Identification, activity, and structural studies of peptides incorporating the phorbol ester-binding domain of protein kinase C.

The family of homologous enzymes known as protein kinase C (PKC) has been the object of intense interest because of its crucial role in cellular signal transduction. Although considerable information about the activation of PKC has been gained through structure-activity, molecular modeling, and synthetic studies of both natural and designed activators, information about the structure of PKC itself has been limited by its large size and requirement for phospholipid cofactors. Additionally, difficulties in the purification of truncated mutants of PKC have thus far prevented their analysis by nuclear magnetic resonance (NMR) or x-ray crystallographic methods.

An open trial of venlafaxine in adult patients with attention deficit hyperactivity disorder.

Stimulant medications are the most widely accepted treatment of attention deficit hyperactivity disorder (ADHD) in spite of controversy over their use. Stimulants have consistently been shown to potentiate noradrenergic brain transmission, a property also characteristic of the recently marketed antidepressant venlafaxine. Eighteen adults who met the Utah Criteria for ADHD in adults were enrolled in an open trial of venlafaxine.

Search for a schizophrenia susceptibility gene on chromosome 18.

Nine multiplex schizophrenia families were genotyped with 15 microsatellite markers mapping to the short and long arm of chromosome 18. Assuming either autosomal dominant or recessive inheritance evidence of linkage was not found. In addition, the non-parametric sib pair test did not reveal significant evidence of linkage.

Schizophrenia and GABAA receptor subunit genes.

Alterations in gamma-aminobutyric acid (GABA) neurotransmission have been indirectly implicated in the pathogenesis of schizophrenia. Using nine multiplex pedigrees, we tested for linkage between schizophrenia and simple sequence repeat polymorphisms for the GABAA receptor alpha 1, alpha 2, alpha 4, alpha 5, alpha 6, beta 1 and beta 3 subunit genes. Evidence of linkage was not found when assuming either autosomal dominant or autosomal recessive inheritance.

Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Replication of the Copenhagen Study in the rest of Denmark.

Background: Our previous investigation of the prevalence of mental illness among the biological and adoptive relatives of schizophrenic adoptees in Copenhagen, Denmark, showed a significant concentration of chronic schizophrenia (5.6%) and what Bleuler called "latent schizophrenia" (14.8%) in the biological relatives of chronic schizophrenic adoptees, indicating the operation of heritable factors in the liability for schizophrenic illness.

Search for mutations in the beta 1 GABAA receptor subunit gene in patients with schizophrenia.

As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetics of schizophrenia, GABAA receptor subunit genes are plausible candidate genes for the illness. We undertook a search for sequence variations in the coding region of beta 1 subunit gene by designing intron-based primers to amplify its 9 exons. Using single strand conformation polymorphism (SSCP) analysis, we found an exon 9 variant present in 3 of 86 unrelated schizophrenic cases derived from families having at least 2 first-degree relatives with schizophrenia.

Analysis of chromosome 22 markers in nine schizophrenia pedigrees.

Previous results of a genome-wide survey for schizophrenia susceptibility genes in nine multiplex families indicated a possible region of linkage on chromosome 22. We therefore tested for linkage using ten highly polymorphic chromosome 22 DNA markers. Lod score analyses were suggestive of linkage for several markers on the distal end of the chromosome; however, no lod score exceeded 3 assuming either autosomal dominant or autosomal recessive transmission.

Genomic scan for genes predisposing to schizophrenia.

We initiated a genome-wide search for genes predisposing to schizophrenia by ascertaining 9 families, each containing three to five cases of schizophrenia. The 9 pedigrees were initially genotyped with 329 polymorphic DNA loci distributed throughout the genome. Assuming either autosomal dominant or recessive inheritance, 254 DNA loci yielded lod scores less than -2.

Analysis of GABAA receptor subunit genes in multiplex pedigrees with manic depression.

The gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in the pathogenesis of manic depression. Tests of this hypothesis can now be carried out due to the recent characterization of simple sequence repeat polymorphisms for the GABAA receptor alpha 1, alpha 2, alpha 4, alpha 5, alpha 6, beta 1, beta 3 and gamma 2 subunit genes. Using both parametric and non-parametric methods, we tested for linkage between manic depression and these polymorphisms in six multi-generational pedigrees.

A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance.

