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Recombinant human receptors and functional assays in the discovery of altinicline (SIB-1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist.

Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act selectively at specific nAChR subtypes might effectively treat Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia, ADHD, depression, anxiety or pain without the accompanying adverse side effects associated with non-selective agents such as nicotine (1) and epibatidine. Altinicline (SIB-1508Y) is a novel, small molecule designed to selectively activate neuronal nAChRs and is undergoing clinical evaluation for the treatment of PD. It was selected from a series of compounds primarily on the basis of results from functional assays, including (a) measurement of Ca2+ flux in stable cell lines expressing specific recombinant human neuronal nAChR subtypes; (b) determination of in vitro and in vivo neurotransmitter release; (c) in vivo models of PD. Biological data on both altinicline and the series of compounds from which it was selected are reported.

Calcium↗

[Estimations of the prevalence of attention deficit hyperactivity disorder in Marabino children].

AIMS: This study reports the findings of research aimed at determining the rate of prevalence of attention deficit hyperactivity disorder (ADHD) in children of school age. SUBJECTS AND METHOD: The epidemiological study was conducted using a community sample extracted by means of multi stage stratified sampling according to socio economic level and schooling and consisted in 1,141 children of both sexes of school age from the city of Maracaibo. The revised Conners scales were used to collect data. RESULTS: The estimated prevalence of ADHD was 7.19% and we also obtained 0.35% for the hyperactive type, 1.14% for the disattentional subtype, and 5.70% for the combined type. Contrary to what was expected, prevalence was higher for females. It was found that 7.45% of the general sample scored higher on the academic problems scales, whereas for the sample identified as having ADHD, academic problems were 50% and the comorbidity between ADHD and academic problems was confirmed. CONCLUSIONS: The estimates for prevalence found in this study are consistent with those reported in the literature, which suggests that ADHD is a valid diagnosis for Marabino children.

Attention Deficit Disorder with Hyperactivity↗

Neuropsychological functioning in relatives of girls with and without ADHD.

BACKGROUND: A limited number of studies have examined neuropsychological functioning in the family members of ADHD youth, and none have focused exclusively on relatives of females. METHOD: Structured diagnostic interviews and neuropsychological batteries were administered to parents and siblings enrolled in a family study of girls with and without ADHD. Relatives were stratified into three groups: relatives of DSM-IV ADHD probands with ADHD (n = 106), relatives of ADHD probands without ADHD (n = 189) and relatives of controls without ADHD (n = 243). Analyses were also conducted on a subgroup of families in which more than one member had RESULTS: The neuropsychological battery as a whole distinguished affected and unaffected ADHD relatives from controls. The Wechsler Oral Arithmetic subtest, the Stroop Word, Color and Color-Word subscales were impaired in affected ADHD relatives, as were the WRAT-R Arithmetic and Reading subtests. Only the Stroop Color-Word and Interference subtests and the WRAT-R Arithmetic subtest showed significant impairments in unaffected relatives. In multiplex families, additional impairments were found in unaffected relatives on the Stroop Color subtest and the Wechsler Oral Arithmetic subtest. Analyses based on DSM-III-R diagnoses produced nearly identical results. Minor differences emerged across relatives of probands with different DSM-IV subtypes. CONCLUSIONS: Data were consistent with our previous study of relatives of boys with ADHD. Neuropsychological impairments in relatives of female ADHD probands were primarily associated with the diagnosis of ADHD, but subtle cognitive impairments that index familial vulnerability to the disorder may exist.

Adolescent↗

Hodgkin's disease presenting below the diaphragm. The experience of the Gruppo Italiano Studio Linfomi (GISL).

