Internalizing behavior problems and scholastic achievement in children: cognitive and behavioral pathways as mediators of outcome.

Examined a conceptual model in which dual developmental pathways (behavioral and cognitive) are hypothesized to account for the relation among internalizing behavior problems, intelligence, and later scholastic achievement using a cross-sectional sample of 325 children. Classroom behavior and select aspects of cognitive functioning (vigilance, short-term memory) were hypothesized to mediate the relations among internalizing problems, IQ, and long-term scholastic achievement. Hierarchical tests applied to a nested series of models demonstrated that (a) individual differences in measured intelligence among children are associated with variations in classroom performance and cognitive functioning, (b) classroom performance and cognitive functioning make unique contributions to prediction of later achievement over and above the influence of intelligence, (c) anxious/depressive features are correlated but separable constructs, and (d) anxiety/depression and withdrawal contribute to prediction of classroom performance and cognitive functioning over and above the effects of intelligence. Classroom performance and cognitive functioning thus appear to mediate the effects of internalizing behaviors as well as intelligence. Particular attention to the presence and potential impact of social withdrawal on children's functioning, both alone and concomitant with anxiety/depression, appears warranted during the course of clinical evaluations owing to the strong continuity among these variables.

Stimulant effects in attention deficit hyperactivity disorder: theoretical and empirical issues.

The explanatory utility of a theory or model of ADHD or any disorder depends fundamentally on its capacity to address issues of causality. What causes a particular child to develop ADHD? What mechanisms are responsible for temporal and setting-related variations in symptom severity, and how are these mechanisms affected by pharmacological intervention? And, what processes determine whether gains in one domain will propagate across one or more others? It should be evident from the foregoing discussion that comprehensive answers to such questions are most likely to emerge through implementation of research strategies that (a) integrate biological and psychological levels of explanation, (b) permit analysis of causal hypotheses, and (c) address mechanisms involved in both etiology and mediation of treatment response. Although extant neurobiological studies of ADHD are as compelling as they are exciting, they are limited by a troubling reductionistic emphasis. The predominant animal models focus on a narrow range of behaviors that are presumed to be central to ADHD because of the topographic similarity they bear to those represented by the diagnostic criteria incorporated into the diagnostic nomenclature. These models would become increasingly valuable to the extent that future research examined the extent to which ecologically relevant behaviors (e.g., social behavior) are compromised in the animal strains and whether the observed compromises are parallel to the correlates of ADHD observed in humans. Similarly, human molecular genetic studies have provided a glimpse into the possible role that genes related to dopaminergic neurotransmission may play in the etiology of ADHD. Yet, the features of ADHD have been conceptualized in these investigations as a unitary collection of characteristics, and this has precluded analysis of what specific syndromal feature (if any single one) is affected by the implicated genes. It is intriguing to speculate whether varying combinations of genes governing properties of DA receptors and reuptake molecules are associated with different patterns of symptom severity or responses to stimulant medications. As testing procedures for determining genotypes with respect to these features become more affordable and available, it should become increasingly feasible to examine such issues empirically. Research on the utility of stimulant drugs as a treatment for ADHD also has yielded useful information. Although the effects of MPH are of short duration, the breadth of their impact is impressive. The clinical effectiveness of these medications is no longer in doubt, and patterns of relations among outcome measures represent a potentially fruitful target of scientific inquiry. Finally, data supporting a neurobiological substrate for ADHD, evidence indicating that task and setting variables moderate the expression of the syndrome's diagnostic features (see Barkley, 1998, for a review), and the causal emphasis of the conceptual model with which the discussion began collectively argue for a diathesis-stress conception of the syndrome. And, as foregoing comments make clear, task and setting variables and the mechanisms through which they influence symptom expression are as important to the phenomenon as are neurobiological predisposing causes. This has significant implications for assessment strategies employed in diagnosis and evaluation of treatment-outcome. Specifically, it suggests that theory-based experimental manipulations of task and setting variables designed to impose challenge on hypothesized core features of the disorder are more likely to yield insights into the causal mechanisms governing behavioral organization in affected children than strategies emphasizing static identification of diagnostic correlates. It is hoped that such an approach will accelerate the discovery of increasingly effective assessment and intervention strategies.

