Systematic Analysis of Quantitative Logic Model Ensembles Predicts Drug Combination Effects on Cell Signaling Networks.

A major challenge in developing anticancer therapies is determining the efficacies of drugs and their combinations in physiologically relevant microenvironments. We describe here our application of "constrained fuzzy logic" (CFL) ensemble modeling of the intracellular signaling network for predicting inhibitor treatments that reduce the phospho-levels of key transcription factors downstream of growth factors and inflammatory cytokines representative of hepatocellular carcinoma (HCC) microenvironments. We observed that the CFL models successfully predicted the effects of several kinase inhibitor combinations. Furthermore, the ensemble predictions revealed ambiguous predictions that could be traced to a specific structural feature of these models, which we resolved with dedicated experiments, finding that IL-1α activates downstream signals through TAK1 and not MEKK1 in HepG2 cells. We conclude that CFL-Q2LM (Querying Quantitative Logic Models) is a promising approach for predicting effective anticancer drug combinations in cancer-relevant microenvironments.

Spontaneous facial expressivity in children with acquired brain injury.

OBJECTIVES: To investigate spontaneous facial behavior during social interaction in children with acquired brain injury (ABI), and to explore possible links between ABI, facial expressivity, and caregiver-reported social competence. DESIGN: Between-group comparisons using t tests, within-group comparisons using correlational analyses, correlational analyses of independent variables and outcome measures. PARTICIPANTS: Sixteen school-aged children with ABI and 32 normally developing children of comparable age and gender. MAIN OUTCOME MEASURE: Aspects of facial expressivity derived from coding scheme designed for this study. RESULTS: Children with ABI were less expressive overall and tended to shift expressions less often than normally developing children. Several measures of expressivity were correlated with measures of social competence. CONCLUSIONS: Brain injury inhibits production of some aspects of spontaneous facial expression. Results are suggestive of links between facial behavior and social skills.

Characterization of the HIV-1 specific humoral immune response during highly active antiretroviral therapy (HAART).

Plasma samples from 19 patients were analyzed for HIV-1 directed humoral immune responses prior to and 1 year after initiation of HAART. Eight of the subjects were classified as virologic successes, defined by a >100-fold decrease in viral load (VL) over the 1-year study period and a final VL <500 copies/ml. The eleven HAART failures were defined as subjects with <10-fold decrease in VL. At study entry (before HAART), VL and CD4 counts were similar between the two groups. Humoral immune responses before therapy and after 1 year of therapy were measured by V3 peptide antibody binding titers and neutralization of HIV-1 MN and four subtype B clinical isolates. Before HAART, neutralizing antibody titers to the clinical isolates and HIV(MN), as well as HIV V3 envelope binding titers to several V3 peptides, were significantly higher among treatment successes compared with treatment failures. After 1 year on HAART, neutralization declined in titer and narrowed in specificity among the HAART successes. In contrast, a significant increase in both neutralizing titer and breadth was seen among HAART failures.

Naming and verbal memory skills in adults with Attention Deficit Hyperactivity Disorder and Reading Disability.

Research suggests that children with Attention Deficit Hyperactivity Disorder (ADHD) and Reading Disability (RD) can be differentiated based on their performance on measures of naming and verbal memory. It is not known whether this same pattern characterizes adults with these disorders. In this study, adults with and without ADHD and RD were compared on naming and verbal memory abilities. Results did not support the hypothesis that adults with ADHD and RD are significantly different from each other, or from a contrast group, on naming and verbal memory measures after controlling for Full-Scale IQ (FSIQ). These results were replicated across two sets of classification criteria used to identify diagnostic groups. Factors that could account for the inconsistency in research findings with children and adult subjects are discussed.

Social problem solving in children with acquired brain injuries.

OBJECTIVES: To assess the performance of children with acquired brain injuries (ABIs) on a measure of social problem solving and to examine the relationships between participant characteristics and performance on the Social Knowledge Interview (SKI) and between parent-reported child behavior and performance on the SKI. DESIGN: Between-group comparisons using correlational analyses, matched pairs t-tests, and analysis of covariance (ANCOVA). PARTICIPANTS: Thirty-one children 6-12 years old with ABI and 31 control participants, matched on age and sex. MAIN OUTCOME MEASURE: The SKI, a measure of social problem-solving skills. RESULTS: Using matched pairs t-tests and ANCOVA, groups were compared on several SKI measures, including the number of unique responses generated for each problem scenario, the quality of those responses, and the ability to select the best response from a set of alternatives. When equated for socioeconomic status (SES), ABI and control participants performed similarly on the SKI; however, a trend for children with ABI to generate more assertive responses was observed. Performance on the SKI was positively correlated with IQ and related to parent-reported adaptive behavior. In children with ABI, performance was also related to primary lesion location and treatment regimen. CONCLUSIONS: Children with ABI are as capable of judging the appropriateness of behavior and generating response options on an analog measure of social problem solving as were their typically developing peers. However, those individual children with ABI who are more likely to have social problems may be identified by the qualitative aspects of their responses on analog tasks. These findings have implications for the identification of children with social skills deficits following ABI and for the development of effective rehabilitation strategies.

