Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation

Abstract: We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean ± SD, 1.21 ± 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4–12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis.     

Multipass Vector (Mpave) Technique with Nonablative Radiofrequency to Treat Facial and Neck Laxity

Background. Redundant facial and neck skin is a major feature of aging and historically has been corrected surgically. Recently, monopolar radiofrequency application has been introduced for nonablative tissue tightening of skin by volumetric heating of the deep dermis. It has been able to improve neck and cheek laxity and periorbital rhytides and to elevate eyebrows. However, questions remain as to the ideal parameters needed to optimize the use of radiofrequency.
Objective. To determine the safety and report on the efficacy of a radiofrequency application that involves a multipass vector (mpave) technique to target facial and neck skin laxity.
Methods. Twenty-five patients (skin types I to V) with mild to severe facial and neck laxity received one treatment session with monopolar radiofrequency. Treatment parameters, adverse events, and digital photographs were recorded. All patients were treated with a multipass vector technique consisting of four to five passes targeted over areas of skin that would most improve facial laxity. The multipass vector (mpave) treatment approach is described. Energy levels ranged from 62 to 91 J/cm2 per pulse.
Results. All patients experienced some immediate erythema and edema, which had completely resolved in most patients within 48 hours. No scarring or dyspigmentation was noted on follow-up at 6 and 12 weeks. Photographic analysis of pre- and post-treatment digital images revealed cosmetic improvement in facial and neck laxity in 96% of patients. The majority of patients demonstrated a moderate or better improvement. Stacked pulses in the submental region were shown to reduce fat.
Conclusions. The direct application of monopolar radiofrequency to facial and neck skin using a multipass vector (mpave) treatment approach was safely tolerated in patients of all skin types. Patient satisfaction correlated well with photographic analysis, and the technique was shown to be efficacious for most patients.     

Decomposing Area of Residence Differences in Multiple Regression Studies: The Relative Contributions of Independent Variables and Model Coefficients

When rural/urban differences are found in health status or health care use, it is often desirable to identify those factors (such as age, social structure, income, etc.) that influence such differences. To this end, researchers often test rural/urban differences in age, social structure, income, etc., for statistical significance. Also, researchers commonly perform multivariate analyses (such as multiple regressions) to examine rural-urban differences in the influence of various independent variables on the dependent variable of interest. Frequently, researchers discover: (1) statistically significant rural/urban differences in the independent variables (such as age, social structure, income, etc.) and (2) statistically significant rural/urban differences in the effects of these independent variables (i.e., statistically significant rural/urban differences in regression coefficients). The analysis typically stops here, without addressing the relative contributions of (1) and (2) to the rural/urban differences in the dependent variable. This paper argues that the relative contributions of (1) and (2) have important implications for the way policy-makers address rural health problems. This paper presents a method for assessing the relative contributions of differences in the independent variables and differences in regression coefficients to observed differences in the dependent variable, and illustrates the application of the method by analyzing rural/urban differences in the risk of institutionalization.     

Ethics of asking trauma-related questions and exposing participants to arousal-inducing stimuli.

This study examined ethical concerns related to exposing participants with childhood victimization histories to both trauma-specific and non-trauma-specific stimuli. We asked participants questions about childhood victimization experiences and exposed participants to a negatively-arousing experimental condition. Following each of these procedures and at a one-week follow-up session, participants completed a measure designed to asses their reactions to participation. The measure included several questions to assess reactions including questions about distress, benefit, and willingness to participate in the study again. Overall, participants reported low levels of distress and described their participation experience as interesting, enjoyable, and somewhat beneficial. Participants also indicated that they would be willing to participate in the study again with the knowledge of what participation was actually like. Participants with childhood trauma histories and PTSD symptoms reported more distress during the childhood maltreatment screening compared to other participants. However, the level of distress they experienced was mild and transitory. Our findings add to the emerging data indicating that individuals find their participation in trauma-related research to be a positive experience overall, rather than a harmful one.     

Prelinguistic predictors of language outcome at 3 years of age.

