A prospective 4-year follow-up study of attention-deficit hyperactivity and related disorders.

BACKGROUND: Previous cross-sectional data showed that children and adolescents with attention-deficit hyperactivity disorder (ADHD) are at increased risk of comorbid conduct, mood, and anxiety disorders as well as impairments in cognitive, social, family, and school functioning. However, longitudinal data were needed to confirm these initial impressions. METHODS: Using DSM-III-R structured diagnostic interviews and raters blinded as to diagnosis, we reexamined psychiatric diagnoses at 1- and 4-year follow-ups in children with ADHD and controls. In addition, subjects were evaluated for cognitive, achievement, social, school and family functioning. RESULTS: Analyses of follow-up findings revealed significant differences between children with ADHD and controls in rates of behavioral, mood, and anxiety disorders, with these disorders increasing markedly from baseline to follow-up assessments. In addition, children with ADHD had significantly more impaired cognitive, family, school, and psychosocial functioning than did controls. Baseline diagnosis of conduct disorder predicted major depression and bipolar disorder at follow-up, and anxiety disorders at baseline predicted anxiety disorders at follow-up. CONCLUSION: These results confirm and extend previous retrospective results indicating that children with ADHD are at high risk of developing a wide range of impairments affecting multiple domains of psychopathology such as cognition, interpersonal, school, and family functioning. These findings provide further support for the value of considering psychiatric comorbidity in both clinical assessment and research protocols involving children with ADHD.

Mutational analysis of the androgen receptor AF-2 (activation function 2) core domain reveals functional and mechanistic differences of conserved residues compared with other nuclear receptors.

A short C-terminal sequence that forms the core of the activation function-2 (AF-2) domain is conserved in members of the nuclear receptor superfamily and is required for their normal biological function. Despite a high degree of sequence similarity, there are differences in the context and structure of AF-2 in different nuclear receptors. To gain deeper insight into these differences, we carried out an extensive mutational analysis of the AF-2 core in the androgen receptor (AR) and compared the changes in transcriptional activity with similar mutations that have previously been generated in other nuclear receptors. Mutagenesis of Met894 to Asp resulted in substantial decreases in both DNA and ligand binding activities and, consequently, a significant drop in ligand-dependent transcriptional activation. In contrast, substitution of Met894 with Ala did not affect DNA or hormone binding, and the transactivation potential was comparable to that of wild-type AR. Mutagenesis of Glu897 either with Val or Ala significantly impaired ligand-dependent activation that was not due to changes in DNA or ligand binding. There are both similarities and distinct differences between these findings compared with previous mutagenesis studies of the corresponding residues in other nuclear receptors. All mutants efficiently interfered with AP-1 activity, indicating that ligand-dependent activation of transcription and interference with AP-1 activity are separable functions in AR. For the Glu897 substitutions, the decrease in ligand-dependent transactivation could partially be reversed by overexpression of GRIP1 (GR-interacting protein 1) or CBP, putative coactivators for AR. However, there was no correlation between ligand-dependent in vitro or in vivo association with coactivators and the ability of the mutants to support ligand-dependent transactivation. This is in contrast to similar mutations in other nuclear receptors that lose interactions with putative coactivators concomitant with their loss of transcriptional activity. However, the Glu897 mutations disrupted the intramolecular interaction between the N-terminal domain and the ligand-binding domain of AR that was recently suggested to be required for normal AR function. We conclude that residues in the AF-2 core domain of AR make distinctly different contributions to its transcriptional activities compared with those of other nuclear receptors studied to date.

Evidence for the independent familial transmission of attention deficit hyperactivity disorder and learning disabilities: results from a family genetic study.

OBJECTIVE: The purpose of the study was to clarify the relationship between attention deficit hyperactivity disorder and learning disabilities. METHOD: The authors assessed learning disabilities in a sample of 140 children with attention deficit hyperactivity disorder and in 120 normal comparison children. They also assessed a sample of the probands' 822 first-degree relatives. RESULTS: The risk for learning disabilities was highest among relatives of probands with both attention deficit hyperactivity disorder and learning disabilities. The two disorders did not cosegregate in families. There was nonrandom mating between spouses with attention deficit hyperactivity disorder and learning disabilities. CONCLUSIONS: The two disorders are transmitted independently in families, and their co-occurrence may be due to nonrandom mating. Attention deficit hyperactivity disorder is likely to be etiologically independent from learning disabilities.

Family study of girls with attention deficit hyperactivity disorder.