Upgrading the science and technology of assessment and diagnosis: laboratory and clinic-based assessment of children with ADHD.

Reviews the usefulness of clinic-based and laboratory-based instruments and paradigms for diagnosing attention deficit hyperactivity disorder (ADHD) and monitoring treatment effects. Extant literature examining the performance of normal children and those with ADHD on an extensive range of neurocognitive tests, tasks, and experimental paradigms indicates that particular types of instruments may be more reliable than others with respect to detecting between-group differences. We review task parameters that may distinguish the more reliable from less reliable instruments. The value of clinic-based and laboratory-based instruments for monitoring treatment response in children with ADHD is questionable when evaluated in the context of ecologically relevant variables such as classroom behavior and academic functioning. We present a general conceptual model to highlight conceptual issues relevant to designing clinic-based and laboratory-based instruments for the purposes of diagnosing and monitoring treatment effects in children with ADHD. Application of the model to currently conceptualized core variables indicates that attention and impulsivity-hyperactivity may represent correlative rather than core features of the disorder. We discuss implications of these findings for designing the next generation of clinic-based and laboratory-based instruments.

Attention-deficit/hyperactivity disorder and scholastic achievement: a model of dual developmental pathways.

A conceptual model has recently been hypothesized in which parallel but correlated developmental pathways exist for attention deficit behaviors and conduct problems. An important component of this model suggests that attention deficit behaviors are related to later scholastic underachievement, whereas conduct problems are unrelated to scholastic underachievement except by their common correlation with attention deficit and intelligence. The present study replicated the general model using a cross-sectional sample of 325 children, and examined whether hypothesized dual pathways (behavioral and cognitive) better account for the relationship between attention deficit, intelligence, and later scholastic achievement. Results of the structural equation modeling analysis were consistent with the hypothesized dual pathway model and suggest that school behavior and select cognitive abilities serve as important mediators between attention deficit, intelligence, and later scholastic achievement. Implications of these results for understanding the developmental trajectory of children with attention deficit and general theoretical models of ADHD are discussed.

Predicting methylphenidate response in children with ADHD: theoretical, empirical, and conceptual models.

OBJECTIVE: To evaluate the theoretical merit and empirical validity of models designed to predict response to methylphenidate (MPH) among children with attention-deficit/hyperactivity disorder (ADHD). METHOD: Seventy-six children with ADHD received each of 4 counterbalanced doses of MPH (5, 10, 15, and 20 mg) in the context of a double-blind, placebo-controlled, within-subject (crossover) experimental design. Logical and conceptual foundations of 3 models of MPH response were subjected to critical scrutiny, and patterns of relationship anticipated on the basis of these models were subjected to empirical analysis. RESULTS: The conceptual foundations of all reviewed models were found to be substantially flawed, and none provided an adequate empirical basis for predicting response to MPH among children with ADHD. CONCLUSIONS: The observed pattern of relationships suggests that magnitudes of response to MPH in domains of classroom attention and behavioral disinhibition are correlated and differentially predictive of response on measures of academic performance and teacher-rated behavior.

Chemokine secretion of human cells in response to Toxoplasma gondii infection.

