Neurotoxicity of valacyclovir in peritoneal dialysis: a pharmacokinetic study

Valacyclovir is an effective oral agent for the treatment of herpes virus infection, however, the pharmacokinetics of the drug are altered in renal failure. It is increasingly recognized that dose adjustment of oral valacyclovir in renal failure is necessary to avoid neurotoxicity. We studied this drug in a continuous ambulatory peritoneal dialysis (CAPD) and immunocompromised patient. She developed neurotoxicity with an adjustment dosage of valacyclovir for a cutaneous zoster infection. The elimination half-time (15 h) was similar to that reported for end-stage renal disease patients, while the steady-state volume of distribution (85 l) and the area under the curve concentration (127 mg/l.h) were greater. The mean CAPD dialysance was only 5.27 ml/min with less than 1% of an administered dose being recovered in the 24-hour dialysate. 48 h after interrupting treatment, she recovered normal neurological status and 500 mg of valacyclovir every 2 days was effective and well tolerated.     

Unification of the revised trauma score

BACKGROUND: The Revised Trauma Score (RTS) calculated with Major Outcome Trauma Study weights (MTOS-RTS) is currently the standard physiologic severity score in trauma research and quality control. It is often confused with the Triage-RTS (T-RTS), a version that is easier to calculate but only intended for clinical triage. OBJECTIVES: To compare the accuracy of the MTOS-RTS to the RTS calculated with weights derived from the study population (POP-RTS) and the T-RTS, for predicting mortality in a trauma population. METHODS: The study population consists of 22,388 patients, drawn from the trauma registries of three Level I trauma centers. The predictive accuracy of the MTOS-RTS, POP-RTS, and the T-RTS were compared using measures of discrimination and model fit from logistic regression models. RESULTS: The MTOS-RTS, the POP-RTS, and the T-RTS had the same discrimination (Area under the Receiver Operating Curve [AUC] = 0.841). The POP-RTS and the T-RTS had a slightly better model fit than the MTOS-RTS (AIC = 8010, 8010, and 8067, respectively). The T-RTS had equal discrimination and equal or better model fit than the MTOS-RTS in the whole sample, in each of the three trauma centers and in the population of patients with severe head trauma. The T-RTS was also equivalent to the POP-RTS in all of these population sub-groups. CONCLUSIONS: The T-RTS could replace the MTOS-RTS as the standard physiologic severity score for trauma outcome prediction. The advantages of using the T-RTS over the MTOS-RTS are ease of calculation, the need for only one measure for triage and mortality prediction purposes and universal adaptation to a broad range of trauma populations.     

Statistical validation of the Glasgow Coma Score

BACKGROUND: To validate the predictive value of the Glasgow Coma Score (GCS) and find the best way to model the score in a logistic regression model predicting mortality. METHODS: Analyses were based on 20,494 patients from the trauma registries of three urban Level I trauma centers in the province of Quebec, Canada. The predictive value of the GCS and its components was evaluated in logistic regression models predicting in-hospital mortality with measures of discrimination and calibration. The performance of the GCS with no transformation and as an ordered categorical variable was compared with two transformation techniques: fractional polynomials and spline regression. RESULTS: The GCS had excellent discrimination (area under Receiving Operator Characteristic Curve=0.833 95% confidence interval=0.820-0.846) but fairly poor calibration (Pearson's Chi-squared statistic=122 on 11 df). The eye component added no predictive information to the verbal and motor components in the whole sample but was important in certain sub-populations. Using the three components separately, rather than the sum, did not improve the predictive model. Fractional polynomial transformation of the GCS improved calibration and spline regression performed even better. GCS modeled as an ordered categorical variable performed badly both in terms of discrimination and calibration. CONCLUSIONS: The GCS in its present form is an efficient predictor of in-hospital mortality, which could benefit from statistical transformation in logistic regression models when the accuracy of estimated probabilities of mortality is important. The common use of GCS categories for modeling mortality leads to loss of information and should be discarded.     

Peritoneal dialysis as prime treatment for diabetic patient with ESRD

In all countries, the number of diabetic patients with end stage renal disease is growing. The question is whether this mode of therapy is the most appropriate for uremic diabetics. The superiority of any type replacement renal therapy (RRT) over another cannot be unequivocally proven in the absence of a truly random long-term prospective study, which for obvious reasons, has not and probably will not be carried out. Today, the decision on the final choice is indeed dependant on patient preferences, medical factors, physician's biais, local facilities and financial aspects. If in most centers, survival analysis results performed in Europe and in North America regarding diabetic patients RRT are conflicting, the interpretation of comparisons of survival rates published in different studies must be treated with great caution. Nevertheless, if diabetic patients survival is significantly lower than that of non diabetic patients independently of the technique chosen there is no argument to assess that survival at 2 years of diabetic patients aged less 55 years is better on PD than on HD. There is no argument to assess that survival at 2 years of diabetic patients aged more 55 years is better or less appropriate on PD than on HD, excepted in the North America where survival seems to be less appropriate on PD. The present report summarizes the major advantages and drawbacks of the PD method in insulin treated diabetic patients.     

Lifestyle factors and the risk of adult leukemia in Canada

Objectives: To evaluate the impact of active smoking, obesity, and dietary intakes on the risk of adult leukemia.Methods: We analysed data obtained from a population-based case–control study conducted in eight Canadian provinces. Risk estimates were generated by applying multivariate logistic regression methods to 1068 incident histologically confirmed leukemia cases and 5039 controls aged 20–74.Results: We found a statistically significant increased risk for acute myeloid leukemia (AML) associated with active smoking, with a clear dose–response relationship and an adjusted odds ratio (OR) of 1.5 (95% confidence interval [CI]=1.1–2.0) for heavy smokers reporting more than 20 pack-years of cigarette smoking. We also observed positive associations with the highest body mass index (BMI) for AML, chronic myeloid leukemia, and chronic lymphoid leukemia with a significant dose–response relationship. No association with leukemia was observed for the intake of fruits and vegetables, and the effect of active smoking on adult leukemia risk was not modified by fruits and/or vegetables consumption or obesity. However, the positive risk for AML associated with active smoking disappeared among subjects with high BMI (≥30 kg/m²).Conclusions: Our study contributes to the accumulating evidence linking AML and active smoking, and provides some evidence that obesity increases the risk of most of the adult leukemia subtypes.     