BACKGROUND AND OBJECTIVE: Infradiaphragmatic Hodgkin's disease is rare, making up 5-12% of cases in clinical stages I and II; consequently, several questions concerning prognosis and treatment strategy remain to be answered. The aim of this study was to analyze the clinical and prognostic characteristics and outcome of this condition. METHODS: A series of 282 patients with CS I-II Hodgkin's disease (HD) was investigated. In 31 patients the disease was confined below the diaphragm (BDHD), and in the remaining above the diaphragm (ADHD). The presenting features and outcomes were compared in the two groups. RESULTS: The BDHD group was older (p < 0.0002), had a higher frequency of males (p < 0.08) and a different histological subtype group distribution (p < 0.0001). Stage II BDHD patients had a worse overall survival rate (OS) than stage II ADHD patients (68.8% vs 86.6% at 8 years, p < 0.01) if age is not considered; patients with more than 40 years of age, in fact, had the same survival rates as those with ADHD. BDHD patients with intra-abdominal disease alone had worse prognostic factors and OS (p = 0.12) than patients with inguinal-femoral nodes. INTERPRETATION AND CONCLUSIONS: Although BDHD patients present distinct features, they have the same OS and relapse-free survival rate as age-adjusted ADHD patients. According to our experience patients with stage I peripheral BDHD respond well to radiotherapy-based regimens. Those with stage II and or intra-abdominal disease are more challenging; chemotherapy or a combined therapy seem to be more suitable approaches for these patients.

Abdominal Neoplasms↗

Externalizing disorders in consecutively referred children and adolescents with bipolar disorder.

We describe a consecutive clinical sample of children and adolescents with bipolar disorder (BD), in order to define the pattern of comorbid externalizing disorders and to explore the possible influence of such a comorbidity on their cross-sectional and longitudinal clinical characteristics. The sample consisted of 59 bipolar patients: 35 males and 24 females, with a mean age 14.6 +/- 3 years (range, 7 to 18 years), diagnosed as either type I or II according to DSM-IV. All patients were screened for psychiatric disorders using historical information and a clinical interview, the Diagnostic Interview for Children and Adolescents-Revised (DICA-R). Severity and subsequent outcome of the symptomatology were recorded with the Clinical Global Impression (CGI), Severity and Improvement Scales, at the baseline and thereafter monthly for a period up to 48 months. BD disorder type I was present in 37 (62.7%) of the patients; 14 (23.7%) were affected by attention deficit-hyperactivity disorder (ADHD) and 10 (16.9%) by conduct disorder (CD). Comorbid ADHD was associated with an earlier onset of BD, while CD was highly associated with BD type I. Anxiety disorders appeared more represented in patients without CD. At the end of the observation, a lower clinical improvement was recorded in patients with CD. In our children and adolescents with BD, comorbidity with externalizing disorders such as ADHD and CD is common. The clinical implications of comorbid ADHD and CD are rather different. ADHD can be viewed as a precursor of a child-onset subtype of BD, while CD might represent a prodromal or a concomitant behavioral complication that identifies a more malignant and refractory form of BD.

Adolescent↗

Autism and attention deficit hyperactivity disorder: assessing attention and response control with the integrated visual and auditory continuous performance test.

Symptoms of attention deficit hyperactivity disorder (ADHD) have been widely reported in children with autism spectrum disorder (ASD). The current study investigated attention and response control in children with ASD, ADHD, and typical development using the Integrated Visual and Auditory Continuous Performance Test. Results indicate that many children with ASD show significant deficits in visual and auditory attention and greater deficits in impulsivity than children with ADHD or typical development. These findings suggest that many of the children with ASD demonstrate significant ADHD-like deficits. These findings are discussed in the context of symptoms, subtypes, and comorbidity.

Analysis of Variance↗

[Estimation of the prevalence of attention deficit hyperactivity disorder among the standard population on the island of Majorca].

