Hyperactive Research Articles

Effect of adding heterologous versus homologous bovine seminal plasma prior to cryopreservation on bull sperm quality after thawing.

SummaryThe aim of this study was to investigate the effect of adding homologous or heterologous bovine seminal plasma (SP) to SP-free sperm samples before freezing on sperm quality after thawing. Ejaculates from bulls of known fertility were used as a source of SP. The SP was removed from further aliquots of the same ejaculates by colloid centrifugation to create SP-free sperm samples; the resuspended sperm pellets were treated with homologous or heterologous SP from high or low fertility bulls at 0%, 1% or 5% before freezing. After thawing, sperm quality was evaluated by computer-assisted sperm analysis and flow cytometry for membrane integrity, reactive oxygen species, chromatin structure, mitochondrial membrane potential and protein tyrosine phosphorylation. Data were analysed using Proc MIXED, SAS®. Post-hoc comparisons were adjusted for multiplicity using Tukey's method. The addition of SP resulted in significant differences in sperm quality, namely velocity class A, Velocity Straight Line (VSL), Velocity Average Path (VAP), Velocity Curved Line (VCL), Amplitude of Lateral Head Displacement (ALH), Hyperactive (HYP), reactive oxygen species (ROS) production and % DNA fragmentation index (DFI) (P<0.05 for each). Although adding 5% homologous SP from high fertility bulls was beneficial to sperm kinematics, 5% heterologous SP from high fertility bulls had a deleterious effect on chromatin integrity and on sperm velocity. In conclusion, adding SP may have either a beneficial effect or a deleterious effect depending on the individuals involved. It might be feasible to use this method to improve sperm quality in some circumstances.

Effects of chronic mild stress on rats selectively bred for behavior related to bipolar disorder and depression

To test the possibility that chronic mild stress (CMS) might be unreliable in producing its often-intended outcome (i.e., decreased preference for sucrose, hypothesized to represent depression-relevant anhedonia) because it is typically applied to “normal” rats, a CMS procedure was applied to rats that may possess genetic susceptibility to affective disorders, having had been selectively-bred to show behavior indicative of such disorders. These rat lines were: Hyperactive (HYPER) rats, which show characteristics of bipolar disorder, Swim-test Susceptible (SUS) and Swim-test Resistant (RES) rats, being susceptible or resistant to effects of stress in the swim test, Swim High-active (SwHi) and Swim Low-active (SwLo) rats, which innately show high or low activity in the swim test. These selectively-bred lines were compared to normal, non-selectively bred (NS) rats. During CMS, HYPER rats, both females and males, as well as RES and SwHi rats, showed reduced consumption of a palatable 2% sucrose solution, and reduced preference for sucrose (vs. water) in comparison to non-stressed rats (no CMS) of the same lines. In contrast, CMS produced no decrease in sucrose consumption or in preference for sucrose in normal NS rats, and actually a caused a slight increase in sucrose consumption and preference in male NS rats. Other measures that indicate depression – food intake and motor activity in the home cage – were also assessed. SwLo and SwHi showed greater sensitivity to having their home-cage ambulatory activity reduced by CMS than did NS rats, but no other such differences relative to NS rats were seen for these other measures; thus, changes in sucrose intake or preference could not be explained by a change in caloric intake. These results suggest that the genetic attributes of animals can influence the outcome of CMS, and that the application of CMS to normal, non-selected rats may account, at least in part, for the unreliability of CMS in decreasing consumption of palatable substances and decreasing preference for such substances.

Blockade of Fatty Acid Synthase Induces Ubiquitination and Degradation of Phosphoinositide-3-Kinase Signaling Proteins in Ovarian Cancer

