Intestinal secretion induced by vasoactive intestinal polypeptide. A comparison with cholera toxin in the canine jejunum in vivo.

The effect of vasoactive intestinal polypeptide (VIP) on intestinal water and electrolyte transport and transmucosal potential difference was investigated in the dog jejunum in vivo and compared to secretion induced by cholera toxin. Isolated jejunal loops were perfused with a plasma-like electrolyte solution. VIP (0.08 mug/kg per min) was administered directly into the superior mesenteric artery by continuous infusion over 1 h. From a dye dilution method, it was estimated that a mean plasma VIP concentration of 12,460 pg/ml reached the loops. VIP caused secretion of water and electrolytes; for example, chloride: control, 8 mueq/cm per h absorption; VIP, 92 mueq/cm per h secretion. A marked increase in transmucosal potential difference (control, -1.0 mV; VIP, -5.9 mV, lumen negative) occurred within 1 min after starting VIP infusion. Analysis of unidirectional fluxes showed increased plasma-to-lumen flux of sodium and chloride and decreased lumen-to-plasma flux of sodium. Chloride and bicarbonate were actively secreted against an electrochemical gradient. Although sodium secretion occurred down an electrochemical gradient, flux ratio analysis suggested a component of active sodium secretion. VIP caused a slight increase in protein output into the loops; light microscopy revealed capillary dilatation and closed intercellular spaces. The effect of VIP was readily reversible. Except for the delayed onset of secretion, the effect of cholera toxin was qualitatively similar to VIP; however, capillary dilatation and increased protein output were not noted with cholera toxin.

The effects of methylphenidate on the mother-child interactions of hyperactive children.

Twenty hyperactive boys were observed while interacting with their mothers during a free play and task period on each of three occasions (no drug, drug, placebo). A triple-blind, drug-placebo crossover design was used to study the effects of methylphenidate on these interactions. A complex objective coding system was used to score the children's responses to various maternal behaviors as well as the mother's responses to a variety of children's behaviors. Results indicated that these children were more compliant with maternal commands during drug treatment. In response, mothers displayed increased attention to compliance while reducing their directiveness toward the boys. However, the hyperactive boys receiving methylphenidate initiated fewer social interactions and tended to show greater nonresponding. Thus, methylphenidate may improve the compliance of hyperactive children but tends to decrease their sociability.

Attention-deficit hyperactivity disorder and the stress response.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a developmental disorder whose three main symptoms are impulsiveness, inattention, and hyperactivity. Researchers have proposed that the central deficit in ADHD is one of poor response inhibition. The present studies were designed to look at the functioning of the hypothalamic-pituitary-adrenal (HPA) axis in response to mental stress in aggressive ADHD subjects participating in a longitudinal study of various psychosocial treatments. METHODS: Pretest and posttest morning salivary samples for cortisol determination were collected from subjects given a battery of tests. RESULTS: The study shows that ADHD subjects who maintained their diagnosis over the first year of the study had a blunted response to the stressor in comparison to those ADHD subjects who no longer retained the disorder 1 year later. CONCLUSIONS: The data suggest that an impaired response to stress may be a marker for the more developmentally persistent form of the disorder.

Effects of diuretic and propranolol on plasma lipoprotein lipids.

Ticrynafen (TCNF), a nonthiazide diuretic, has been reported to be nonhyperlipidemic. To define the effects of these drugs on plasma lipoproteins, experiments were performed in hypertensive subjects after placebo therapy, 4 wk after therapy with either hydrochlorothiazide (HCTZ) or TCNF, 3 mo after diuretic with propranolol, and 1 mo after therapy with propranolol alone. Plasma lipoproteins were separated by ultracentrifugation and the lipid fractions isolated by extraction and silicic acid thin-layer chromatography. Plasma low-density lipoprotein (LDL) total cholesterol fell and high-density lipoprotein (HDL) total cholesterol rose in subjects receiving TCNF. TCNF had no effect on plasma low-density lipoprotein (VLDL) triglyceride or phospholipid. There was no significant changes in LDL or HDL total cholesterol in subjects on HCTZ. HCTZ tended to increase plasma VLDL triglyceride and phospholipid. The addition of propranolol to either diuretic had no effect on LDL or HDL total cholesterol but increased VLDL triglyceride, especially in subjects on HCTZ. Propranolol alone had no effect on any of the lipids measured.

DSM-IV field trials for oppositional defiant disorder and conduct disorder in children and adolescents.