AIM: To determine the rate of prevalence of attention-deficit/ hyperactivity disorder (ADHD) in children of school age (6-11 years) in the Island of Mallorca. SUBJECTS AND METHODS: The epidemiological study was conducted using a community sample extracted by means of multi-stage stratified sampling according to areas (rural, city and touristy) and schooling (public, private and concerted) and consisted in 1,509 children of both sexes. The ADHD Rating Scales-IV (ADHD RS-IV) for home and school setting were used to collect data. The optimal approach to do a diagnostic evaluation, according with the literature, was using a cut-off point of 90 centil. RESULTS: The estimated prevalence of ADHD was 4.57% (CI at 99%: 3.0-5.8%) and we also obtained 1.26% for the hyperactive subtype, 1.06% for the disattentional subtype, and 2.25% for the combined subtype. Contrary to what was expected, prevalence was higher for females but no statistically significant. There were no statistically significant differences between levels, schools or areas. CONCLUSIONS: The estimates for prevalence found in this study are consistent with those reported in the literature (between 3-5%). Using the ADHD rating scale which has different cut-off point regarding age, sex and setting and the fact that it was a poblational based study could explain the higher prevalence in the females. We propose a normalization of the scales in our area in other to confirm our findings.

Attention Deficit Disorder with Hyperactivity↗

Cross sectional review of children with ADHD presenting to an outpatient psychiatric institute in Pakistan.

OBJECTIVE: To establish baseline demographic information for Attention Deficit Hyperactivity Disorder (ADHD) in the children of Pakistan and to compare the results with similar studies elsewhere. MATERIALS AND METHODS: This study was a cross sectional review. We reviewed medical records of all children less than 14 years of age, presenting to The Institute of Behavioural Sciences (IBS), Karachi during a two year period. Twenty-six children diagnosed with ADHD were included in the study. The data was entered and analyzed using SPSS. RESULTS: Among the twenty-six children, there were 20 boys and 6 girls (male to female ratio 3:1). Mean age at onset of symptoms was 4.48 years. Fifteen children were diagnosed with the combined subtype, seven with the hyperactive subtype and four with the inattentive subtype. The most significant comorbids included mental retardation (MR) (53.8%) and epilepsy (23.1%). The combined subtype was found to be significantly associated with MR. Risk factors for brain damage, and hence ADHD, found in the history included maternal problems like eclampsia and prolonged labor, and perinatal problems like sepsis and low birth weight. Delayed milestones were present in 61.5% of children. CONCLUSION: Our study provides a broad view of ADHD in Pakistani children. This study can provide a platform for future analytical studies about this challenging research issue.

Ambulatory Care Facilities↗

Are there cognitive subtypes in adult attention deficit/hyperactivity disorder?

There has been increasing knowledge of the treatment, diagnosis, and demographics of adults with residual attention deficit/hyperactivity disorder (ADHD). However, less is known about the neuropsychological functioning in adults with residual ADHD. In comparing the clinical neuropsychological test performance of a group of adult clinic patients with residual ADHD (N = 30) with that of normal controls (N = 10), we found the patients performed worse on the Trail Making Test, a visual continuous performance test, and the "Brown-Peterson" Auditory Consonant Trigrams Test, but not on any other neuropsychological measures. This pattern indicated a deficit in the area of executive control type functioning, a functional deficit that could be linked to dysregulation of frontal lobe brain systems. Of equal interest was that patients diagnosed with ADHD/hyperactive impulsive type (ADHD+) and patients diagnosed with ADHD/inattentive type (ADHD-) had different types of executive system deficits. ADHD+ was associated with relative deficiency on the Wisconsin Card Sorting Test. ADHD- was associated with relative deficiency on the "Brown-Peterson" Auditory Consonant Trigrams Test, a measure of working memory, as well as less olfactory identification on a smell identification test. The data are discussed in terms of recent localization theories of frontal lobe function. The preliminary data suggest that the different cognitive weaknesses of ADD subtypes may be linked to dysregulation of separate frontal brain regions and/or neurotransmitter systems.

Adult↗

Familial links between attention deficit hyperactivity disorder, conduct disorder, and bipolar disorder.

