Maximum a posteriori Bayesian estimation of oral cyclosporin pharmacokinetics in patients with stable renal transplants

OBJECTIVE: To develop a maximum a posteriori probability (MAP) Bayesian estimator for the pharmacokinetics of oral cyclosporin, based on only three timepoints, and evaluate its performance with respect to a full-profile nonlinear regression approach. PATIENTS: 20 adult patients with stable renal transplants given orally administered microemulsified cyclosporin and mycophenolate. METHODS: Cyclosporin was assayed by liquid chromatography-mass spectrometry. Nonlinear regression and MAP Bayesian estimation were performed using a home-made program and a previously designed pharmacokinetic model including an S-shaped absorption profile described by a gamma distribution. OUTCOME MEASURES AND RESULTS: MAP Bayesian estimation using the best limited sampling strategy (before administration, and 1 and 3 hours after administration) was compared with nonlinear regression (taken as the reference method) for the prediction of the different pharmacokinetic parameters and exposure indices. Median relative prediction error was -0.49 and -3.42% for area under the concentration-time curve over the administration interval of 12 hours (AUC12) and estimated peak drug concentration (Cmax), respectively (nonsignificant). Relative precision was 2.00 and 4.32%, and correlation coefficient (r) was 0.985 and 0.955, for AUC12 and Cmax, respectively. CONCLUSION: This paper reports preliminary results in a stable renal transplant patient population, showing that MAP Bayesian estimation can allow accurate prediction of AUC12 and Cmax with only three samples (0, 1 and 3 hours). Although these results require confirmation by further studies in other clinical settings, using other drug combinations, other analytical methods and commercially available pharmacokinetic software, the method seems promising as a tool for the therapeutic drug monitoring of cyclosporin in clinical practice or for exposure-controlled studies.     

Metabolic and electrophysiological alterations in subtypes of temporal lobe epilepsy: a combined proton magnetic resonance spectroscopic imaging and depth electrodes study

PURPOSE: This study compared the metabolic regional alterations, characterized by proton magnetic spectroscopic imaging ((1)H-MRSI), with electrophysiological abnormalities recorded by using depth electrodes and with structural lesions, in patients with several subtypes of temporal lobe epilepsy (TLE). METHODS: Twenty-five subjects were investigated, including 15 controls and 10 patients with drug-resistant unilateral TLE, nine of whom had structural abnormalities identified by MRI. All patients underwent noninvasive presurgical evaluation and then stereoelectroencephalography (SEEG). We performed an original metabolic exploration combining two (1)H-MRS imaging acquisitions associated with two single-voxel acquisitions (temporal poles) to map the most informative regions of interest (ROIs) including mesial and neocortical localizations. The N-acetyl aspartate/(choline+creatine) ratio was chosen as a metabolic index. SEEG analysis allowed the classification of each ROI as electrically normal or abnormal (i.e., involved in ictal and/or interictal discharges). Groups were compared by using a nonparametric Mann-Whitney U test. RESULTS: N-Acetyl aspartate/(choline+creatine) was significantly lower in all regions involved in SEEG electrophysiological epileptic abnormalities than in controls (p < 0.05). In contrast, the regions without any electrophysiological abnormalities were not metabolically different from those in controls (p > 0.05) except in one ROI. No differences between the metabolic profiles of epileptogenic and irritative zones were found. The metabolic alterations included, but also extended beyond, the lesions. The presence of metabolic abnormalities in mesial structures was not specific for the mesial subtype and generally extended outside the mesial structures. CONCLUSIONS: These results indicate that metabolic abnormalities are linked to ictal and interictal epileptiform activities rather than to structural alterations in TLE.     

Pancreatic islet transplantation using the nonhuman primate (rhesus) model predicts that the portal vein is superior to the celiac artery as the islet infusion site

We've established a nonhuman primate islet allotransplant model to address questions such as whether transplanting islets into the gut's arterial system would more safely and as effectively support long-term islet allograft survival compared with the traditional portal vein approach. We reasoned that islets make up <2% of pancreatic cell mass but consume an estimated 20% of arterial blood flow, suggesting an advantage for the arterial site. Access to the arterial system is also easier and safer than the portal system. Pancreatectomized rhesus macaques were transplanted with allogeneic islets infused into either the portal vein (n = 6) or the celiac artery (n = 4). To prevent rejection, primates were given daclizumab, tacrolimus, and rapamycin. In five of six portal vein experiments, animals achieved normoglycemia without exogenous insulin. In contrast, none of the animals given intra-arterial islets showed even transient insulin independence (P = 0.048). Two of the latter animals received a second islet transplant, this time to the portal system, and both achieved insulin independence. Thus, intraportal islet transplantation under conventional immunosuppression is feasible in primates and can result in long-term insulin independence when adequate immunosuppression is maintained. Arterial islet injection, however, does not appear to be a viable islet transplantation technique.     