Parent assessment of psychological and behavioral functioning following pediatric acquired brain injury.

OBJECTIVE: Compare the measured prevalence rate of psychopathology and behavior disorders in 29 children with acquired brain injuries using four parent-report instruments. METHOD: Two questionnaires, the Child Behavior Checklist (CBCL) and the Personality Inventory for Children (PIC-R) and two interview measures, the Diagnostic Interview for Children and Adolescents (DICA-R) and the Vineland Adaptive Behavior Scales (VABS), were completed following injury or diagnosis. RESULTS: The DICA-R identified the highest prevalence of anxiety disorders and acting-out behaviors, whereas the CBCL identified the lowest prevalence. Opposite results were found within the domain of attentional problems. Interview measures were more concordant for global psychological impairment than were questionnaires. DISCUSSION: Discordant findings across measures are discussed in terms of type of disorder, classification model, response format, item characteristics, and scaling.

Cognitive-behavioral remediation of problem solving deficits in children with acquired brain injury.

The inability to problem solve can have a deleterious impact on a student's academic performance and social adjustment. Children with an acquired brain injury (ABI) are at risk for deficits in problem solving skills. This case study and series of multiple baseline experiments examined the effects of a multi-component cognitive-behavioral training program on the remediation of problem solving deficits in five children with ABI. Results indicated that the training program resulted in a substantial decrease in errors on a computerized problem solving task used to monitor problem solving performance during baseline and treatment. In addition, significant improvements were found on two of four standardized measures of problem solving abilities. Finally, students, parents and teaching staff reported a high degree of satisfaction with and generalization of the training program.

Cholinergic treatment of an amnestic man with a basal forebrain lesion: theoretical implications.

Cholinergic deficient states, such as in Alzheimer's disease, are associated with amnesia. Therapeutic trials with cholinergic augmentation in Alzheimer's disease have had only equivocal results, but mechanisms other than cholinergic deficiency may contribute to the memory deficit. Normally the diagonal band of Broca provides much of the hippocampal cholinergic input. To learn if amnesia secondary to cholinergic deficiency can be ameliorated by cholinergic augmentation, we treated an amnestic man who had a lesion located primarily in the right diagonal band of Broca with physostigmine and lecithin. During the initial best-dose-finding phase, he demonstrated an inverted U-shaped curve for immediate recall of word lists, with peak performances at 3.0 and 3.5 mg of physostigmine. Single photon emission tomography showed decreased blood flow in the medial temporal region ipsilateral to the lesion at baseline, with a reversal of the asymmetry on 3.5 mg of physostigmine. A follow-up double-blind, placebo-controlled study on 3.5 mg of physostigmine, however, failed to demonstrate that cholinergic treatment improved memory.

Anomalous cerebral structure in dyslexia revealed with magnetic resonance imaging.

OBJECTIVE: To develop quantitative methods for identifying cerebral anomalies on magnetic resonance images of subjects with language disorders and other learning disabilities. DESIGN: Partially blinded comparison of subjects with dyslexia, unaffected relatives, and a control group balanced for age and socioeconomic status. Criterion standard: clinical diagnosis of dyslexia by physician or learning disabilities specialist on the basis of clinical assessment and family history. SETTINGS: Hospital pediatric neurology clinic and private reading clinic. VOLUNTEERS: individuals with dyslexia (seven male and two female, aged 15 to 65 years) from professional families; unaffected first- and second-degree relatives (four male and six female, aged 6 to 63 years) available in the geographical area; and controls (five male and seven female, aged 14 to 52 years). INTERVENTIONS: Gradient echo three-dimensional scan in Seimens 1-Tesla Magnetom; 128 1.25-mm consecutive sagittal images. MAIN OUTCOME MEASURES: (1) Average length of the temporal (T) and parietal (P) banks of the planum temporale; (2) interhemispheric coefficients of asymmetry for T and P banks: Left-Right interhemispheric coefficients of asymmetry = (L-R)/[(L+R)/2]; (3) intrahemispheric coefficients of asymmetry = (T-P)/[(T+P)/2]; and (4) qualitative assessment of gyral variants in the parietotemporal operculum. RESULTS: All groups had left-sided asymmetry for the temporal bank and right-sided asymmetry for the parietal bank. The group with dyslexia had exaggerated asymmetries, owing to a significant shift of right planar tissue from the temporal to parietal bank. They also had a higher incidence of cerebral anomalies bilaterally (subjects with dyslexia, six of nine; relatives, two of 10; and controls, zero of 12). CONCLUSIONS: Quantitative assessment of high-resolution magnetic resonance images can reveal functionally relevant variations and anomalies in cerebral structure. Further refinement of these measurement techniques should improve the diagnosis, classification, and treatment of language disorders and other learning disabilities.