OBJECTIVE: The purpose of the field trials for oppositional defiant disorder and conduct disorder was to select valid diagnostic thresholds for these disorders and to compare the psychometric properties of DSM-IV criteria for oppositional defiant disorder and conduct disorder with previous DSM diagnostic formulations. METHOD: Structured diagnostic interviews, standardized clinician's validation diagnoses, and multiple measures of impairment were obtained for 440 clinic-referred children and adolescents aged 4-17 years. RESULTS: A diagnostic threshold of four symptoms of oppositional defiant disorder optimized identification of impaired children, improved agreement somewhat with the clinician's validation diagnosis, and had somewhat better test-retest agreement than DSM-III-R. In the case of conduct disorder, the optimal time window for ascertainment of symptoms was clarified. A diagnostic threshold of three symptoms of conduct disorder maximized accurate identification of impaired children and agreement with the clinician's validation diagnosis and resulted in slightly better test-retest agreement than DSM-III-R. Compared with the DSM-III-R definition, the DSM-IV definition of oppositional defiant disorder was somewhat more prevalent, but the prevalence of conduct disorder was essentially unchanged. CONCLUSIONS: DSM-IV definitions of oppositional defiant disorder and conduct disorder are somewhat better than DSM-III-R definitions in terms of internal consistency and test-retest agreement, and the validity of the DSM-IV definition of oppositional defiant disorder is slightly better than that of DSM-III-R.

DSM-IV field trials for attention deficit hyperactivity disorder in children and adolescents.

OBJECTIVE: Optimal diagnostic thresholds were determined for DSM-IV attention deficit hyperactivity disorder, and the psychometric properties were compared to alternative definitions. METHOD: Structured diagnostic interviews of multiple informants for 380 clinic-referred youths aged 4-17 years were conducted. In addition, standardized clinicians' validation diagnoses of attention deficit disorder were obtained to assess agreement with clinical judgment. Measures of impairment were obtained to assess the accuracy of identifying youth with an impairing condition. RESULTS: Three subtypes of attention deficit hyperactivity disorder (predominantly inattentive, predominantly hyperactive-impulsive, and combined types) were distinguished on the basis of the degree of deviance on separate dimensions of inattention and hyperactivity-impulsivity. These three subtypes were found to differ in terms of types of impairment, age, and sex ratio, but not ethnicity. In terms of case identification of attention deficit hyperactivity disorder, DSM-IV was found to be very similar to DSM-III-R, except that DSM-IV identified more impaired girls and preschool children. CONCLUSIONS: These results support the decision to subdivide the heterogeneous category of DSM-III-R attention deficit hyperactivity disorder into three subtypes. The resulting DSM-IV definition appears to be somewhat less biased toward the symptom pattern typical of elementary school boys.

Motor vehicle driving competencies and risks in teens and young adults with attention deficit hyperactivity disorder.

PURPOSE: To evaluate the motor vehicle driving knowledge, skills, and negative driving outcomes of older teens and young adults with attention deficit hyperactivity disorder (ADHD). LOCATION: A university medical center clinic for adult ADHD. SUBJECTS: A total of 25 young adults with ADHD and 23 young adults without ADHD 17 to 30 years old drawn from the community and equated for age, gender, and educational level. MEASURES: Structured interview, behavior ratings by self- and others, video test of driving knowledge, computer simulated driving test, and official motor vehicle records. RESULTS: ADHD young adults were cited more often for speeding, were more likely to have had their licenses suspended, were involved in more crashes, were more likely to have had crashes causing bodily injury, and were rated by themselves and others as using poorer driving habits. Official driving records corroborated these negative outcomes. Although no group differences in driving knowledge were evident, young adults with ADHD had more crashes, scrapes, and erratic steering during the computer-stimulated driving test than did the control subjects. CONCLUSIONS: Findings supported previous research suggesting that greater driving risks are associated with ADHD and suggested that ADHD does not interfere with driving knowledge so much as with actual performance (motor control) during vehicle operation.

Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation.