Dyslipidaemia and its management after immunosuppressive treatment

This article summarises the mechanisms responsible for the hyperlipidaemia observed after immunosuppressive treatment. Much progress has been achieved in the treatment of organ transplantation over the last 10 years, in particular because of the use of new immunosuppressive drugs with less nephrotoxicity. However, hypercholesterolaemia and hypertriglyceridaemia persist among many patients, who are thus more likely to develop cardiovascular diseases. We first reviewed the effects of immunosuppressive drugs on biliary acid biosynthesis, which is the main pathway of cholesterol degradation. The inhibition of this biosynthesis pathway, and especially of some key cytochrome P450s (CYP) such as CYP27A1, could contribute to the increased cholesterolaemia. Immunosuppressive drugs may also modify the activity of lipoprotein receptors or the expression of different apolipoproteins involved in cholesterol and triglyceride transport by lipoproteins. Finally, the fact that hypertriglyceridaemia is more frequently observed after certain immunosuppressive treatments may be partly caused by changes in the synthesis and elimination of triglycerides involving lipoprotein lipase or some apolipoproteins which serve as its cofactors (apoCII or apoCIII).     

Automatic recognition of abnormal respiratory events during sleep by a pacemaker transthoracic impedance sensor

INTRODUCTION: A number of pacemakers use transthoracic impedance to derive minute ventilation as a sensor for rate adaptation. Transthoracic impedance is also able to track fluctuations in tidal volume occurring in sleep apnea/hypopnea syndromes (SAS). We evaluated the feasibility of a transthoracic impedance-derived pacemaker algorithm for monitoring sleep respiratory disturbances. METHODS AND RESULTS: Forty-two patients who presented with a conventional indication for DDD pacing or cardiac resynchronization underwent conventional polysomnography 1 month after implantation of a Talent trade mark 3 pacemaker (ELA Medical). The respiratory disturbance index (RDI) stored in the pacemaker memory was compared to the apnea/hypopnea index (AHI) derived from polysomnography. The ability of the pacemaker to identify severe SAS patients (AHI > or = 30) was assessed. A minimal systematic error was observed from a Bland and Altman plot (bias = 0.9 events/hour). The ability of the pacemaker RDI to identify severe SAS patients was determined by analysis of the receiver operator characteristic. A cutoff RDI value of 30.6/hour of recording was found to yield 75% sensitivity, 94% specificity, 75% positive predictive value, and 94% negative predictive value. CONCLUSION: The RDI monitoring function appears to be of value in screening pacemaker patients for SAS. Its performance is comparable to existing simple screening techniques. The ability to permanently monitor respiration, in combination with other diagnostic capabilities (such as Holter functions), presents a unique opportunity to monitor the association between arrhythmias and disturbances of breathing during sleep.     

Acute pulmonary embolism: a rare complication of a large non-parasitic hepatic cyst

A 56-year-old patient with a non-parasitic hepatic cyst developed acute dyspnoea. Pulmonary embolism was diagnosed. Bleeding into the hepatic cyst, leading to its enlargement and compression of the inferior vena cava, was the only likely cause of the pulmonary embolism. This complication of a non-parasitic liver cyst has not been reported previously. The patient was treated with heparin. Surgical evacuation of the cyst using the 'fenestration' technique was also performed. There was no recurrent pulmonary embolism or hepatic cyst during a 1-year follow-up period.     