Amnesia following a discrete basal forebrain lesion.

Destructive lesions of the basal forebrain are associated with memory impairment in both humans and experimental animals. The basal forebrain is thought to contribute to memory function by providing cholinergic innervation to critical memory structures such as the hippocampus and amygdala. In previously reported clinical cases of basal forebrain amnesia, multiple neuroanatomical regions have been damaged, preventing identification of the minimal critical lesion necessary to produce an amnestic syndrome. We describe a patient who developed persistent, global anterograde and retrograde amnesia following resection of a low-grade glioma. Post-surgical magnetic resonance imaging studies revealed a small discrete lesion, centred in the right diagonal band of Broca, that included the preoptic area, the anterior hypothalamus, the lamina terminalis and the paraterminal gyrus. The septal nuclei and the cell bodies of the nucleus basalis of Meynert appeared to have been spared, as were other structures in the medial temporal lobe and diencephalon. Our case provides critical support for the independent contribution of the basal forebrain, in particular the diagonal band nuclei, in memory function. We propose that our patient's amnesia resulted from disconnection of pathways between the diagonal band nuclei and the hippocampal region, depriving the hippocampus of cholinergic innervation.

The effects of various modes of therapy for end stage renal disease on cognitive performance in a pediatric population--a preliminary report.

Visuomotor, visuoanalytic, vigilance, and verbal memory functions of sixty-eight children and adolescents with renal disease were assessed. All patients with renal disease either had successful kidney transplants, were receiving dialysis therapy by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), or had advanced renal failure not yet requiring dialysis. The patients showed a deficit in visuomotor skills related to attentional and visuoanalytic function. The transplant recipients appeared to be the least affected. Children undergoing dialysis therapy by CAPD or who had received a successful kidney transplant showed better performance on vigilance and memory tasks than the patients who received therapy by hemodialysis. There were correlations in all groups between performance on the memory tasks and performance on the vigilance tasks suggesting that the memory dysfunction in uremia is related in part to an attentional deficit.

Cognitive functioning in children with end stage renal disease pre- and post-dialysis session.

Eighteen ESRD and 18 Control subjects equated for age and intellectual level were assessed pre- and post-dialysis on measures of learning, problem solving and immediate memory. No significant differences were found between ESRD and Control subjects on any of the measures. Both groups showed significant learning over trials on the Paired Associate Learning Task. No correlational associations of statistical or clinical significance were found between the cognitive measures and blood pressure, blood urea nitrogen or serum creatinine. There was no difference between pre- and post-dialysis session performance by the ESRD subjects. These findings were inconsistent with prior research showing immediate improvement in cognition post-dialysis.

Effects of kidney transplantation on cognitive performance in a pediatric population.

The cognitive functioning of 20 children and adolescents with end-stage renal disease was assessed 1 to 3 weeks prior to the onset of hemodialysis, and at 1 month and 1 year after successful kidney transplantation, and results were compared with those of a matched control group. A battery of intelligence, achievement, problem solving, learning, memory, and attention tasks were administered. Both groups had significantly improved scores over time on most measures. The group with renal disease exhibited significantly greater improvement than the control group from initial testing to 1 month after transplantation on the performance IQ and full-scale IQ as well as in mathematics achievement. This significant difference was not maintained, however, at 1 year after transplantation. Cognitive performance was less impaired the later the onset of renal failure or the fewer the years in end-stage renal disease. BUN nitrogen, serum creatinine levels, and BP did not consistently correlate with any of the cognitive or academic achievement measures.