The ubiquitous protozoan parasite Toxoplasma gondii is a major cause of morbidity and mortality in neonates and immunocompromised hosts. Both acute invasion and reactivation of latent infection result in an inflammatory reaction with lymphocytes, macrophages, and neutrophils. The mechanisms responsible for triggering the local host response to toxoplasmosis are not fully understood. Infection of monolayers of human HeLa epithelial cells and fibroblasts with T. gondii resulted in a marked increase in the expression of interleukin-8 (IL-8)-specific mRNA and secretion of the proinflammatory and chemoattractant cytokines interleukin-8 (IL-8), GROalpha, and MCP-1. Host cell invasion and lysis were required for this response, as tachyzoite lysates alone had no effect on IL-8 secretion. IL-8 release was dependent on the release of soluble host cell factors: IL-1alpha in HeLa cells and an additional mediator in fibroblasts. HT-29 epithelial cells, which lack IL-1alpha or another IL-8-inducing activity, did not release IL-8 after infection, although they were efficiently infected with T. gondii and increased IL-8 secretion in response to added IL-1alpha. These data suggest that proinflammatory chemokine secretion is an important host cell response to toxoplasmosis and that the release of IL-1alpha and other mediators from lysed host cells is critical for this chemokine response.

Systemic calciphylaxis associated with massive gastrointestinal hemorrhage.

A 38-year-old woman with insulin-dependent diabetes mellitus, hypertension, and end-stage renal disease developed digital ischemia, widespread cutaneous necrosis and eschar formation of both lower extremities, and extensive ulceration of the large intestine and cecum resulting in gastrointestinal hemorrhage. A mesenteric arteriogram revealed multiple stenotic areas and filling defects of the superior mesenteric artery and its tributaries, suggestive of vasculitis. A diagnosis of calciphylaxis was suspected, on antemortem skin biopsy, and was later confirmed by postmortem examination. This case further documents the relationship between calciphylaxis and significant visceral injury, and it represents, to our knowledge, the first case of calciphylaxis associated with massive gastrointestinal hemorrhage.

Titrating methylphenidate in children with attention-deficit/hyperactivity disorder: is body mass predictive of clinical response?

OBJECTIVE: To evaluate the hypothesis that gross body mass is functionally related to methylphenidate (MPH) response in children with attention deficit disorder/hyperactivity disorder (ADDH). METHOD: Seventy-six children with ADDH received each of five counterbalanced doses of MPH (placebo, 5 mg, 10 mg, 15 mg, 20 mg) in the context of a double-blind, placebo-controlled, within-subject (crossover) experimental design. Dependent measures included direct observations of attention, academic efficiency, and teacher ratings of behavior in the classroom. RESULTS: Dose-response profiles did not differ across children varying incrementally in body mass, nor were systematic variations in dose-response curve parameters observed across discrete groups of children differing in mean body mass. Neither did these groups differ with respect to gains from placebo at each dose. Finally, body mass failed to predict optimal dose or gains achieved at optimal dose and did not distinguish between drug responders and nonresponders. CONCLUSIONS: Collectively, the findings fail to support the practice of titrating MPH on the basis of body weight in children with ADDH.

Amebic meningoencephalitis caused by Balamuthia mandrillaris: case report and review.

Balamuthia mandrillaris, formerly referred to as a leptomyxid ameba, is a free-living ameba that has recently been identified as a cause of meningoencephalitis. Previously, only two genera, Naegleria and Acanthamoeba, were recognized as causes of central nervous system (CNS) infections in humans. In contrast to Naegleria, Balamuthia causes a subacute-to-chronic infection of the CNS. Distinct from Acanthamoeba, which appears to favor the immunocompromised host, Balamuthia is capable of infecting both healthy and immunosuppressed hosts. Retrospective analyses as well as an accumulation of newly identified cases have demonstrated that this ameba is an increasingly important pathogen to recognize. We report the isolation, histopathologic features, and confirmation by indirect immunofluorescence of B. mandrillaris in a case of fatal amebic meningoencephalitis.

Methylphenidate and attentional training. Comparative effects on behavior and neurocognitive performance in twin girls with attention-deficit/hyperactivity disorder.