Aberrations within the phosphoinositide-3-kinase (PI3K) pathway occur in greater than 45% of ovarian carcinomas. The PI3K cascade transmits signals from ErbB receptors downstream to S6 and 4EBP1, which are involved in protein biosynthesis. Many ovarian carcinomas reveal hyperactivation of ErbB1 (epidermal growth factor receptor) or ErbB2 (HER2/neu). Unfortunately, the benefit of anti-ErbB drugs is yet rather limited in ovarian carcinomas. Thus, novel targeting strategies are needed for ovarian carcinomas. The lipogenic enzyme fatty acid synthase (FASN) is overexpressed in approximately 80% of ovarian carcinomas. It stimulates cell growth and signifies poor prognosis. FASN inhibition impedes (ErbB) membrane receptor signaling and sensitizes cells against anti-ErbB drugs. Here, we show that the FASN inhibitor C75 and FASN-targeting siRNAs abrogate growth, induce apoptosis, and downregulate phosphorylation/expression of the PI3K effectors AKT, mTOR, p70S6K, S6, and 4EBP1. In contrast, FASN inhibition impairs expression but only weakly affects phosphorylation of ERK1/2 mitogen-activated protein kinases in ovarian carcinoma cells. Cycloheximide-mediated blockade of protein translation reveals that C75- or FASN siRNA-induced shutdown of FASN accelerates decomposition of signaling proteins. This effect is caused by C75- or FASN siRNA-dependent stimulation of ubiquitination followed by lysosomal-autophagosomal proteolysis. In contrast, PI3K inhibitor LY294002 blocks phosphorylation but does not reduce expression/stability of PI3K effectors. Forced expression of hyperactive (HA) AKT1, unlike HA-MEK1, impairs the growth-inhibitory action of C75. We provide first evidence that the anticancer action of FASN inhibitors is at least partially mediated by drug-dependent proteolysis of PI3K effectors. FASN is a promising cancer target, whose inhibition not only abrogates lipogenesis, which is indispensable for cancer growth, but also downregulates oncogenic PI3K signaling.

Rats selectively-bred for behavior related to affective disorders: Proclivity for intake of alcohol and drugs of abuse, and measures of brain monoamines

Several lines of rats potentially useful for studying affective disorders have been developed in our laboratory though selective breeding for behavioral characteristics. The propensity of these lines to consume alcohol and other drugs of abuse (amphetamine and cocaine) was examined. Also, measurement of the concentration of brain monoamines – norepinephrine, dopamine, and serotonin – as well as estimation of their metabolism by measurement of the major extracellular metabolites of these monoamines was carried out to examine possible relationships of brain chemistry to the behavioral characteristics shown by these lines, as well as to their propensity for drug usage. The lines of rats are: Swim Low-active (SwLo) and Swim High-active (SwHi), which show either very low (SwLo) or very high (SwHi) amounts of motor activity in a swim test; Swim-test Susceptible (Susceptible or SUS) and Swim-test Resistant (Resistant or RES), which are highly susceptible (SUS) or highly resistant (RES) to having their swim-test activity depressed by being exposed to a stressful condition prior to the swim test; and Hyperactive (HYPER), which show spontaneous nocturnal hyperactivity compared to non-selectively bred (i.e., normal) rats as well as both extreme hyperactivity and behavioral depression after being exposed to a stressful condition. Regarding alcohol and drug usage, SUS rats readily consume alcohol while all other lines including non-selected, normal rats do not, and SwLo rats show a strong tendency to consume amphetamine and cocaine. Marked differences in brain monoamines were found between the various lines and normal rats, with salient differences seen in norepinephrine, particularly in the hippocampus, and in dopamine in forebrain regions (striatum and nucleus accumbens).

Examining Subtypes of Behavior Problems among 3-Year-Old Children, Part II: Investigating Differences in Parent Psychopathology, Couple Conflict, and Other Family Stressors

This study examined family stressors among 3-year-old children who were classified as hyperactive (HYP), hyperactive and oppositional defiant (HYP/OD), and non-problem based on mothers' reports of behavior. Children with HYP/OD were found to experience higher levels of family stressors than non-problem children on almost every family stressor variable. Compared to children with HYP, families of children with HYP/OD also tended to report more Axis II maternal psychopathology, Axis I paternal psychopathology, and high intensity couple conflict tactics. However, the HYP and HYP/OD group did not significantly differ on maternal Axis I psychopathology, paternal Axis II psychopathology, parental marital status, negative life events, frequency of couple conflict, or use of lower intensity couple conflict tactics. Parents of children with HYP and HYP/OD reported more negative life events, more maternal adult ADHD symptoms, and more maternal avoidance and verbal aggression during marital conflict than parents of non-problem children. Implications for treatment and etiology are discussed.