PURPOSE: The purpose of this study was to examine the predictive validity of a collection of prelinguistic skills measured longitudinally in the 2nd year of life to language outcome in the 3rd year in children with typical language development. METHOD: A collection of prelinguistic skills was assessed in 160 children early (M = 14.31 months; SD = 1.36) and late (M = 19.76 months; SD = 1.16) in their 2nd year by using the Communication and Symbolic Behavior Scales Developmental Profile Behavior Sample (A. Wetherby & B. Prizant, 2002). The relation between the prelinguistic skills and the receptive and expressive language near the 3rd birthday was examined. RESULTS: Significant correlations were observed between many prelinguistic skills and language outcome. Regression analyses indicated that comprehension both early and late contributed unique variance to receptive and expressive language outcome. In addition, early in the 2nd year, inventory of conventional gestures contributed uniquely to receptive language outcome, and acts for joint attention contributed uniquely to expressive outcome. Late in the 2nd year, inventory of consonants contributed uniquely to expressive outcome. CONCLUSIONS: The findings demonstrate continuity between prelinguistic and linguistic skills and how individual differences in a number of prelinguistic skills contribute collectively and uniquely to language outcome in typically developing children.     

Psychosocial factors in medical and psychological treatment avoidance: the role of the doctor-patient relationship

A community sample of 1106 adults was examined to assess the impact of the doctor-patient relationship on participants' avoidance of treatment for a recognized medical or psychological problem. Of five aspects of participants' previous experience with their physicians, all but waiting time predicted participants' self-reported treatment avoidance. In two logistic regression models participants who felt their physicians listened more to their concerns were less likely to avoid treatment for both medical and psychological problems during the previous 12 months. These findings suggest that patients' perceptions of how they are treated by physicians may help explain why many people delay or avoid healthcare treatment, even when faced with a significant health problem.     

Incidences of selected lesions in control female Harlan Sprague-Dawley rats from two-year studies performed by the National Toxicology Program

The NTP has a long history of using Fischer rats and has compiled a large database of incidences of lesions seen in control animals. Such a database is lacking for Harlan Sprague-Dawley (SD) rats. The intention of this paper is to report spontaneous lesions observed in female vehicle control Harlan SD rats, and to compare the incidence in 2 strains of rats (Fischer and Harlan SD) used in NTP studies. Female Harlan SD rats served as the test animals for a special series of 2-year studies. Male rats were not used in these studies. Complete histopathology was performed on all animals, and the pathology results underwent comprehensive NTP pathology peer review. The most commonly observed neoplasms in these female control Harlan SD rats were mammary gland fibroadenoma (71%), tumors of the pars distalis of the pituitary (41%) and thyroid gland C-cell tumors (30%). Female Fischer rats had incidences of 44% for mammary gland fibroadenomas, 34% for tumors of the pars distalis, and 16% for thyroid gland C-cell tumors. Fischer rats had a 15% incidence of clitoral gland tumors, while the Harlan SD rats had an incidence of < 1%. In contrast to Fischer F344 rats, the Harlan SD rats had a high incidence of squamous metaplasia of the uterus (44.2%). Squamous metaplasia is not a lesion commonly observed in NTP control Fischer rats. The Harlan SD rats had a very low incidence of mononuclear cell leukemia (0.5%), compared with an incidence of 24% in female Fischer rats.     

Cerebellar damage impairs automaticity of a recently practiced movement

It has been suggested that the cerebellum plays a critical role in learning to make movements more "automatic" (i.e., requiring less attention to the details of a movement). We hypothesized that cerebellar damage compromises learning of movement automaticity, resulting in increased attentional demands for movement control. The purpose of our study was to determine whether cerebellar damage disrupts the ability to make a practiced movement more automatic. We developed a dual task paradigm using two tasks that did not have overlapping sensory or motor requirements for execution. Our motor task required subjects to maintain an upright posture while performing a figure-8 movement using their arm. This motor task was chosen to simulate requirements of everyday movements (e.g., standing while reaching for objects), but it was novel enough to require practice for improvement. Our secondary task was an auditory vigilance task where subjects listened to letter sequences and were asked to identify the number of times a target letter was heard. We tested controls and people with cerebellar damage as they practiced the movement task alone and then performed it with the auditory task. We recorded 3D position data from the arm, trunk, and leg during the movement task. Errors were recorded for both the movement and the letter tasks. Our results show that cerebellar subjects can improve the movement to a very limited extent with practice. Unlike controls, the motor performance of cerebellar subjects deteriorates to prepractice levels when attention is focused away from the movement during dual task trials. Control subjects' insensitivity to dual task interference after practice was due to learned movement automaticity and was not a reflection of better dual task performance generally. Overall, our findings suggest that the cerebellum may be important for shifting movement performance from an attentionally demanding (unpracticed) state to a more automatic (practiced) state.