The frequency and severity of 17 side effects presumably associated with stimulant medication were assessed during a rigorous, triple-blind, placebo-controlled, crossover evaluation of methylphenidate, 0.3 and 0.5 mg/kg twice a day, in 83 children with attention deficit hyperactivity disorder. Side effects were rated by parents and teachers at the end of each weekly drug condition. Three children (3.6%) had side effects that were sufficiently serious to warrant immediate discontinuation of medication. Parent ratings indicated that only the side effects of decreased appetite, insomnia, stomachaches, and headaches increased significantly in frequency and severity during the two active medication doses as compared with the placebo condition. Fewer than half of the children experienced these side effects and among those who did, ratings of mean severity remained in the mild range. Teacher ratings showed little change over drug conditions, except on ratings of staring, sadness, and anxiety, which declined with increasing dose of medication. Parent ratings indicated that only the side effects of decreased appetite, insomnia, stomachaches, and headaches increased significantly in frequency and severity during the two active medication doses as compared with the placebo condition. Fewer than half of the children experienced these side effects and among those who did, ratings of mean severity remained in the mild range. Teacher ratings showed little change over drug conditions, except on ratings of staring, sadness, and anxiety, which declined with increasing dose of medication. Surprisingly, a high frequency of these behavior side effects were reported during the placebo condition. Stimulant medication within this therapeutic range, therefore, results in few, generally mild side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Attention deficit disorder with and without hyperactivity: clinical response to three dose levels of methylphenidate.

The response of 23 children with attention deficit disorder (ADD) with hyperactivity (+H) and 17 children with ADD without hyperactivity (-H) to three doses of methylphenidate (5, 10, and 15 mg twice a day) was evaluated in a triple-blind, placebo-controlled cross-over design using parent and teacher ratings of behavior, laboratory tests of ADD symptoms, and behavioral observations during academic performance. Results indicated that the children with ADD+H were rated as having more pervasive behavioral problems at home and more pervasive and severe conduct problems at school than the children with ADD-H. Laboratory tests found the children with ADD+H to be impaired in behavioral inhibition and vigilance whereas children with ADD-H were more impaired in the consistent retrieval of verbally learned material Drug effects were noted on the parent and teacher ratings and on most laboratory measures, with all three doses typically producing significant changes but rarely differing among themselves in effectiveness. The groups were not found to differ significantly on any measures in their response to methylphenidate. However, more children with ADD-H were clinically judged as having either no clinical response (24%) or responding best to the low dose (35%) of medication. In contrast, most ADD+H (95%) children were judged to be positive responders and most were recommended to receive the moderate to high dose (71%).

Driving-related risks and outcomes of attention deficit hyperactivity disorder in adolescents and young adults: a 3- to 5-year follow-up survey.

OBJECTIVE: To determine whether teenagers and young adults with attention deficit hyperactivity disorder (ADHD) have more motor vehicle citations and crashes and are more careless drivers than their normal peers. DESIGN: A comparison of two groups of teenagers and young adults (ADHD and normal) followed up 3 to 5 years after original diagnosis. SETTING: A university medical center clinic for ADHD patients. PATIENTS: Thirty-five subjects with ADHD and 36 control subjects between 16 and 22 years of age, all of whom were licensed drivers. MAIN OUTCOME MEASURES: Parent ratings of current symptoms of ADHD, oppositional defiant disorder, and conduct disorder, a survey of various negative driving outcomes, and a rating scale of driving behavior. RESULTS: Subjects with ADHD used less sound driving habits. This deficiency was associated with greater driving-related negative outcomes in all categories surveyed. Subjects with ADHD were more likely than control subjects to have had auto crashes, to have had more such crashes, to have more bodily injuries associated with such crashes, and to be at fault for more crashes than control subjects. They were also more likely to have received traffic citations and received more such citations than control subjects, particularly for speeding. The sub-group of teenagers with ADHD having greater comorbid oppositional defiant disorder and conduct disorder symptoms were at highest risk for such deficient driving skills/habits and negative driving-related outcomes. CONCLUSIONS: ADHD, and especially its association with oppositional defiant disorder/conduct disorder, is associated with substantially increased risks for driving among teenagers and young adults and worthy of attention when clinicians counsel such patients and their parents.

Isolation of Aeromonas species from clinical sources.

In a period of one year, in a general hospital, Aeromonas hydrophila was isolated from 13 patients and Aeromonas shigelloides from one patient. Eight of the patients had superficial infections, two had urinary tract infections, and four had bacteriaemia. The association of Aeromonas bacteriaemia with cirrhosis of the liver and malignant disease, which has been previously reported, was observed in three of the four bacteriaemic patients. The key to laboratory diagnosis of this genus is the routine performance of the oxidase test in bacteriological procedures for the identification of Gram-negative bacilli.

Toward a broader definition of the age-of-onset criterion for attention-deficit hyperactivity disorder.