OBJECTIVE: Because attention deficit hyperactivity disorder (ADHD) is relatively infrequent among girls, little is known about the causes of ADHD in girls. To help fill this gap in the literature, the authors assessed the familial transmission of ADHD in families ascertained through girls. METHOD: Interviewers who were blind to diagnosis administered structured psychiatric interviews to 140 girls with ADHD and their 417 first-degree relatives and to 122 girls without ADHD and their 369 first-degree relatives. RESULTS: The relatives of the ADHD girls had a significantly higher prevalence of ADHD, according to either the DSM-III-R or DSM-IV definition, than the relatives of the comparison girls. However, this did not differ from the prevalence the authors reported previously for families of boys with ADHD. Like the boys' families, the relatives of the girl probands also had significantly higher prevalences of antisocial, mood, anxiety, and substance use disorders, although the prevalence of familial antisocial disorders was lower than had been observed in the boys' families. There was no association between the DSM-IV subtypes of the probands and relatives. CONCLUSIONS: The familial transmission of ADHD and comorbid disorders generalizes to families of girls with ADHD. Neither proband gender nor subtype influences the familial transmission of ADHD.

Multimerization potential of the cytoplasmic domain of the human cytomegalovirus glycoprotein B.

In the present study the coding sequence of the cytoplasmic tail of the human cytomegalovirus glycoprotein B (gB) was expressed. The secondary structure of the purified recombinant protein was analyzed by circular dichroism, and the quaternary structure was investigated by gel permeation chromatography, and electron microscopy. Our data indicate that the cytoplasmic gB domain contains alpha-helix structures and assembles into tetramers, suggesting that the authentic gB may represent a homotetramer.

Influence of Epstein-Barr virus genomes on patient survival in Hodgkin's disease.

In previous studies, Epstein-Barr virus was considered a possible etiologic factor in Hodgkin's disease. Two hundred twenty-nine cases of Hodgkin's disease were investigated for the presence of Epstein-Barr virus DNA using the polymerase chain reaction technique on formalin-fixed, paraffin-embedded lymph node tissue to clarify the clinical importance of the incidence of this genome. In 42 cases (18.3%), genomic DNA was not amplifiable. The remaining 187 cases included the following subtypes: lymphocyte-predominant type (n = 13), nodular sclerosis type (n = 98), mixed cellularity type (n = 68), and lymphocyte-depleted type (n = 8). Sixty-six cases (35.2%) were positive for Epstein-Barr virus DNA. In the statistical analysis of available follow-up data from 130 patients, no influence of a positive Epstein-Barr virus DNA finding on length of survival time was revealed. This was true within the cohort of all patients and within the histologically defined subtypes of Hodgkin's disease. In this investigation, detection of Epstein-Barr virus DNA by polymerase chain reaction showed no prognostic relevance for patients with Hodgkin's disease.

The N-terminal domain of thyroid hormone receptor-alpha is required for its biological activities.

Thyroid hormone (T3) receptors (T3Rs) are ligand-modulated transcription factors that belong to the nuclear receptor superfamily. Whereas the well-conserved DNA-binding domain and the relatively well-conserved ligand-binding domain in T3Rs have been characterized in detail, limited information is available on the contribution of the variable N terminus to the transcriptional properties of T3Rs. To gain greater insight into the function of the N terminus, we generated a deletion mutant of T3Ralpha, T3Ralpha-deltaN1, that lacks amino acids 7-45 and assessed the effect of this deletion on all known transcriptional activities of T3Ralpha. Despite the fact that T3Ralpha-deltaN1 was expressed and bound T3 with an affinity similar to that of wildtype T3Ralpha, all of its common transcriptional activities were lost. That is, T3Ralpha-deltaN1 did not activate transcription from a positive or negative T3 response element, and it could not interfere with AP-1 transcriptional activity. Surprisingly, T3Ralpha-deltaN1 lost its ability to bind DNA, which can account for its deficiencies as a transcriptional activator. In contrast, the ability of T3Ralpha-deltaN1 to interact with putative coactivators or corepressors was not significantly altered from that of wildtype T3Ralpha. However, overall folding of T3Ralpha-deltaN1 was altered, as indicated by differential sensitivity to limited protease digestion. These data document that the N terminus of T3Ralpha, albeit relatively short and representing a variable and unconserved region when compared with other nuclear receptors, has a critical role in proper folding of the DNA-binding domain and is required for the biological activities of full-length T3Ralpha.

CBCL clinical scales discriminate prepubertal children with structured interview-derived diagnosis of mania from those with ADHD.

OBJECTIVE: To evaluate the discriminative ability of the Child Behavior Checklist (CBCL) to identify children with structured interview-derived diagnosis of bipolar disorder. METHOD: We evaluated the convergence of CBCL scales with the diagnosis of mania in 31 children with mania, 120 children with attention-deficit hyperactivity disorder, and 77 prepubertal normal control children aged 12 years or younger. We evaluated the strength of association between each CBCL scale and structured interview-derived diagnoses with total predictive value and the odds ratio. RESULTS: Excellent convergence was found between the CBCL scales of Delinquent Behavior, Aggressive Behavior, Somatic Complaints, Anxious/Depressed, and Thought Problems and the diagnosis of mania. CONCLUSIONS: These findings indicate that the CBCL could serve as a rapid and useful screening instrument to identify manic children in clinical settings.

