P-glycoprotein (P-gp) function in T cells: implications for organ transplantation

P-glycoprotein (P-gp), a member of the adenosine triphosphate (ATP)-binding cassette (ABC) family of transporter molecules, is responsible for maintaining low intracellular concentrations of a variety of extracellular compounds and xenobiotics, and for transport of various intracellular molecules. Many drugs are P-gp substrates and intracellular concentrations of these agents may be critical for drug action. Experience in oncology indicates that repeated exposure to P-gp substrate cytotoxic drugs leads to the selection of drug-resistant tumor cells that overexpress P-gp. Since immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus and corticosteroids are substrates for P-gp and since T-cells also express P-gp, it is conceivable that an analogous mechanism exits for therapy-resistant graft rejection. As will be discussed in this article, P-gp may interfere with the response to immunosuppressive therapy through several distinct mechanisms, and as such may represent an attractive therapeutic target.     

The Effect of Antiepileptic Drugs on Cognition: Patient Perceived Cognitive Problems of Topiramate versus Levetiracetam in Clinical Practice

Summary:  Introduction: Neurocognitive complaints may interfere with long-term antiepileptic drug (AED) treatment and are an important issue in clinical practice. Most data about drug-induced cognitive problems are derived from highly controlled short-term clinical trials. We analyzed such cognitive complaints for the two most commonly used AEDs in a clinical setting using patient perceived problems as primary outcome measure.
Method: All patients of the epilepsy center Kempenhaeghe that received topiramate (TPM) or levetiracetam (LEV) from the introduction to mid 2004 were analyzed using a medical information system, an automated medical file. Patients were analyzed after 6, 12, and 18 months of treatment.
Results: Four hundred and two patients used either TPM (n = 260) or LEV (n = 142); 18 months retention showed a statistically significant difference, revealing 15% more patients that continued LEV compared to TPM: 18 months retention 46% for TPM and 61% for LEV [F (1.400) = 3.313, p = 0.043]. Neurocognitive complaints accounted for a significant number of drug discontinuations and especially the high frequency of neurocognitive complaints in the first period of TPM treatment appeared to be significant different from LEV [F(2,547) = 3.192, p = 0.042]. In the remaining patients, the difference in neurocognitive complaints was not statistically significant.
Conclusion: cognitive complaints are common in TPM treatment and frequently lead to drug withdrawal. The impact of LEV on cognitive function is only mild. This leads to a much higher (15%) drug discontinuation rate for TPM compared to LEV.     

Current determinants of 30-day and 3-month mortality in over 2000 aortic valve replacements: Impact of routine laboratory parameters.

OBJECTIVE: Haematological and biochemical measurements are performed routinely before surgery to exclude organ malfunction and blood cell and coagulation abnormalities. We aimed to test routinely obtained laboratory data as factors predicting operative risk. METHODS: Between 1996 and 2003, 2198 patients underwent aortic valve replacement (AVR) (908 of them with concomitant CABG) in our institute. The mean age of the study population was 69+/-11 years (range 13-91, 43% female). Clinical and laboratory parameters based on the consolidated data mart set were evaluated by multiple logistic regression analysis. RESULTS: The overall operative mortality (within 30 days) was 3.8% and the mortality after 3 months was 5.9%. In addition to clinical characteristics, the following laboratory values were identified as independent predictors of 30-day mortality: fasting blood glucose, antithrombine III, partial thromboplastine time and creatinine kinase. As independent predictors of 3-month mortality, the following laboratory values were indentified: fasting blood glucose, serum creatinine, antithrombine III, partial thromboplastine time, lactate dehydrogenase, sodium concentration and serum proteins. The discriminative power of the models increased if laboratory parameters were included in addition to preoperative clinical characteristics (from 0.75 to 0.79 and from 0.75 to 0.78 for 30-day and 3-month mortality, respectively). The discriminative power using the logistic EuroScore was lower (0.71 and 0.7, for 30-day and 3-month mortality, respectively). CONCLUSIONS: Laboratory parameters as objective markers for organ function and nutritional status are useful data for the prediction of 30-day and 3-month mortality after aortic valve replacement. Using modern methods of information technology, these valuable data which are stored electronically in most hospitals, can be used efficiently for research and quality control.     

Pretreatment with aldosterone or corticosterone blocks the memory-enhancing effects of nimodipine,captopril, CGP 37 849, and strychnine in mice

Oral pretreatment with aldosterone or corticosterone blocked the memory-enhancing effects of the calcium antagonist nimodipine, the ACE inhibitor captopril, the NMDA blocker CGP 37 849, and the glycine antagonist strychnine in a passive-avoidance test in mice. The memory-disturbing effects of phenobarbitone, diazepam, CGP 37 849 and scopolamine were not influenced by the hormonal pretreatment. These findings could indicate the involvement of a steroid-sensitive mechanism in drug-induced improvement of memory. In the light of clinical observations showing elevated cortisol levels in Alzheimer patients, the results might also explain why only a limited number of these patients respond to therapy with memory enhancers.     

Percutaneous transluminal coronary angioplasty in a patient with paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired chronic hemolytic anemia associated with an unusual susceptibility to hemolytic crisis, infection, and venous thrombosis which would be aggravated by a number of factors including surgery. We report a case of PNH undergoing percutaneous transluminal coronary angioplasty and discuss the corresponding perioperative management.     