The effectiveness of four doses (5-mg, 10-mg, 15-mg, 20-mg) of methylphenidate (MPH) and attentional training (AT) were evaluated using neurocognitive instruments (Continuous Performance Test; Matching Unfamiliar Figures Test), narrow- and broad-band rating scales in the context of a double-blind, placebo-control, within-subject reversal design for dizygotic twin girls with Attention-Deficit/Hyperactivity Disorder (ADHD). Both interventions proved effective for improving neurocognitive test performance and behavior, although broad-band ratings revealed dose-response curves different from those obtained from the neurocognitive tests. Implications for clinical management of girls with ADHD are discussed.

Attention deficit disorder and methylphenidate: normalization rates, clinical effectiveness, and response prediction in 76 children.

OBJECTIVE: To evaluate the magnitude and clinical significance of methylphenidate (MPH) effects on the classroom behavior and academic performance of 76 children with attention deficit disorder/hyperactivity (ADDH). METHOD: A double-blind, placebo controlled, within-subject (crossover) experimental design was used to evaluate acute MPH effects at four dose levels (5 mg, 10 mg, 15 mg, and 20 mg) on children's attention, academic functioning, and behavior in regular classroom settings. Results were contrasted with a normal control sample. RESULTS: Standard statistical analysis revealed MPH effects on classroom functioning that were primarily linear. Analysis of the clinical significance of effects indicated that large proportions of treated children exhibited significantly improved or normalized classroom functioning; however, a large subset of them failed to show improved academic functioning. Overall, children failing to respond at lower dose levels have a high probability of improving or becoming normalized as a function of increasing dose. CONCLUSIONS: For a majority of children with ADDH, MPH results in significantly improved or normalized attention and classroom behavior. A significant subset, however, fail to realize gains in their academic functioning and will require supplemental interventions.

Platelet MAO concentration and molecular activity: I. New methods using an MAO B-specific monoclonal antibody in a radioimmunoassay.

New methods for determination of specific concentration and molecular activity of monoamine oxidase (MAO) in platelets are described and evaluated in parallel with specific activity measures, performed in whole platelets and platelet extracts. Platelet MAO specific concentration is determined in platelet extracts by a radioimmunoassay, using a monoclonal antibody that recognizes human MAO B, the form that occurs in platelets, but not MAO A. All four platelet MAO measures are found to be reliable and stable, and thus are suitable for long-term comparisons of normal and clinical populations, such as those reported in Part II of this report. The new measures of enzyme concentration and molecular activity make available important information about the state of MAO B molecules in a given individual that reflects the genetic expression and control of the enzyme.

Platelet MAO concentration and molecular activity: II. Comparison of normal and schizophrenic populations.

Platelet monoamine oxidase (MAO B) in 59 normal and 57 RDC-diagnosed medicated and unmedicated schizophrenic subjects was analyzed for whole platelet and extracted activities, specific concentration, and molecular activity. A novel radioimmunoassay using a monoclonal antibody elicited to human platelet MAO was used. Female schizophrenics showed no differences from female normals in MAO measures; however, these data could not be clearly evaluated because of confounding effects of age and drugs. Male schizophrenics treated with neuroleptics expressed significantly reduced whole platelet MAO activity, compared to untreated male patients. Compared with normal males, male schizophrenics showed significantly lowered molecular activities, along with elevated specific concentrations, which did not appear to be explained solely by drug usage. Additional mechanisms explaining the diminished molecular activity in male schizophrenics may be the presence of an endogenous irreversible inhibitor or a genetically determined, possibly structural, variant of MAO B.

The eye blink electro-oculogram.

An electro-oculogram (EOG) was derived from potentials recorded from electrodes placed above and below the eye during voluntary vertical eye movements. Concurrent measurement of the amplitude of eye blink potentials recorded from the same electrodes produced curves which were highly correlated with the EOG measured from stereotyped eye movements. Recordings from a patient with a missing globe, owing to trauma, revealed eye movement and blink responses only from the intact side. A patient with no light perception showed blink responses which were less variable than responses measured during attempts voluntarily to move the eyes vertically in 60 degrees excursions. An EOG calculated by measurement of eye blink potentials may be possible in clinical situations where traditional electro-oculography techniques are not feasible.