Examining Subtypes of Behavior Problems Among 3-Year-Old Children, Part I: Investigating Validity of Subtypes and Biological Risk-Factors

This study examined 3-year-old children who were classified as hyperactive (HYP), oppositional-defiant (OD), hyperactive and oppositional defiant (HYP/OD), and non-problem based on mothers' reports of behavior. Using fathers,' teachers,' and observers' ratings of children's behavior, concurrent validity was excellent for the HYP/OD group, moderate for the HYP group, and poor for the OD group. As predicted, both the HYP/OD and HYP groups reported more prenatal/perinatal birth complications and a greater family history of hyperactivity than did non-problem children. Furthermore, the HYP/OD group showed a greater family history of conduct disorder and oppositional defiant disorder (ODD) symptoms than did non-problem children; however, the HYP group also showed a greater family history of ODD than did non-problem children. Results suggest that as early as age 3, these behavior subtypes appear to be linked to biologically-based risk-factors in ways that are consistent with theories of the development of ADHD.

Examining Subtypes of Behavior Problems Among 3-Year-Old Children, Part III: Investigating Differences in Parenting Practices and Parenting Stress

This study examined parenting of mothers and fathers of 3-year-old children who were classified as hyperactive (HYP), hyperactive and oppositional defiant (HYP/OD), and non-problem based on mothers' reports of behavior. Parents of children with HYP/OD were less warm, showed more negative affect, and more laxness than parents of non-problem children; however, contrary to prediction, they did not differ significantly from parents of children in the HYP group. Compared to mothers of non-problem children, mothers of children in the HYP/OD group reported significantly more parenting stress across all domains, whereas mothers of children in the HYP group only reported elevated levels of stress associated with having a difficult child. Theoretical and treatment implications are discussed.

Cardiomyocyte function associated with hyperactivity and/or hypertension in genetic models of LV hypertrophy

We examined cardiomyocyte intracellular calcium ([Ca2+]i) dynamics and sarcomere shortening dynamics in genetic rat models of left ventricular (LV) hypertrophy associated with or without hypertension (HT) and with or without hyperactive (HA) behavior. Previous selective breeding of the spontaneously hypertensive rat (SHR) strain, which is HA and HT, with the Wistar-Kyoto (WKY) rat strain, which is not hyperactive (NA) and not hypertensive (NT), has led to two unique strains: the WKHA strain, selected for HA and NT, and the WKHT strain, selected for NA and HT. Cardiomyocytes were isolated from young adult males and females of each strain, paced at 2, 3, and 4 Hz in 1.2 mM external Ca2+ concentration at 37 degrees C, and cardiomyocyte [Ca2+]i and sarcomere dynamics were recorded simultaneously. Under these conditions, LV cardiomyocyte systolic and diastolic [Ca2+]i dynamics and diastolic sarcomere dynamics in the WKHT were significantly enhanced compared with WKY controls, suggesting an underlying LV hypertrophic response that successfully compensated for HT in the absence of HA. LV cardiomyocyte [Ca2+]i dynamics in the WKHA and SHR were strikingly similar to each other and only slightly reduced compared with WKY. LV cardiomyocyte systolic and diastolic sarcomere dynamics, on the other hand, were significantly reduced in the SHR compare with WKHA and more so in male than in female SHR. We conclude from these data that HT alone is an insufficient descriptor of the cause of LV hypertrophy and diminished LV cardiomyocyte function in the SHR rat. These data further suggest that HA (augmented by male sex) in the SHR may interact with the HT state to initiate impaired cardiomyocyte function and thereby inhibit or undermine an otherwise compensatory response that may occur with HT in the absence of HA.

Do hyperactive children have motor organization and/or execution deficits?

Hyperactive children have been described as motorically clumsy. To explore the validity of this assertion, an experiment using the additive factor method was designed to examine motor organization and execution in hyperactive children. Four groups of boys aged 7 to 8 years took part in the study: (1) a pure hyperactive (HA) group, N=20; (2) a pure conduct-disordered (CD) group, N=18; (3) a mixed hyperactive/conduct-disordered (HA+CD) group, N=12; (4) a normal (N) control group, N=22. While the small sample size precluded a definitive conclusion, the results indicated that neither HA nor CD children showed any motor organization or execution deficit in a simple sequential key-tapping task. Given previous findings indicating that hyperactive children show deficits in more complex motor coordination skills, the generalizability of our negative results needs to be examined on other more complex tasks.