Total unilateral lung gangrene in Hodgkin's disease: treatment by thoracostomy.

Total gangrene of the left lung developed in a 30-year-old male patient with a pulmonary recurrence of Hodgkin's disease after mediastinal irradiation and chemotherapy. Clinically, tension pyopneumothorax and severe septic shock were present. Surgical repair was done by thoracostomy, resecting three ribs. A 2 x 0.5-cm hole in the necrotic wall of the left main bronchus was covered with an intercostal muscle bundle. The necrotic pleural surfaces were treated openly by daily change of dressings. The patient recovered satisfactorily and underwent four further courses of chemotherapy without any complications.

Clinical correlates of ADHD in females: findings from a large group of girls ascertained from pediatric and psychiatric referral sources.

OBJECTIVE: The scientific literature about attention-deficit hyperactivity disorder (ADHD) is based almost exclusively on male subjects, and girls with ADHD may be underidentified and undertreated. The aim of this study was to examine clinical correlates of ADHD in females using comprehensive assessments in multiple domains of functioning. METHOD: Subjects were 140 girls with ADHD and 122 comparison girls without ADHD ascertained from pediatric and psychiatric referral sources of the same age and social class. Subjects were assessed with structured diagnostic interviews, psychometric tests assessing intellectual functioning and academic achievement, as well as standardized assessments of interpersonal, school, and family functioning by raters who were blind to clinical diagnosis. RESULTS: Compared with female controls, girls with ADHD were more likely to have conduct, mood, and anxiety disorders; lower IQ and achievement scores; and more impairment on measures of social, school, and family functioning. CONCLUSIONS: These results extend to girls previous findings in boys indicating that ADHD is characterized by prototypical core symptoms of the disorder, high levels of comorbid psychopathology, and dysfunction in multiple domains. These results not only support findings documenting phenotypic similarities between the genders but also stress the severity of the disorder in females.

Anosmia induced with alpha interferon in a patient with chronic hepatitis C.

This is a report of the alpha interferon-induced acute anosmia in a 37-year old patient with chronic hepatitis C. This exceptionally rare side-effect started in our patient as a smelling problem 2 weeks after the initiation of the therapy, and anosmia is still present 13 months after the discontinuation of the alpha interferon. We presume that neurotoxic mechanism could be responsible for this side-effect.

Flutamide-induced acute hepatitis in advanced prostate cancer patients.

OBJECTIVE: To describe the characteristics of 3 patients hospitalized in the Department of Gastroenterology, University Hospital Center, Rijeka, as the result of acute hepatitis, a rare adverse drug reaction to flutamide. PATIENTS AND RESULTS: All 3 patients with advanced prostate carcinoma were treated with oral flutamide at a dose rate of 250 mg 3 times daily. The patients developed clinical signs (jaundice, anorexia, nausea, dark urine etc.) and laboratory liver function test changes (high aminotransferase and bilirubin level), indicative of acute hepatitis, 20-22 weeks after commencing flutamide treatment. The flutamide therapy was immediately discontinued and this resulted in spontaneous remission (clinical and liver function test results returned to normal) during the next 8 weeks. CONCLUSION: Our data clearly suggest that flutamide causes acute hepatitis and that the monitoring of the patients' liver function tests in order to detect these changes as early as possible, is important.

Acute hepatitis induced by alpha-interferon in a patient with chronic hepatitis C.

Hepatic adverse effects occur very rarely with alpha-interferon therapy. A case of acute hepatitis induced by alpha-interferon in a 33-year-old man with chronic hepatitis C is described. The patient developed acute hepatitis with very high aminotransferase activity and jaundice. After discontinuing alpha-interferon therapy, hepatitis resolved rapidly. The immune-mediated mechanism is the most probable cause of this hepatitis.

Congenital choledochal cysts in adults--comparative study.

Congenital choledochal cysts are rare anomalies of the biliary tree and their presentation in adults is infrequent. They are more common in Asia. Females are more commonly affected. Surgery remains the treatment of choice. Nine patients were operated for congenital choledochal cysts in the last fifteen years, i.e. from 1988 to 2002. The diagnosis was established by case history, clinical features and laboratory tests. The imaging methods proved to be the most informative among them. Classification of the choledochal cysts was based on modified Todani classification. All patients have undergone cyst excision with Roux-en-Y hepaticojejunostomy. The complications, like recurrent cholangitis or pancreatitis, were avoided.