OBJECTIVE: To critique the age-of-onset criterion (AOC) for the diagnosis of attention-deficit hyperactivity disorder (ADHD). METHOD: The specific AOC of 7 years for symptoms producing impairment as part of the diagnostic criteria is examined from historical, empirical, conceptual, and pragmatic perspectives. RESULTS: No support could be found for the continued use of this criterion for either clinical or research diagnostic purposes. While both empirical and conceptual grounds exist for viewing ADHD as a disorder that typically has its onset of symptoms during childhood, no support exists for the selection of age 7 years for onset of a valid disorder, either for symptom onset or for onset of impairment. CONCLUSIONS: Several reasons favor dispensing with a precise AOC, either for symptom onset or onset of impairment, not the least of which is that it is scientifically indefensible, poses unwarranted practical problems for the study of older adolescents and adults, and may be arbitrarily discriminatory. Until such time as an empirical justification can be marshaled for a precise AOC for ADHD, the current AOC should be either abandoned or generously broadened to include onset of symptoms during the entire childhood years, in keeping with its conceptualization as a childhood-onset disorder.

The DSM-III-R field trial of disruptive behavior disorders.

The members of the DSM-III-R Advisory Committee responsible for the diagnostic criteria for the disruptive behavior disorders (attention deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder) were able to reach agreement on potential items to be included in the final diagnostic criteria. However, there was considerable disagreement about the relative utility of different items for the three disorders and no agreement on how many items should be required from a final list of discriminating items to establish each of the diagnoses. This article describes the method and results of a national field trial of the proposed criteria. Using as a standard the diagnosis of these disorders made by expert clinicians with experience with these disorders, the diagnostic criteria that were finally included in DSM-III-R demonstrated high sensitivity, specificity, and internal consistency.

Response of children with ADHD to methylphenidate: interaction with internalizing symptoms.

OBJECTIVE: The purpose of this study was to examine differences in methylphenidate (MPH) response between groups of children with attention-deficit hyperactivity disorder (ADHD) who exhibited varying degrees of internalizing symptoms. METHOD: A sample of 40 children with ADHD was subdivided into three groups based on the severity of comorbid internalizing symptoms. Differential effects of three doses of MPH (5 mg, 10 mg, 15 mg) were evaluated in a double-blind, placebo-controlled fashion using multiple outcome measures across home, school, and clinic settings. RESULTS: Children with ADHD and comorbid internalizing symptoms were significantly less likely to respond positively to MPH than were their noninternalizing counterparts according to teacher ratings and behavioral observations during a clinic-based academic task. CONCLUSIONS: Children who exhibit comorbid symptoms of ADHD and internalizing disorder are less likely to respond to MPH in classroom settings and on academic tasks. A significant minority of children with comorbid conditions may be at a higher risk for an adverse medication response relative to patients with ADHD who are not exhibiting internalizing symptoms. Further research is necessary to delineate the characteristics of possible adverse responders.

The adolescent outcome of hyperactive children diagnosed by research criteria: I. An 8-year prospective follow-up study.

The psychiatric outcome is reported for a large sample of hyperactive children (N = 123), meeting research diagnostic criteria, and normal control children (N = 66) followed prospectively over an 8-year period into adolescence. Over 80% of the hyperactives were attention deficit hyperactivity disorder (ADHD) and 60% had either oppositional defiant disorder and/or conduct disorder at outcome. Rates of antisocial acts were considerably higher among hyperactives than normals, as were cigarette and marijuana use and negative academic outcomes. The presence of conduct disorder accounted for much though not all of these outcomes. Family status of hyperactives was much less stable over time than in the normal subjects. The use of research criteria for diagnosing children as hyperactive identifies a pattern of behavioral symptoms that is highly stable over time and associated with considerably greater risk for family disturbance and negative academic and social outcomes in adolescence than has been previously reported.

The adolescent outcome of hyperactive children: predictors of psychiatric, academic, social, and emotional adjustment.

OBJECTIVE: To investigate predictors of adolescent outcome in a large sample of hyperactive children. METHOD: 123 hyperactive children were followed prospectively over an 8-year period. Multiple linear and logistical regression equations were used to relate childhood predictor variables to adolescent academic, psychiatric, social, and emotional adjustment. RESULTS: Adolescent academic skills were related to childhood cognitive and academic competence while school conduct was predicted by other variables including early family stress. Duration of mental health treatment received often was negatively related to outcome, apparently serving as a marker variable for severity of disturbance in the child. Childhood impulsivity-hyperactivity and paternal antisocial acts were associated with later oppositional-defiant behaviors. Only child defiance and not hyperactivity predicted later arrests, however. Emotional problems in adolescence were predicted by more special education enrollment. Adolescent social competence was associated with parental personal competence, whereas maternal mental health status at outcome was related to variables unassociated with child adjustment. CONCLUSIONS: Various outcome domains had different sets of predictors; no single predictor cut across all domains. Although a limited amount of variance in outcome was explained, findings suggest that promoting family and parental competence as well as assessing and treating defiance and aggression very early may improve outcome.