Separation and comorbidity of hyperactivity and conduct disturbance in Chinese schoolboys.

In a two-stage community study of 3069 Chinese schoolboys in Hong Kong, those entering stage 2 were classified by scores on Rutter's teacher and parent questionnaires into: (1) a mixed hyperactive/conduct-disturbed (HA-CD) group; (2) a pure hyperactive (HA) group; (3) a pure conduct-disturbed (CD) group; and (4) a normal control group. The four groups of children were compared on a series of psychosocial, cognitive and neurodevelopmental measures. This was followed by a regression analysis to examine the specificity of the differential patterns of associations between HA and CD. There was a mix of negative and positive findings defying a simple, definitive conclusion. However, the positive findings that did emerge supported a growing body of recent literature which favoured a separation of HA from CD and their cross-cultural validity: the former was associated with neurodevelopmental impairments, the latter with family disharmony. The mixed condition, HA-CD, was a hybrid of its two constituent conditions, displaying the attributes of both.

Validation of Hyperactive, Aggressive, and Mixed Hyperactive/Aggressive Childhood Disorders: A Research Note

Eighty-five non-referred school children were divided into four groups based upon the IOWA Conners Teacher's Questionnaire: pure hyperactive (HYP), pure aggressive (AGG), mixed hyperactive/aggressive (HYP/AGG), and normal controls. The groups were compared on neurobehavioral tests believed to assess inattention and impulsivity. A continuous performance test indicated that the HYP group was more inattentive than the other groups and the HYP/AGG group was most impulsive. The AGG group did not differ from controls. The data support the distinction between HYP, AGG and HYP/AGG groups of children selected by the IOWA Conners.

Relative efficacy of pharmacological, behavioral, and combination treatments for enhancing academic performance

The role of stimulant drugs in facilitating academic performance in hyperactive (HA), learning disabled (LD), and hyperactive-learning disabled (HA-LD) children has been a matter of controversy for over a decade. The findings from 16 studies that compared the effects of medication and behavioral interventions on academic performance are reviewed with consideration for methodological issues and clinical implications. It was concluded that certain academically oriented behavioral interventions were clearly superior to medication and that there was only limited support for the notion stimulant drugs markedly enhance the efficacy of the former. Suggestions on how the procedures in and the findings from these studies might apply to the clinical decision-making process are presented.

Self-control behavior in hyperactive and nonhyperactive children.

This study was aimed at evaluating the self-control behaviors of hyperactive (HA) and nonhyperactive ( NHA ) first-grade pupils under conditions of repeated failure on a previously learned concept formation task. Subjects were divided into HA and NHA groups on the basis of their scores on the Conners (1969) Teacher Rating Scale. During the training stage of the experiment the children learned a concept formation task under a schedule of contingent positive reinforcement. In the test stage they performed the same task but under a negative noncontingent reinforcement schedule. The results revealed no differences in initial rate of learning the task between the groups. After the introduction of the negative noncontingent reinforcement schedule, however, the HA group showed a marked decrease in the use of effective problem-solving strategies. The HA children's performance on the concept formation task was accompanied by the emission of negative self-evaluations and solution-irrelevant statements. The NHA group used significantly more statements showing useful goal-directed cognitive mediations than the HA children. The results suggested that HA children may have deficits in self-control skills.

Childhood brain function differences in delinquent and non-delinquent hyperactive boys

