has been found that intravenous administration of nociceptin (0.4 mg/kg) prevents development of aconitine-induced arrhythmias but has no effect on the incidence of occlusion, reperfusion, CaCl2-induced arrhythmias, and exacerbates epinephrine-evoked dysrhythmias. Pretreatment with hexamethonium, atropine, guanethidine and naloxone did not abolish the arrhythmic effect of nociceptin. Intracerebroventricular infusion of orphanin FQ was shown to increase cardiac tolerance of arrhythmogenic influence of aconitine, but this effect is completely abolished by hexamethonium administration. It has been suggested that stimulation of both central and peripheral ORL1 receptors increases cardiac resistance against arrhythmogenic effect of aconitine via different mechanisms.

Objective: To verify the influence of moderate- or high-pressure balloon inflation during primary coronary stent implantation for acute myocardial infarction., Methods: After successful coronary stent implantation, 82 patients were divided into 2 groups according to the last balloon inflation pressure: group 1 (> or = 12 to < 16 atm) and group 2 (> or = 16 to 20 atm), each with 41 cases. All patients underwent late coronary angiography., Results: In group 1, the mean stent deployment pressure was 13.58 +/- 0.92 atm, and in the group 2 it was 18.15 +/- 1.66 atm. Stents implanted with moderate pressures (> or = 12 to < 16 atm) had a significantly smaller post-procedural minimal lumen diameter, compared to with those with higher pressure, with lesser acute gain (2.7 +/- 0.4 mm vs 2.9 +/- 0.4 mm; p = 0.004), but the late lumen loss (0.9 +/- 0.8 mm vs 0.9 +/- 0.6 mm) and the restenosis (22% vs. 17.1%) and target-vessel revascularization rates (9.8% vs 7.3%) were similar between the groups., Conclusion: During AMI stenting, the use of high pressures (> or = 16 atm) did not cause a measurable improvement in late outcome, either in the late loss, its index, and the net gain, or in clinical and angiographic restenosis rates.

Epidemiologic information about snakebites in Ecuador is scarce. Snakebites are more common in the lowlands east of the Andes, in the Amazon basin. In the present study, a retrospective review of all ( n = 142) snakebite admissions to Hospital Pio XII, a regional health center/hospital in the canton of Sucúa, Morona Santiago, Ecuador was carried out between the years of 1996 and 2000. Bites occurred more frequently during the months of March to May. The largest group of patients were in the 15- to 49-year-old range (52.5%), and agricultural workers were the most affected of all patients by occupation (> 40%). In most cases of snakebite, patients could not identify the type of snake that had bitten them. A small number of patients ( n = 60, 42.3%) received some type of treatment prior to arrival at the hospital. Bites occurred most frequently on the left lower extremity (31.7%). Typical symptoms included pain and local edema at the snakebite site; generalized symptoms such as fever, nausea, and vomiting were less frequent. Most patients (almost 90%) received antivenin during hospitalization in addition to supportive care. The mean hospital stay was 4.3 days. More than 90% of all 142 patients recovered, about 8% with local abscesses. Mortality was 2.9% and occurred as a result of complications, including renal failure, respiratory failure, and disseminated intravascular coagulation.

Background: We have previously reported the safety and effectiveness of sirolimus-eluting stents for the treatment of de novo coronary lesions. The present investigation explored the potential of this technology to treat in-stent restenosis., Methods and Results: Twenty-five patients with in-stent restenosis were successfully treated with the implantation of 1 or 2 sirolimus-eluting Bx VELOCITY stents in São Paulo, Brazil. Nine patients received 2 stents (1.4 stents per lesion). Angiographic and volumetric intravascular ultrasound (IVUS) images were obtained after the procedure and at 4 and 12 months. All vessels were patent at the time of 12-month angiography. Angiographic late loss averaged 0.07+/-0.2 mm in-stent and -0.05+/-0.3 mm in-lesion at 4 months, and 0.36+/-0.46 mm in-stent and 0.16+/-0.42 mm in-lesion after 12 months. No patient had in-stent or stent margin restenosis at 4 months, and only one patient developed in-stent restenosis at 1-year follow-up. Intimal hyperplasia by 3-dimensional IVUS was 0.92+/-1.9 mm(3) at 4 months and 2.55+/-4.9 mm(3) after 1 year. Percent volume obstruction was 0.81+/-1.7% and 1.76+/-3.4% at the 4- and 12-month follow-up, respectively. There was no evidence of stent malapposition either acutely or in the follow-up IVUS images, and there were no deaths, stent thromboses, or repeat revascularizations., Conclusion: This study demonstrates the safety and the potential utility of sirolimus-eluting Bx VELOCITY stents for the treatment of in-stent restenosis.

