AraU accumulation in patients with renal insufficiency as a potential mechanism for cytarabine neurotoxicity

Neurotoxicity of cytarabine (AraC) is believed to be related to renal insufficiency. We examined the plasma pharmacokinetics of AraC and its deamination product uracil arabinoside (AraU) in four patients with AML and concomitant severe renal insufficiency after treatment with AraC. Additionally, in one of these patients the concentration of intracellular AraCTP, the active metabolite of AraC, was analysed. Patients 2 and 3 were treated with AraC 1.0 g/m² infused for 3 h at 12-h intervals on days 1–4. Patient 1 received the same schedule of AraC with 0.5 g/m² and patient 4 with 0.25 g/m² AraC. Plasma concentrations of AraC, AraU and the intracellular concentration of AraCTP were analysed at different time points using HPLC. AraC pharmacokinetics in patients with severe renal insufficiency was comparable to patients with normal renal function. Peak plasma levels as well as intracellular AraCTP kinetics were also not significantly influenced by renal dysfunction. As expected from the high dose AraC pharmacokinetic parameters, the AraU serum levels accumulated during treatment. Under the conditions of renal impairment, AraU half-life was about 75 h and the AUC was about 12-fold higher than for patients with normal renal function. AraU could be the pathophysiologic cause for the known correlation between the incidence of neurotoxicity and renal insufficiency in high-dose AraC. To avoid AraU accumulation, intermittent hemodialysis during high-dose AraC treatment could be a suitable method considering the low protein-binding and low distribution volume of AraU.     

Acute maternal stress in pregnancy and schizophrenia in offspring: A cohort prospective study

Background

The Mental Health Inventory (MHI-5) and the Mental Health Component Summary score (MCS) derived from the Short Form 36 (SF-36) instrument are well validated and reliable scales. A drawback of their construction is that neither has a clinically validated cutpoint to define a case of common mental disorder (CMD). This paper aims to produce cutpoints for the MHI-5 and MCS by comparison with the General Health Questionnaire (GHQ-12).

Methods

Data were analysed from wave 9 of the British Household Panel Survey (2000), providing a sample size of 14,669 individuals. Receiver Operating Characteristic (ROC) curves were used to compare the scales and define cutpoints for the MHI-5 and MCS, using the following optimisation criteria: the Youden Index, the point closest to (0,1) on the ROC curve, minimising the misclassification rate, the minimax method, and prevalence matching.

Results

For the MHI-5, the Youden Index and the (0,1) methods both gave a cutpoint of 76, minimising the misclassification rate gave a cutpoint of 60 and the minimax method and prevalence matching gave a cutpoint of 68. For the MCS, the Youden Index and the (0,1) methods gave cutpoints of 51.7 and 52.1 respectively, minimising the error rate gave a cutpoint of 44.8 and both the minimax method and prevalence matching gave a cutpoint of 48.9. The correlation between the MHI-5 and the MCS was 0.88.

Conclusion

The Youden Index and (0,1) methods are most suitable for determining a cutpoint for the MHI-5, since they are least dependent on population prevalence. The choice of method is dependent on the intended application. The MHI-5 performs remarkably well against the longer MCS.     

A 21-year-old man with systemic-onset juvenile rheumatoid arthritis, cough and progressive dyspnea

Primary or nonobstructive, endogenous lipoid pneumonia is a rare clinical entity usually associated with an underlying systemic disease. The present report describes a case involving a 21-year-old man with systemic-onset juvenile rheumatoid arthritis who developed primary endogenous lipoid pneumonia. Multiple treatment regimens were attempted; however, definitive management was only achieved through double-lung transplantation.