Rotational ablation of coronary artery lesions using single,large burrs

Previous clinical use of the Rotablator^(TM) In coronary artery disease has involved a sequential increase in burr sizes up to 2 mm in diameter and has often utilized balloon adjunct to achieve an optimal result. We report our experience and describe our technique using a single, large burr (2.25, 2.5, or 2.75 mm diameter) without balloon assistance. The burr size was selected to approximate 70–90 percent of the apparent normal lumen diameter. Thirty-one patients with 36 lesions of complex morphology (eccentric, irregular, calcified, ulcerated, at bends, at bifurcations, completely occluded, as well as balloon failures) were successfully treated with the Rotablator^(TM). Results were assessed by computerized quantitative angiography. The percent diameter stenosis (mean ± SD) for the group was reduced from 69.8 ± 11.3% to 30.9 ± 10% (p < 0.001). The mean absolute diameter stenosis increased from 0.9 ± 0.3 mm to 2.2 ± 0.3 mm (p < 0.001). Angiographically visible dissections were seen in 4 patients and were uncomplicated in 2. One patient had a non-Q-wave myocardial infarction. A fourth patient had a presumed acute occlusion 36 hr after the procedure, necessitating emergency bypass surgery, but without Q waves on the electrocardiogram or wall-motion abnormalities on the echocar-diogram. Nitroglycerin was infused through the Rotablator^(TM) catheter and has considerably lowered the degree and frequency of spasm. No other acute complications occurred. The mean procedure time using a single burr was shorter than when multiple burrs were used: 56.5 vs. 97.3 min, respectively (p < 0.05). The use of a single, large-size Rotablator^(TM) burr is an effective method of treating complex coronary stenoses without balloon assistance and has an encouragingly low complication rate and short procedure time. © 1992 Wiley-Liss, Inc.     

A likelihood approach to HLA serology.

A likelihood approach to HLA serology has been developed in which the aim is not to define a recognition set for a serum but to describe the serum's ability to react with each and every antigen in the test cells, this ability being quantified in terms of the probability of a positive reaction. For a given set of probabilities, one for each antigen, it is possible to derive the probability of the observed set of reactions (the likelihood of the set of probabilities). The maximum possible value of the likelihood for any possible combination of the probability set can then be sought, but this requires a maximization of likelihood with respect to 60-100 independent parameters. Theoretical considerations of the shape of the likelihood surface prove that, in this particular case, this is a feasible proposition. This approach allows the recognition of three groups of antigens: those for which there is considerable evidence of a specificity, those for which there is either no specificity or a very weak specificity, and those for which there is insufficient evidence on which to base a conclusion. The existence of a specificity can be tested using a log likelihood ratio as a statistic, but the usual assumption of a chi 2 distribution of this statistic cannot automatically be made in this situation. Therefore, the distribution is estimated by simulation. A serologist using this approach would receive considerably more information as to the serum's reaction patterns and valid statistics for the existence, or not, of a specificity.     

Piperacillin-Tazobactam Pharmacokinetics in Patients With Intraabdominal Infections

Study Objective . To determine the appropriate compartmental and noncompartmental pharmacokinetic parameters for intravenous piperacillin and tazobactam. Design . Sequential selection of patients entered into a randomized, open-label clinical efficacy trial. Setting . Los Angeles County-University of Southern California Medical Center. Participants . Sequential sample of 18 patients admitted for intraabdominal infections and consented into a comparative antibiotic trial. Interventions . Patients received piperacillin 4 g plus tazobactam 500 mg by intravenous intermittent infusion every 8 hours. Measurements and Main Results . The estimated noncompartmental pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam, respectively, were as follows: maximum concentration in plasma 218.7 ± 48.9 μg/ml and 27.8 ± 9.1 μg/ml; half-life 1.07 ± 0.22 hours and 1.00 ± 0.27 hours; elimination rate constant 0.67 ± 0.13 hr⁻¹ and 0.73 ± 0.18 hr⁻¹; area under the concentration-time curve from zero hour to infinity 288.5 ± 71.25 mg·hr/L and 36.3 ± 9.55 mg·hr/L; total plasma clearance 14.75 ± 3.93 L/hour and 14.78 ± 4.39 L/hour; renal clearance 5.69 ± 1.94 L/hour and 7.85 ± 3.37 L/hour; volume of distribution at steady state 21.00 ± 4.18 L and 22.47 ± 8.27 L; and mean residence time 1.72 ± 0.29 hours and 1.79 ± 0.35 hours. Conclusion . Our findings were similar to those in other surgical patient models. The two-compartmental model best described piperacillin and tazobactam disposition in our patients. Bayesian analyses of the two-compartment models of piperacillin and tazobactam were able to predict trough, peak, and 2-hour postadministration levels without bias.     

Effects of prolactin on secretion and synthesis of human chorionic gonadotropin in human term placentas in vitro: short-term increase in secretion, followed by medium-term suppression of synthesis and secretion.

We studied the influence of human prolactin on the secretion and de novo synthesis of human chorionic gonadotropin (hCG) in the human term placenta in culture. Placental tissue from 14 patients with uncomplicated pregnancies and deliveries was prepared mechanically, with addition of a Percoll gradient step. hCG levels were determined in the culture media and in the cytosolic fraction of cells by means of an enzyme immunoassay with coated beads. The amount of newly synthesized hCG was measured by the extent of incorporation of 35S-methionine into the hCG molecule. Our results showed that human prolactin had two different effects in vitro: between 1/2 and 1 h, prolactin slightly increased secretion of hCG into the culture medium without affecting de novo synthesis; after 2 h, prolactin began to cause a significant decrease in both secretion and de novo synthesis of hCG over several hours. It appears that both effects are receptor mediated, for ovine prolactin failed to produce any response. We conclude that prolactin is one of the main factors regulating the synthesis and secretion of hCG in the human trophoblast at term.