Rhabdomyolysis is a known complication of hepatic 3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor (statin) therapy for posttransplant hyperlipidemia, and thus monitoring for this effect is indicated. We report a case of an herbal preparation-induced rhabdomyolysis in a stable renal-transplant recipient, attributed to the presence of red yeast rice (Monascus purpureus) within the mixture. The condition resolved when consumption of the product ceased. Rice fermented with red yeast contains several types of mevinic acids, including monacolin K, which is identical to lovastatin. We postulate that the interaction of cyclosporine and these compounds through the cytochrome P450 system resulted in the adverse effect seen in this patient. Transplant recipients must be cautioned against using herbal preparations to lower their lipid levels to prevent such complications from occurring.

Adenine and guanine nucleotides have been shown to exert multiple roles in central and peripheral nervous systems, and the sequential breakdown of these nucleotides by enzymatic systems is an important step in the modulation of their extracellular effects. The aim of this study was to investigate whether nucleotide hydrolysis also occurs in the cerebrospinal fluid (CSF) of rats. CSF was able to hydrolyze all guanine and adenine nucleotides investigated (2.0 mM): GDPz.Gt;ADP=ATP=GTPz.Gt;AMP=GMP. More detailed studies with the diphosphate nucleotides showed that the hydrolysis of ADP and GDP was linear with incubation time and protein concentration. The apparent K(M) (Henry-Michaelis-Menten constant) and V (maximal velocity) values for ADP and GDP were 164.3+/-54.7 microM and 12.2+/-3.8 nmol P(i)/min per mg protein, and 841.0+/-90.2 microM and 22.8+/-8.0 nmol P(i)/min per mg protein. The sum of ADP, GDP and UDP hydrolysis (2.0 mM) upon individual incubations with CSF was similar to the hydrolysis observed when all three nucleotides were incubated together. This pattern of hydrolysis strongly suggests the involvement of more than one enzyme activity. The higher maximum activity for GDP and UDP compared to ADP is compatible with presence of a soluble NTDPase5.

Background: Metabolic alkalosis (MA) is common after orthotopic liver transplantation (OLT)., Methods: The study was conducted to identify factors associated with MA after 285 OLTs. MA, defined as total carbon dioxide content of 30 mEq/L or greater, developed in 115 patients (40%) within the first 3 postoperative days., Results: By univariate analysis, patients with MA had a greater preoperative carbon dioxide content (24.4 +/- 3 versus 22.9 +/- 2.9 mEq/L; P < 0.0001) and hematocrit (35% +/- 5% versus 33% +/- 6%; P < 0.02), but lower creatinine (0.9 +/- 0.5 versus 1.2 +/- 1.2 mg/dL; P < 0.001) and blood urea nitrogen levels (15 +/- 12 versus 19 +/- 17 mg/dL; P < 0.001) compared with controls. Patients with MA were administered more citrate intraoperatively compared with controls (6.2 +/- 5.2 versus 4.5 +/- 3.6 mEq/kg of body weight; P < 0.02). Patients with MA had a lower postoperative potassium level (3.7 +/- 0.4 versus 4 +/- 0.5 mEq/L; P < 0.0001) and cumulative fluid balance (-0.66 +/- 1.87 versus +0.003 +/- 3.9 L; P < 0.007) compared with controls. By multivariate analysis, preoperative carbon dioxide content (odds ratio, 1.19; 95% confidence interval [CI], 1.08 to 1.31 per mEq/L), creatinine level (odds ratio, 0.61; 95% CI, 0.39 to 0.96 per mg/dL), intraoperative administered citrate (odds ratio, 3.35; 95% CI, 1.71 to 6.53 per 10 mEq/kg body weight), and postoperative potassium level (odds ratio, 0.32; 95% CI, 0.18 to 0.57 per mEq/L) were independently associated with MA. MA was not associated with increased hospital mortality (7.8% versus 8.2%, MA versus controls). However, patients with MA spent more time on mechanical ventilation than controls (5 +/- 0.8 versus 3 +/- 0.6 days; P < or = 0.03)., Conclusion: Preoperative total carbon dioxide content, renal function, intraoperative administered citrate, and postoperative potassium level are independently associated with MA after primary OLT., (Copyright 2002 by the National Kidney Foundation, Inc.)