Early androgen treatment decreases cognitive function and catecholamine innervation in an animal model of ADHD.

The spontaneously hypertensive rat (SHR) has been used as an animal model of attention deficit hyperactivity disorder (ADHD). The present study was designed to determine whether exposure to elevated androgen levels early in development demonstrated impairments in cognitive functioning, neuroendocrine control, and brain development parallel to those seen in ADHD children. The animals (SHR and Wistar (WKY) controls) were implanted with testosterone on postnatal day 10 and tested for behavior in a spatial cognition paradigm on postnatal day 45. Plasma samples were collected for determination of adrenocorticotrophin hormone (ACTH) and corticosterone levels as indicators of the basal tone of the pituitary-adrenal neuroendocrine axis. In addition, the density of tyrosine hydroxylase-immunoreactive fibers (an indicator of catecholamine innervation) in the frontal cortex was compared between animals. The current data show that early testosterone treatment in SHR animals resulted in additional deficits in spatial memory in the water maze, but was ineffective in altering the response of WKY animals. Furthermore, SHR rats had high basal ACTH and low corticosterone levels that may indicate a dysfunctional stress axis similar to other reports in humans with persistent ADHD. Finally, there was a further suppression of tyrosine hydroxylase-immunoreactivity in the frontal cortex of androgen-treated SHR rats. These results support the hypothesis that early androgen treatment may support the neurobiology of animals with genetic predisposition to hyperactivity, impulsivity and inattention in a manner consistent with the enhanced expression of ADHD-like behaviors.

The response of aggressive and nonaggressive ADHD children to two doses of methylphenidate.

Differences between 37 aggressive and 37 nonaggressive children with attention deficit hyperactivity disorder (ADHD) were evaluated as was their response to two doses of methylphenidate (0.3 and 0.5 mg/kg) using a multimethod battery of behavior ratings, laboratory tests, and direct observations. Aggressive ADHD children differed little from nonaggressive ADHD children except that nonaggressives displayed more problems with inattentiveness at school than aggressives while mothers of aggressives reported more symptoms of psychopathology in themselves than mothers of nonaggressives. In their drug responding, aggressives and nonaggressives were quite similar. The few exceptions were on measures of conduct, on which the aggressives were initially rated as more extreme and subsequently showed the greater degree of improvement from medication than nonaggressives. Results replicated those of a previous study and further indicate that aggressive and nonaggressive ADHD children share a common disorder of ADHD but aggressives have more impaired family situations.

Adolescents with ADHD: patterns of behavioral adjustment, academic functioning, and treatment utilization.

Adolescents with attention deficit hyperactivity disorder (ADHD) were compared with a control group on a comprehensive assessment battery. More ADHD teenagers had oppositional defiant disorder (68%) and conduct disorder (39%) and were rated as more impaired in social competence, behavioral and emotional adjustment, and school performance by parents and teachers than control teens. The ADHD youths, however, rated themselves as better adjusted than did their parents and teachers, differing only from controls in depressive symptoms and antisocial acts. Poorer performances in verbal learning and vigilance and greater ADHD behaviors during a math task also distinguished the ADHD from control teenagers.

DSM-IV field trials for the disruptive behavior disorders: symptom utility estimates.

OBJECTIVE: We tested the predictive utility of symptoms for proposed DSM-IV definitions of the disruptive behavior disorders using indices corrected for symptom and diagnosis base rates. METHOD: The field trials sample consisted of 440 clinic-referred youths who were consecutive referrals to a heterogeneous group of mental health clinics. Multiple informants were interviewed to determine the presence of symptoms and diagnoses. RESULTS: Some symptoms which were either not in DSM-III or DSM-III-R, or were modifications of DSM-III-R symptoms, had greater diagnostic efficiency than did several existing symptoms. Symptom utility estimates were generally similar for different ages and genders, although some interesting age and sex trends emerged for a few symptoms. CONCLUSIONS: The results supported the inclusion of more restricted definitions of "lying" and "truancy" to increase their association with a conduct disorder diagnosis and they supported the elimination of "swearing" in the oppositional defiant disorder criteria. In addition to their relevance for developing optimal criteria for DSM-IV, these results can aid DSM-IV users by providing a useful guide to the relative efficiency of individual symptoms based on data from a large heterogeneous clinic population.