Long-term sequelae of therapy for childhood acute lymphoblastic leukaemia

Childhood ALL has provided the model for basic therapeutic principles in the past and now provides the model for late effects studies. Common threads which run throughout the literature in this area of clinical research are the importance of young age with increased vulnerability to long-term treatment induced sequelae and the relatively large contribution of radiation as compared with chemotherapy in the pathogenesis of adverse sequelae. Previous retrospective studies of long-term childhood ALL survivors focused on neuropsychologic changes and anatomic changes in the CNS after cranial irradiation. More recent retrospective studies have made the following new observations: (i) the high frequency of significant short adult stature in those less than 6 years of age at diagnosis who received 24 Gy cranial irradiation; (ii) actuarial risk of 2.5% of developing a second malignancy with approximately one-half of secondary malignancies occurring in the CNS in children 5 years of age or less who received cranial irradiation; (iii) the association of secondary ANLL with epipodophyllo-toxin use, and (iv) delayed cardiac toxicity despite anthracycline dosage reduction. Current therapy regimens, especially in high-risk patients, are both more successful and more intensive than those used in the past. While it will be another decade before many of the long-term sequelae begin to emerge, one can anticipate, based on current experience, some of the problems that will occur.     

Maternal punitiveness as affected by situational stress: An experimental analogue of child abuse.

To test hypothesized variables involved in punishment and child abuse, 2 techniques were used to increase child-dependent and child-independent situational demands placed on mothers in a controlled laboratory situation while they monitored their children's performances. 10 23–29 yr old mothers and their 4–8 yr old children participated in concurrent tasks. Whether these stressors were directly related to their children's behaviors or independent of them, heightened stress resulted in increases in punitiveness toward the children. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Engineering of the Escherichia coli Im7 immunity protein as a loop display scaffold

Protein scaffolds derived from non-immunoglobulin sources are increasingly being adapted and engineered to provide unique binding molecules with a diverse range of targeting specificities. The ColE7 immunity protein (Im7) from Escherichia coli is potentially one such molecule, as it combines the advantages of (i) small size, (ii) stability conferred by a conserved four anti-parallel alpha-helical framework and (iii) availability of variable surface loops evolved to inactivate members of the DNase family of bacterial toxins, forming one of the tightest known protein-protein interactions. Here we describe initial cloning and protein expression of Im7 and its cognate partner the 15 kDa DNase domain of the colicin E7. Both proteins were produced efficiently in E.coli, and their in vitro binding interactions were validated using ELISA and biosensor. In order to assess the capacity of the Im7 protein to accommodate extensive loop region modifications, we performed extensive molecular modelling and constructed a series of loop graft variants, based on transfer of the extended CDR3 loop from the IgG1b12 antibody, which targets the gp120 antigen from HIV-1. Loop grafting in various configurations resulted in chimeric proteins exhibiting retention of the underlying framework conformation, as measured using far-UV circular dichroism spectroscopy. Importantly, there was low but measurable transfer of antigen-specific affinity. Finally, to validate Im7 as a selectable scaffold for the generation of molecular libraries, we displayed Im7 as a gene 3 fusion protein on the surface of fd bacteriophages, the most common library display format. The fusion was successfully detected using an anti-Im7 rabbit polyclonal antibody, and the recombinant phage specifically recognized the immobilized DNase. Thus, Im7 scaffold is an ideal protein display scaffold for the future generation and for the selection of libraries of novel binding proteins.     

Deterioration of intellect among children surviving leukemia: IQ test changes modify estimates of treatment toxicity.

Assessed the association of young age at treatment, cranial irradiation, and time since treatment with intellectual deterioration among 49 long-term survivors of childhood leukemia. Ss had been randomized to receive low-dose cranial radiation therapy or high-dose chemotherapy. Longitudinal assessments of intellect were conducted. No significant effects of treatment group or age at treatment were detected. A small but statistically significant decline in mean full-scale IQ was noted over time (M?=?–3.6). Reanalysis with IQ test version included as a covariate eliminated IQ declines found initially. Results suggest that there has been reduced toxicity of these methods of treatment and that the magnitude and direction of error introduced by changing tests may approximate the magnitude of adverse effects on IQ expected from treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Parental discipline as affected by the sex of the parent, the sex of the child, and the child's apparent responsiveness to discipline.

40 parents (mean age 31 yrs) were made to believe they were teaching their children (mean age 55.7 mo) a task by selecting rewarding and punishing consequences for the children's successes and errors. The children actually had been separated from their parents, and their "responding" was electromechanically controlled. Initially, responses were 50% successful on the trials, independent of their parents' disciplinary strategies. Next, successes were manipulated to be contingent on parents' selection of high, and later low, levels of punishment following errors. Finally, no successful responses were given regardless of parents' administration of discipline. The children's simulated responding was found to exert functional control over the intensities of punishments that their parents administered. Furthermore, parents' and children's gender and the children's apparent responsiveness to the parents' disciplinary strategies combined to determine the manner in which punishers and rewards were given by the parents. (12 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Barriers to student computer usage: staff and student perceptions

Ensuring that all graduates are able to exploit new technologies is a primary goal of all UK universities and a variety of assumptions have underpinned policies designed to promote this goal. This paper explores some of these assumptions through the findings of a longitudinal study involving a cohort of over 800 university students. The study adopted a student perspective to examine the factors affecting their use of computers over a three year period. Unsurprisingly, the results indicated that situational factors (e.g. access, training and time) influence the extent to which students use computers, but a disparity was found in the importance attributed to these factors by the academic staff, who focused on the needs of their department, and by the students, who focused on their individual needs. Results suggest that increased attention to a student perspective may lead to improved strategic planning in students' use of computers.     

A two-year dietary carcinogenicity study of the antiestrogen toremifene in Sprague-Dawley rats

The carcinogenic potential of the nonsteroidal triphenylethylene antiestrogen toremifene (Fareston) was evaluated in a standard 104-week rat dietary carcinogenicity study. The doses were 0, 0.12, 1.2, 5.0 and 12 mg/kg/day and the number of animals 50/sex/dose group. The body weight gain and food consumption were monitored once weekly (study weeks 1-16) or once every four weeks thereafter (study weeks 17-104). Blood samples were taken at weeks 34, 52 and 104 and the plasma concentrations of toremifene, as well as the two main metabolites (deaminohydroxy)toremifene and N-demethyltoremifene, were measured. All doses of toremifene reduced food intake and body weight gain. Toremifene caused a significant reduction in mortality, which was mainly due to reduced incidences of pituitary tumors. This was evident in all dose groups. Drug-related decrease of mammary tumors in females (at all doses) and testicular tumors in male rats (doses > or = 1.2 mg/kg/day) were also evident. The incidence of the preneoplastic foci of basophilic hepatocytes were significantly decreased in treated female groups. Toremifene induced no preneoplastic or neoplastic lesions. Based on histopathology, no obvious toxicity could be observed. Drug-related changes were observed in the genital organs, thyroid, spleen, mammary gland, adrenal, kidney, stomach and lung. These changes were due to hormonal disturbances or as a result of reduced food consumption or reduced incidences of pituitary, mammary or testicular tumors. This study indicates that toremifene is an efficient antiestrogen in long-term treatment, is well tolerated and has no tumorigenic potential in rats.