Although family, twin, and adoption studies indicate that attention deficit hyperactivity disorder (ADHD) is a familial condition with a robust genetic component, molecular genetic studies of candidate genes have produced inconsistent findings. One of the challenges to elucidating the genetic architecture of ADHD is its potential genetic heterogeneity. Therefore, efforts are needed to identify etiologically homogeneous subgroups of subjects with ADHD for use in genetic studies. The current article reviews evidence suggesting that parsing ADHD subjects based on comorbidity with conduct and bipolar disorders may yield familial subtypes that are suitable for genetic analyses.

Attention Deficit Disorder with Hyperactivity↗

Examining the relationship between obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in children and adolescents: a familial risk analysis.

BACKGROUND: To use family study methodology to examine the relationship between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. METHODS: We assessed for ADHD and OCD in the 1533 first-degree relatives of three groups of index children: those with ADHD and OCD, those with ADHD but no OCD, and matched controls with neither disorder. RESULTS: The risk for ADHD was similarly elevated in families of ADHD youth with (18.9%) and without OCD (20.1%; p = .91), and both groups had significantly higher rates of ADHD compared with controls (4.6%; p < or = .001), which was consistent with previous research showing a strong familial risk for ADHD. The risk for OCD was significantly elevated only among relatives of youth with ADHD plus comorbid OCD (13.0%) compared with controls (.5%; p < or = .001) and was consistent with previous research showing a strong familial risk for OCD. Relatives affected with ADHD had a significantly elevated risk for OCD compared with relatives unaffected by ADHD (7.4% vs. 1.3%; p < .001), suggestive of co-segregation between these disorders. There was no evidence of nonrandom mating between ADHD- and OCD-affected spouses. CONCLUSIONS: These results extend previously reported findings regarding the heritability of both ADHD and OCD and provide new evidence of a familial relationship between ADHD and pediatric OCD that best fits the hypothesis of a unique familial subtype.

Adolescent↗

Genetic influences on attention deficit hyperactivity disorder.

In this article we review behavioral and molecular genetics studies of attention deficit hyperactivity disorder (ADHD). Family, twin, and adoption studies, along with segregation analyses and molecular genetic studies, all support the hypothesis that both genetic and environmental factors contribute to the etiology of ADHD. Despite this strong evidence for the familial transmission of ADHD, the mode of transmission requires further clarification. In addition, because ADHD appears to be genetically heterogeneous, more work is needed to delineate genetically homogeneous subtypes and describe the range of expression of their underlying genotypes.

Adolescent↗

[Neuropsychological subtypes of the inattention and hyperactivity syndrome].

INTRODUCTION: One of the commonest neurological development disorders is the syndrome of inattention with hyperactivity, ADHD. The complex neurobiological network which intervenes in paying attention permits us to maintain a basal state of alertness, to focalize and maintain attention for long periods, select the stimulus-signal required and analyze its components, and also to simultaneously carry out processes of input-output and performance (tutorial, controlling). DEVELOPMENT: Damage to the various systems participating in 'paying attention' leads to a syndrome of inattention, with or without hyperactivity. The distinction into clinical sub-types (combined, mainly lacking attention or mainly hyperactive and impulsive) gives a primary differentiation of the syndrome. However, from the neuropsychological point of view, some degree of heterogeneity within the groups which defines academic behaviour and conduct may also be recognized. This type of study permits a more specific neuro-cognitive and pharmacological approach. Some clinical characteristics of the syndrome of inattention improve with different drugs, such as the state of alterness (methylphenidate), impulsivity (pipamperone) and selective attention (tiapride). However, this treatment is symptomatic and in most cases is useful to accompany the ultimate biological development of the neocortical control mechanisms. CONCLUSIONS: A neuro-cognitive approach which permits acquisition of habits of control, functional strategies, sequential planning of activities and per- and post-functional surveillance is fundamental. The EFE programme for training executive functions is directed towards working with the damaged processing mechanisms in each neuropsychological subtype.

Attention Deficit Disorder with Hyperactivity↗

Nicotinic receptor subtypes and cognitive function.

