Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

CY in combination with BU is a widely used conditioning regimen for haematopoietic SCT (HSCT). The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg) followed by CY (160-200 mg/kg) both over 4 days before HSCT. A population PK model was developed to describe the disposition of CY and HCY and the inter-individual (IIV) and inter-occasion variability (IOV). The model was also used to determine the effects covariates including: demographics, Lucarelli classification and polymorphisms in enzymes involved in the metabolism or biotransformation of CY had on CY and HCY disposition. Overall, 17-114% IIV and 12-103% IOV in CY and HCY PK parameters were observed. Body weight and age were the main covariates, which explained the largest portion of the IIV. In addition, CYP2C9*2 explained a significant portion of the IIV in the clearance (P<0.002) and thus the area under the concentration curve (P<0.05) of CY. This covariate model may be used to design and plan targeted dose therapy in this group of pediatric patients, if clinical outcome association with CY PK are proved and target range established.     

A study of silent disengagement and distressing emotion in psychotherapy

Abstract

Fifty-two psychotherapy sessions were coded for silences that reflect processes of client disengagement (e.g., withdrawal, resistance). The study examined the presence of these silences and clients' reports of in-session emotion and symptom change. Results indicated that disengagement predicted poorer proximal and distal outcome as measured by the Beck Depression Inventory for Primary Care (BDI-PC) and poorer proximal outcome on the Symptom Checklist-5, but it was not significantly predictive of Outcome Questionnaire-45 scores. Interitem analyses revealed that disengagement had a significant proximal effect on depressive mood and negative self-evaluative items assessed by the BDI-PC, but across time these effects were sustained for the negative self-evaluative items only.     

Physical Activity and Health Outcomes Among HIV-Infected Men Who Have Sex with Men: A Longitudinal Mediational Analysis

Background

Low physical activity is associated with depression, which may, in turn, negatively impact antiretroviral therapy (ART) adherence among HIV-infected individuals; however, prior studies have not investigated the relationships between physical inactivity and ART non-adherence.

Purpose

The purpose of this study was to examine the association of physical inactivity, depression, ART non-adherence, and viral load in HIV-infected men who have sex with men.

Methods

The sample (N?=?860) was from a large, multicenter cohort of HIV-infected patients engaged in clinical care.

Results

Across time, depression mediated the relationship between physical inactivity and ART non-adherence (γ?=?0.075) and the relationship between physical inactivity and viral load (γ?=?0.05). ART non-adherence mediated the relationship between depression and viral load (γ?=?0.002) and the relationship between physical inactivity and viral load (γ?=?0.009).

Conclusions

Low levels of physical activity predicted increased depression and poor ART adherence over time, which subsequently predicted higher viral load.     

Activation of human dendritic cells by p-phenylenediamine

Exposure to p-phenylenediamine (pPD), a primary intermediate in hair dye formulations, is often associated with the development of allergic contact dermatitis. Such reactions involve activation of the subject's immune system. The aim of these studies was to explore the relationship between pPD oxidation and functional maturation of human monocyte-derived dendritic cells in vitro. Dendritic cells were incubated with pPD and Bandrowski's base (BB) for 16 h, and expression of the costimulatory receptors CD40, CD80, CD83, CD86, and major histocompatibility complex class II intracellular glutathione levels and cell viability were measured. In certain experiments, glutathione (1 mM) was added to culture medium. Liquid chromatography-mass spectrometry (LC-MS) analysis and exhaustive solvent extraction were used to monitor the rate of [(14)C]pPD oxidation and the extent of pPD binding to cellular and serum protein, respectively. Proliferation of allogeneic lymphocytes was determined by incorporation of [(3)H]thymidine. Exposure of dendritic cells to pPD (5-50 microM), but not BB, was associated with an increase in CD40 and MHC class II expression and proliferation of allogeneic lymphocytes. Dendritic cell activation with pPD was not associated with apoptotic or necrotic cell death or depletion of glutathione. Neither pPD nor BB altered dendritic cell expression of CD80, CD83, or CD86. LC-MS analysis revealed pPD was rapidly oxidized in cell culture media to BB. Addition of glutathione inhibited BB formation but did not prevent covalent binding of pPD to dendritic cell protein or dendritic cell activation. Collectively, these studies show that pPD, but not BB, selectively activates human dendritic cells in vitro.     

Doppler ultrasound in noninvasive cardiac evaluation. The growing range of applications

Ultrasound is of proven clinical utility for imaging cardiac structures. Doppler ultrasonic techniques can be used with or without echocardiography for noninvasive hemodynamic studies. The usefulness of Doppler ultrasonic techniques in the noninvasive laboratory has been shown recently at the Massachusetts General Hospital, Boston. In 61 of 100 consecutive patients in a prospective study, Doppler ultrasound provided clinical information that could not be obtained with echocardiographic studies alone. The advantages of this technique for noninvasive cardiac studies are now being recognized in the general medical community. The results of ongoing clinical investigations will help define the role of Doppler echocardiography as a clinically useful diagnostic tool for cardiac evaluation.     

Dapsone for chronic idiopathic thrombocytopenic purpura in children and adults--a report on 90 patients

Data on 90 patients (55 adults and 35 children) with chronic idiopathic thrombocytopenic purpura (ITP) and a platelet count of <50 x 10(9)/L treated with dapsone at a dose of 1-2 mg/kg/d are presented. A response was observed in 57 (63.3%) patients. The average time for response was 3.5 months (range 1-9) and the average duration of treatment with dapsone was 10.4 months (range 4-14). Overall response rates of 65.7% and 61.8% were observed in children and adults respectively. Side effects requiring discontinuation of therapy were observed in three (2%) patients. These results demonstrate that dapsone is an effective, inexpensive and well-tolerated treatment for chronic ITP, in both children and adults and could be considered for patients who fail steroid therapy.     

The effect of medroxyprogesterone acetate on gonadotropin secretion in girls with precocious puberty.

Plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) as detected by radioimmunoassay have been found to be present in prepubertal children and show a gradual rise until the onset of puberty. Children with idiopathic true precocious puberty have plasma gonadotropin levels which are appropriate for their advanced degree of sexual development. A potent progestational agent, 6-methyl-17-hydroxyprogesterone acetate or medroxyprogesterone has been used in the treatment of precocious puberty and will suppress its physical manifestations. In this study the effect of medroxyprogesterone on gonadotropin levels was investigated in seven girls with true precocious puberty. Plasma LH values were found to be significant lower in patients receiving this agent than in a group of normal prepubertal girls. FSH values did not differ from the control group. One patient was evaluated prior to treatment and showed decreasing levels of LH after therapy was begun. These data suggest that medroxyprogesterone may act on the pituitary-hypothalamic axis to suppress the pubertal levels of LH.