Childhood electrophysiological and clinical measures were obtained in 110 hyperactive (HA) and 76 normal children, who were later followed up as adolescents. Official arrest data were obtained on all subjects and used to measure outcome. The usual interpretation, that the presence of a brain function abnormality suggests a poor prognosis, does not apply to the clinical EEG, EEG spectral and ERP measures obtained on these HA boys. In fact, the converse was found to be true, that is EEG and ERP measures abnormalities were associated with a good outcome, while normal values of these measures were associated with a poor outcome. Data were presented that suggest that there may be two distinct subgroups of HA boys. The first group was characterized by abnormalities in childhood brain function, abnormal changes in brain function with age, less antisocial and hyperactive behavior in childhood, and absence of delinquency in adolescence. The second group was characterized by normal childhood brian function, normal changes in brain function with age, more antisocial and hyperactive behavior in childhood, and teenage delinquency. Childhood EEG and ERP measures were found to be significantly different in these delinquent and non-delinquent HA groups, while social, familial and cognitive attributes were not. The N2 amplitude of the AERP in delinquent hyperactive (DHA) boys was found to be significantly larger than in the non-delinquent hyperactive (NDHA) boys. This N2 amplitude may prove clinically useful in selecting HA boys for delinquency prevention programs.

Effects of stimulant drugs on academic performance in hyperactive and learning disabled children.

The effect of stimulant drugs upon academic performance in hyperactive (HA), learning disabled (LD), and hyperactive-learning disabled (HA-LD) children has been a matter of controversy for over a decade. Research on this topic is reviewed with attention to specific academic skills, methodological issues, relative efficacy of drug, educational, and multimodal interventions, and clinical implications. It is concluded that while stimulants may increase academic productivity, (a) the effect on standardized achievement test scores is not particularly robust; (b) individual reaction is quite variable; (c) the clinical implications for adult outcome appears to be minimal; and (d) some behavioral interventions are clearly superior. However, the number of pertinent subject, task, treatment, and setting variables is so great that a definitive answer with regard to the relationship between pharmacotherapy and academic performance is anything but close at hand.

1113 SACCADIC EYE MOVEMENTS DURING VISUAL PURSUIT AND FIXATION IN HYPERACTIVE AND NORMAL BOYS

20 normal and 14 hyperactive (HA) boys were tested on a visual pursuit task. They tracked a 1° dot that moved back and forth in the horizontal plane over 30° at a constant velocity. The number and mean amplitude of saccades made during pursuit were determined for 2 trials given 30 min. apart. Irregular pursuit occurred more frequently in HA's than in normals. HA's made more saccades, their average saccades were larger, and they looked away from the pursuit path more frequently than normals. Both HA's and normals made fewer saccades when they were tested repeatedly, but the differences between the groups were maintained. The mean size of saccades did not change across repeated trials. Significant differences between normal and HA's in number and amplitude of saccades during visual pursuit were maintained over a 3 year period. The children were also tested for ability to maintain fixation for periods of one minute. HA's broke fixation before normals, with younger HA's having more difficulty holding fixation than older HA's. Faulty attention to stimuli as well as hypermobility could have contributed to the differences between normals and HA's on both fixation and visual pursuit. The data show that examination of the oculomotor system can be useful tool for study of hyperactivity. It may also provide an objective technique for differentiating HA's and normals. Supported by NIMH Grant #MH 29853

32 DOSE DEPENDENT EFFECTS OF METHYLPHENIDATE ON HYPERACTIVE CHILDREN

The clinical problem of hyperactivity is primarily regarded as an attentional deficit. The purpose of this study was to investigate the nature of this attentional deficit and the effect of various dosage schedules of methylphenidate (MP) upon it. 41 hyperactive (HA) children, ages 7-11 years, were tested prior to drug, at two week intervals for eight weeks, after eight weeks on maximum dosage, and after two weeks off drug. Initial dosage was .2 mg/kg and, in the absence of adverse effects, was increased by .2 mg/kg every two weeks up to .8 mg/kg/day. 33 of the 41 subjects were judged to successfully respond to MP . There was a significant improvement in parent and teacher's rating scores and a significant increase in accuracy in attentional performance from pre-drug to end of drug treatment; further there were significant decrements in these measures during the off-drug period. The mean dosage at which greatest response was obtained was .4-.5 mg/kg. Increasing dosage beyond this range did not improve ratings or performance for most drug responders. These findings provide objective evidence that methylphenidate often improves the ability to sustain attention, decreases impulsive responding, and improves behavior as rated by parents and teachers. Such improvement is achieved with relatively low dosage schedules. Higher doses are associated with the appearance of adverse personality changes, such as nervousness, apathy, and aggression, and defeat the purposes of improving school or social adaptation of hyperactive children.