Nicotinic receptor systems are involved in a wide variety of behavioral functions including cognitive function. Nicotinic medications may provide beneficial treatment for cognitive dysfunction such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Nicotine has been shown to improve attentional performance in all of these disorders. Better efficacy with fewer side effects might be achieved with novel nicotinic ligands selective for particular nicotinic subtypes. To develop these novel selective nicotinic ligands it is important to use animal models to determine the critical neurobehavioral bases for nicotinic involvement in cognitive function. Nicotine-induced cognitive improvement in rats is most consistently seen in working memory tasks. We have found that both acute and chronic nicotine administration significantly improves working memory performance of rats in the radial-arm maze. The pharmacologic and anatomic mechanisms for this effect have been examined in our laboratory in a series of local drug infusion studies. Both alpha 4 beta 2 and alpha 7 nicotinic receptors in the ventral hippocampus and basolateral amygdala are involved in working memory function. Working memory impairments were caused by local infusion of either alpha 4 beta 2 or alpha 7 antagonists. Ventral hippocampal alpha 4 beta 2 blockade-induced working memory deficits are reversed by chronic systemic nicotine treatment, while ventral hippocampal alpha 7 blockade-induced working memory deficits were not found to be reversed by the same nicotine regimen. Interestingly, alpha 4 beta 2 and alpha 7 induced deficits were not found to be additive in either the ventral hippocampus or the basolateral amygdala. In fact, in the amygdala, alpha 7 antagonist cotreatment actually reversed the working memory impairment caused by alpha 4 beta 2 antagonist administration. These studies of the neural nicotinic mechanisms underlying cognitive function are key for opening avenues for development of safe and effective nicotinic treatments for cognitive dysfunction.

Amygdala↗

Inattentive behavior in childhood: epidemiology and implications for development.

Poor concentration is a relatively common childhood problem. The current North American psychiatric diagnostic classification system (Diagnostic and Statistical Manual of Mental Disorders, fourth edition; DSM-IV), American Psychological Association, 1994) differentiates children whose problems are distinguished primarily by symptoms of inattention (ADHD-I) from those whose difficulties are characterized by overactive, impulsive behavior by providing various subtypes within a broad diagnostic category. Yet, comparatively little is known about children who exhibit purely inattentive behavior. This study aims to redress this issue by using a large, community-based, epidemiological sample of 7-year-old children to compare the developmental functioning, social, and environmental backgrounds of children with pure inattentive behavior to that of children with pure overactive behavior and combined problems of inattentive and overactive behavior. Five hypotheses, centered on the validity of distinguishing inattentive behavior from overactivity, are tested. Children with pure inattentive behavior were more likely to have general cognitive delays, particularly in the area of language development, and were more likely to come from a family in which the father was of low occupational status. The results are discussed in relation to the implications for research and the identification of needs and intervention with children who exhibit pure inattentive behavior.

Attention↗

[Executive dysfunction in attention deficit hyperactivity disorder in childhood].

INTRODUCTION: The principal problem of ADHD is the difficulty to execute inhibitory control. The inhibition is an executive function that is develop during childhood. AIM: To know if other executive functions shower a lower performance in ADHD versus control group and these were different between ADHD-I and ADHD-C. PATIENTS AND METHODS: Fifty three children, between 7 to 10 years old, participated and were assess with EMIC and Simon task. RESULTS: The results showed similar profile in working memory and verbal span. In contrast, ADHD-C showed lower performance in Simon task and more impulsively. On an other hand, ADHD-I showed lower performance in memory working tasks and planning. CONCLUSIONS: These results suggest differences in the executive profile between ADHD-I and ADHD-C and these support the hypothesis of Barkley about the necessity to differ both clinical subtypes.

Attention Deficit Disorder with Hyperactivity↗

Implementing the American Academy of Pediatrics attention-deficit/hyperactivity disorder diagnostic guidelines in primary care settings.