The preoperative impairment of renal function is associated with the need for postoperative renal replacement therapy (RRT) in patients undergoing liver transplantation. The principal goal of this investigation was to identify other factors apparent before or during transplant that were independently associated with the need for RRT in the early posttransplant period. A total of 260 consecutive adult patients who received a primary liver transplant were studied. Twenty-eight patients required early RRT (RRT initiated within 1 wk of transplant); 23 for control of volume overload. Preoperative blood urea nitrogen (odds ratio [95% CI], 1.52 [1.15 to 2.01] per 10 mg/dl), serum creatinine (1.91 [1.06 to 3.44] per 1 mg/dl), and urine output (0.12 [0.03 to 0.44] L/d) were independently predictive of the need for early RRT and in combination formed a parsimonious model that discriminated well (area under the receiver operating characteristic curve, 0.877) and had excellent fit (P = 0.699 to reject model fit). No other potential predictors meaningfully improved predictions of which patients would require early RRT. Patients requiring early RRT consumed more healthcare resources than patients who did not require early RRT, spending more time in intensive care (15 +/- 13 d versus 7 +/- 11 d; P < 0.001) and in the hospital (34 +/- 27 d versus 19 +/- 20 d; P < 0.001). The need for early RRT was strongly associated with death before hospital discharge (29% mortality versus 4% mortality among all others; P < 0.001). The data demonstrate that dependency on RRT in the first week after orthotopic liver transplantation stems almost entirely from preoperative renal dysfunction.

Studies of nociceptin/orphanin FQ (NC) have been hampered by the paucity of available ligands with activity at the nociceptin receptor (NCR). In this study we have compared the agonist profile of NC and a novel NCR agonist, Ro65-6570, in a series of radioligand binding studies and effects on forskolin-stimulated cAMP formation in Chinese hamster ovary (CHO) cells expressing the recombinant human NCR (CHOhNCR). In addition, we report the effects of three antagonists, [Nphe1]NC(1-13)NH2, J-113397 and III-BTD, on these responses. In radioligand binding studies Ro65-6570, [Nphe1]NC(1-13)NH2, J-113397 and III-BTD displaced [3H]NC with similar pKi values (8.4-8.8). This compares with a pK(D) of 10.2 for NC in a direct saturation experiment. [Nphe1]NC(1-13)NH2 and J-113397 showed at least 100-fold selectivity over classical opioid receptors. Both NC and Ro65-6570 produced a concentration-dependent inhibition of cAMP formation with pEC50 values of 9.56+/-0.06 and 8.68+/-0.04, respectively. Maximum inhibition achieved was 100%. [Nphe1]NC(1-13)NH2, J-113397 and III-BTD produced a parallel rightward shift in the concentration-response curves to both NC and Ro65-6570 with pK(B) values of approximately 6.5, approximately 7.5 and approximately 7.7, respectively. Importantly, all three antagonists were devoid of residual agonist activity. Collectively, these data indicate the value of Ro65-6570, [Nphe1]NC(1-13)NH2, J-113397 and III-BTD in studies of the physiological role played by NC. However, due to the relatively poor selectivity of Ro65-6570 and III-BTD caution should be exercised when using tissues that co-express micro-opioid receptors.

Chick embryo retinas were labelled in ovo by single injections of [3H]thymidine at selected times between days 2 and 12 of incubation. Embryos were later removed, at different stages of development, and the retinas processed for autoradiography of either serial sections or dissociated cell preparations. Analysis of unlabelled cells shows that neurogenesis starts, on day 2 of incubation, in a dorsotemporal area of the central retina, close to the posterior pole and to the optic nerve head. A gradient of neurogenesis spreads from this central area to the periphery, where neurogenesis ends, shortly after day 12, when the last few bipolar cells withdraw from the cell cycle. Additional dorsal-to-ventral and temporal-to-nasal gradients can be discerned in our autoradiographs. In all retinal sectors, ganglion cells start first to withdraw from the cell cycle, followed, with substantial overlapping, by amacrine, horizontal, photoreceptor plus Müller, and bipolar neuroblasts. Ganglion cells are also the first to reach the 50% level of unlabelled cells, followed this time by horizontal, photoreceptor, amacrine, Müller and bipolar cells. Finally, 100% levels of unlabelled cell populations are attained simultaneously by ganglion, horizontal and photoreceptor cells, followed by amacrine, then by Müller, and last by bipolar cells. Although all classes of neurons, in varying proportions, are being produced most of the time, our results also demonstrate that, in any given retinal area, the first cells leaving the cycle are determined to become ganglion cells, and the last ones bipolar cells, and not other types.