Multiple imputation of the Glasgow Coma Score

BACKGROUND: To investigate whether multiple imputation (MI) of missing Glasgow Coma Scale (GCS) values generates more accurate GCS frequency distributions and less biased parameter estimates in logistic regression models predicting mortality than the standard procedure of excluding observations with missing GCS values. METHODS: The study population consisted of 5,065 patients with complete GCS information from the trauma registry of a Level 1 trauma center. Missing GCS values were imposed on the data set, and the performance of MI (extrapolating missing GCS from a data prediction model) and of deleting all data observations with missing GCS (list-wise deletion) were evaluated. GCS and Trauma and Injury Severity Score (TRISS) frequency distributions and parameter estimates were compared with true values from the original data set. RESULTS: GCS and TRISS frequency values generated by MI were much more accurate than those generated by list-wise deletion. GCS and TRISS parameter estimates generated by MI all had acceptable bias and coverage rates when compared with true values. List-wise deletion provided biased parameter estimates for the GCS, the Revised Trauma Score, and the Injury Severity Score. CONCLUSION: MI is a valid solution to the problem of missing GCS data in trauma research. It allows the conservation of precious data observations and leads to unbiased estimates in consequent analyses. Analyses, which exclude observations with missing GCS data, provide biased results.     

Synthesis of Telechelic Oligomers via Atom Transfer Radical Polymerization, 3

Summary: ATRP of butyl α‐fluoroacrylate (FABu) was carried out at 90 °C using methyl 2‐bromoisobutyrate (2‐MBiB) as initiator and the homogeneous catalyst CuBr/1,1,4,7,10,10‐hexamethyltriethylenetetramine (HMTETA). Telechelic oligomers were obtained by coupling the bromo terminated polymers in the presence of Cu⁽⁰⁾ and 2,2′‐bipyridyl ligand. The ¹H and ¹⁹F NMR, SEC and MALDI TOF analyses show that the poly(FABu) chains recombination was the main reaction (80% yield). About 20% of disproportionation reaction also occurs in the process, whereas transfer reactions can be neglected.

Compounds produced by recombination, disproportionation and transfer during the coupling reaction of poly(FABu) oligomers.     

Mutations in the human leptin and leptin receptor genes as models of serum leptin receptor regulation

A part of serum Ob leptin, an adipocyte-secreted peptide, is bound to a soluble Ob receptor (sObR). Immunoreactive sObR was measured in 125 lean or obese control subjects (group 1), 18 individuals with a mutation in the leptin gene impairing leptin secretion (group 2), and 10 individuals with a mutation in the ObR gene, leading to production of a truncated ObR not anchored to cell membranes (group 3). In group 1, sObR levels were negatively correlated with age and BMI in children and with BMI in adults. sObR levels were also negatively correlated with leptin levels. Leptin binding activity and sObR levels coeluted in gel-filtration chromatography. In group 2, sObR levels did not differ from those in lean control subjects and were not correlated with BMI. A single peak was detected in chromatographic fractions. In group 3, sObR levels were high and positively correlated with BMI. Immunoreactive sObR coeluted with leptin binding activity. These data demonstrate that leptin is not needed for ObR gene expression, and they suggest that leptin plays a role in receptor downregulation because sObR levels are negatively correlated with leptin levels and BMI in control subjects, whereas sObR levels are not depressed in obese leptin-deficient or leptin receptor-deficient individuals.     

Monitoring the activation state of insulin/insulin-like growth factor-1 hybrid receptors using bioluminescence resonance energy transfer

In cells expressing both the insulin receptor isoform A (IRA) and the insulin-like growth factor-1 receptor (IGF1R), the presence of hybrid receptors, made up of an alphabeta-IRA chain associated with an alphabeta-IGF1R chain, has been demonstrated. These heterodimers are found in normal cells, and they also seem to play crucial roles in a number of cancers. However, they remain difficult to study, due to the concomitant presence of IRA and IGF1R homodimers. Using bioluminescence resonance energy transfer (BRET), we have developed assays to specifically monitor the activation state of IRA/IGF1R hybrids, both in vitro and in living cells. The first assay allowed the study of ligand-induced conformational changes within hybrid receptors purified from cells cotransfected with one type of receptor fused to Renilla reniformis luciferase (Rluc), and the other type of receptor fused to yellow fluorescent protein (YFP). In these conditions, only hybrid receptors were BRET-competent. In the second assay, the activation state of IRA/IGF1R hybrids was monitored in real time, in living cells, by cotransfection of kinase-dead versions of IRA-Rluc or IGF1R-Rluc, wild-type untagged IRA or IGF1R, and a YFP-tagged soluble version of the substrate-trapping mutant of protein tyrosine phosphatase 1B (YFP-PTP1B-D181A-Cter). In hybrid receptors, trans-phosphorylation of the kinase-dead alphabeta-Rluc moiety by the wild-type alphabeta moiety induced the recruitment of YFP-PTP1B-D181A-Cter, resulting in a hybrid-specific ligand-induced BRET signal. Therefore, both methods allow monitoring of the activity of IRA/IGF1R hybrid receptor and could be used to detect molecules of therapeutic interest for the treatment of cancer.