OBJECTIVES: To evaluate the feasibility of the San Diego Attention-Deficit/Hyperactivity Disorder Project (SANDAP) protocol, a pediatric community-initiated quality improvement effort to foster implementation of the American Academy of Pediatrics (AAP) attention-deficit/hyperactivity disorder (ADHD) diagnostic guidelines, and to identify any additional barriers to providing evidence-based ADHD evaluative care. METHODS: Seven research-naïve primary care offices in the San Diego area were recruited to participate. Offices were trained in the SANDAP protocol, which included 1) physician education, 2) a standardized assessment packet for parents and teachers, 3) an ADHD coordinator to assist in collection and collation of the assessment packet components, 4) educational materials for clinicians, parents, and teachers, in the form of handouts and a website, and 5) flowcharts delineating local paths for referral to medical subspecialists, mental health practitioners, and school-based professionals. The assessment packet included the parent and teacher versions of the Vanderbilt ADHD Diagnostic Rating Scales. In this study, we chose a conservative interpretation of the AAP ADHD guidelines for diagnosing ADHD, requiring that a child met criteria for ADHD on both the parent and teacher rating scales. A mixed-method analytic strategy was used to address feasibility and barriers, including quantitative surveys with parents and teachers and qualitative debriefing sessions conducted an average of 3 times per year with pediatricians and office staff members. RESULTS: Between December 2000 and April 2003, 159 children were consecutively enrolled for evaluation of school and/or behavioral problems. Clinically, only 44% of the children met criteria for ADHD on both the parent and teacher scales, and 73.5% of those children were categorized as having the combined subtype. More than 40% of the subjects demonstrated discrepant results on the Vanderbilt scales, with only the parent or teacher endorsing sufficient symptoms to meet the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Other mental health and learning problems were common in the sample; 58.5% of subjects met screening criteria for oppositional defiant disorder/conduct disorder, 32.7% met screening criteria for anxiety/depression, and approximately one-third had an active individualized education program in place or had received an individualized education program in the past. On evaluation, the SANDAP protocol was acceptable and feasible for all stakeholders. However, additional barriers to implementing the AAP ADHD guidelines were identified, including 1) limited information in the guidelines regarding the use of specific ADHD rating scales, the evaluation and treatment of children with discrepant and/or negative results, and the indications for psychologic evaluation of learning problems, 2) families' need for education regarding ADHD and support, 3) characteristics of physical health and mental health plans that limited care for children with ADHD, and 4) limited knowledge and use of potential community resources. CONCLUSIONS: Our results indicate that children presenting for evaluation of possible ADHD in primary care offices have complex clinical characteristics. Providers need mechanisms for implementing the ADHD diagnostic guidelines that address the physician education and delivery system design aspects of care that were developed in the SANDAP protocol. Additional barriers were also identified. Careful attention to these factors will be necessary to ensure the sustained provision of quality care for children with ADHD in primary care settings.

Attention Deficit Disorder with Hyperactivity↗

The relation between sluggish cognitive tempo and DSM-IV ADHD.

To test the relation between sluggish cognitive tempo (SCT) and DSM-IV ADHD symptoms, parent and teacher ratings of the 18 DSM-IV ADHD items and five potential SCT items were obtained in a community sample of 8-18 year-old twins that was overselected for ADHD and learning disabilities (n = 296). Confirmatory factor analyses revealed that a three-factor model provided the best fit to the data for both parent and teacher ratings. DSM-IV inattention and hyperactivity-impulsivity symptoms loaded on two factors consistent with the DSM-IV model, and five SCT symptoms loaded primarily on a third factor. The SCT and inattention factors were highly correlated, whereas SCT and hyperactivity-impulsivity were weakly related. Both raters indicated that children meeting symptom criteria for the combined and inattentive subtypes exhibited significantly more SCT symptoms than those meeting symptom criteria for hyperactive-impulsive type and the comparison group without ADHD. Children meeting symptom criteria for the inattentive type exhibited significantly more SCT symptoms than those meeting criteria for the combined type, based on teacher ratings. These results suggest that SCT is an internally consistent construct that is significantly associated with DSM-IV inattention.

Attention↗