Completion pancreatectomy for postoperative peritonitis after pancreaticoduodenectomy: early and late outcome

HYPOTHESIS: Completion pancreatectomy in patients with pancreatic leakage associated with postoperative peritonitis after pancreaticoduodenectomy is a viable salvage procedure. DESIGN: Retrospective analysis from a cohort of consecutive patients admitted between January 1, 1989, and December 31, 1999, for postoperative peritonitis originating from pancreaticojejunostomy leakage. SETTING: Tertiary referral center with surgical intensive care unit specializing in the treatment of intra-abdominal sepsis. PATIENTS: Eight consecutive patients with postoperative peritonitis originating from pancreaticojejunostomy after pancreaticoduodenectomy, with a mean Acute Physiology and Chronic Health Evaluation II score of 18.6. We excluded patients with pancreatic fistulas or abscesses amenable to percutaneous drainage or other conservative treatment. INTERVENTION: Completion pancreatectomy. MAIN OUTCOME MEASURES: Mortality, morbidity, and long-term outcome, which was assessed by interview. RESULTS: Three patients died in the postoperative period: 2 required early reoperation during the postoperative period and died of hemorrhage and sepsis, and 1 died of multiorgan failure without reoperation. Recurrence of carcinoma was responsible for late death of 2 other patients. CONCLUSIONS: Postoperative peritonitis after pancreaticoduodenectomy still has high mortality; however, completion pancreatectomy may represent the only means to achieve source control of infection in cases of postoperative peritonitis.     

Rhabdomyolysis, acute renal failure, and multiple focal neuropathies after drinking alcohol soaked with centipede

Many Chinese like to drink alcohol soaked with creatures for promoting health. This study reports a 49-year-old male who presented with multiple focal neuropathies of the upper limbs, coagulopathy, erythematous swelling of the bilateral upper extremities and trunk with bullous skin lesions, and rhabdomyolysis associated with acute renal failure after drinking alcohol soaked with centipede. Soaking a centipede, Scolopendra subspinipes mutilans, in 53% alcohol, produced the wine. Supportive treatment was administered, and the skin lesions and renal failure improved with subsequent neurologic deficit during the week following initial presentation. Alcohol binge or immobilization was the likely cause of neuropathy, bullous skin lesions and rhabdomyolysis in the patient. However, there is a possibility that centipede venom also contributed to the illness in this patient.     

The cuff leak test to predict failure of tracheal extubation for laryngeal edema

OBJECTIVE: Laryngeal edema secondary to endotracheal intubation may require early re-intubation. Prior to extubation the absence of leak around an endotracheal tube may predict laryngeal edema after extubation. We evaluated the usefulness of a quantitative assessment of such a leak to identify the patients who will require early re-intubation for laryngeal edema. METHODS: This prospective study included 76 patients with endotracheal intubation for more than 12 h. The leak, in percent, was defined as the difference between expired tidal volume measured just before extubation, in volume-controlled mode, with the cuff inflated and then deflated. The best cut-off value to predict the need for re-intubation for significant laryngeal edema was determined and the patients were divided into two groups, according to this cut-off value. RESULTS: Eight of the 76 patients (11%) needed re-intubation for laryngeal edema. Patients requiring re-intubation had a smaller leak than the other patients [9 (3-18) vs 35 (13-53)%, p<0.01]. The best cut-off value for gas leak was 15.5%. The high leak group included 51 patients, of whom only two patients (3%) required re-intubation. The low leak group included 25 patients, among whom six patients (24%) required re-intubation ( p<0.01). The sensitivity of this test was 75%, the specificity 72.1%, the positive predictive value 25%, the negative predictive value 96.1% and the percent of correct classification 72.4%. CONCLUSIONS: A gas leak around the endotracheal tube greater than 15.5% can be used as a screening test to limit the risk of re-intubation for laryngeal edema.     

Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition

Bloom's syndrome (BS) arises through mutations in both copies of the BLM gene that encodes a RecQ 3'-5' DNA helicase. BS patients are predisposed to developing all the cancers that affect the general population, and BS cells exhibit marked genetic instability. We showed recently that BLM protein contributes to the cellular response to ionizing radiation by acting as downstream ATM kinase effector. We now show that following UVC treatment, BLM-deficient cells exhibit a reduction in the number of replicative cells, a partial escape from the G2/M cell cycle checkpoint, and have an altered p21 response. Surprisingly, we found that hydroxyurea-treated BLM-deficient cells exhibit an intact S phase arrest, proper recovery from the S phase arrest, and intact p53 and p21 responses. We also show that the level of BLM falls sharply in response to UVC radiation. This UVC-induced reduction in BLM does not require a functional ATM gene and does not result from a subcellular compartment change. Finally, we demonstrate that exposure to UVC and hydroxyurea treatment both induce BLM phosphorylation via an ATM-independent pathway. These results are discussed in the light of their potential physiological significance with regard to the role of BLM in the cellular pathways activated by UVC radiation or HU-mediated inhibition of DNA synthesis.