Manic-depressive illness (MDI), also known as "bipolar affective disorder," is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, we ascertained eight moderately sized pedigrees containing multiple cases of the disease.

The Wender Utah Rating Scale: an aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder.

Objective: In an attempt to surmount the problem of retrospectively establishing the childhood diagnosis of attention deficit hyperactivity disorder, the authors constructed the 61-item Wender Utah Rating Scale (WURS) for adults to use to describe their own childhood behavior. In this paper they present their initial data collection and evaluation of the instrument's validity.

Method: The scale was administered to 81 adult outpatients with attention deficit hyperactivity disorder, 100 "normal" adults, and 70 psychiatric adult outpatients with unipolar depression.

Risk for affective disorder and alcohol and other drug abuse in the relatives of affectively ill adoptees.

We investigated the risk for substance abuse in the biological relatives of adoptees with affective illness, controlling for potential confounds, and additionally assessed risk by probands' and relatives' gender. Our sample consisted of 67 index adoptees with affective illness, matched control adoptees, and their biological and adoptive relatives. Both affective illness and substance abuse were more common in the biological relatives of affectively ill adoptees than in controls' relatives.

Linkage analysis of the D1 dopamine receptor gene and manic depression in six families.

Disturbances in dopaminergic activity may play an important role in the pathogenesis of manic depression. The effects of dopamine are mediated by at least five G protein coupled receptors, D1, D2, D3, D4 and D5. Recently, three separate research groups have cloned and characterized the D1 dopamine receptor, which localizes to 5q35.

Tyrosine hydroxylase gene not linked to manic-depression in seven of eight pedigrees.

We ascertained 8 multigenerational pedigrees afflicted with multiple cases of bipolar and recurrent major depressive disorder. Alterations in dopaminergic and noradrenergic neurotransmission have been implicated in the pathogenesis of this disease, and tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of these two catecholamines. As TH mutations could underlie susceptibility to manic-depression, we carried out a linkage analysis between this disease in 8 families and two RFLP probes that map to the TH gene region on the short arm of chromosome 11.

Codistribution of a sensory gating deficit and schizophrenia in multi-affected families.

Because the clinical diagnosis of schizophrenia has not generally been an adequate phenotypic marker to detect the genes that convey risk for schizophrenia, efforts have been directed toward the identification of more elementary neuronal dysfunctions in schizophrenic patients and their families. Psychophysiological studies of sensory gating and selective attention suggest that defects in these brain functions are present in schizophrenic patients and some of their relatives. This study examines one of these defects in sensory gating, failure to suppress the P50 evoked response to repeated auditory stimuli.

Spontaneous selective attention in schizophrenia.

A visual word identification task was used to measure the type of selective attention that occurs spontaneously when there are multiple stimuli, all potentially relevant, and insufficient time to process each of them fully. This task presents two words simultaneously, one above the other, for 200 ms, and periodically requires the subject to identify either the upper or the lower word. We tested schizophrenic patients, manic-depressive patients, and normal controls under a baseline divided attention condition with no predictability and then introduced a degree of predictability into the upper location that normally results in selective attention to the lower nonpredictable location.

Studies on DNA-cleaving agents: computer modeling analysis of the mechanism of activation and cleavage of dynemicin-oligonucleotide complexes.

Dynemicin A is a recently identified antitumor antibiotic. Upon activation, dynemicin is reported to cause double-stranded cleavage of DNA, putatively through the intermediacy of a diradical. Computer modeling of this activation and cleavage process is described herein as part of an effort to establish a structural hypothesis for this mechanistic sequence and for the design of simple analogues.

Bupropion treatment of attention-deficit hyperactivity disorder in adults.

The authors treated 19 adults with attention-deficit hyperactivity disorder with an open trial of bupropion. These patients had received maintenance stimulant medication or monoamine oxidase inhibitors for an average of 3.7 years.

Modeling of the bryostatins to the phorbol ester pharmacophore on protein kinase C.

The bryostatins are macrocyclic lactones that represent an additional structural class of potent activators of protein kinase C. These marine animal biosynthetic products are of unusual interest because they induce only a subset of the biological responses induced by the phorbol esters. We have now determined the binding affinities of naturally occurring and semisynthetic bryostatins for protein kinase C by competition analysis with [26-3H]bryostatin 4 as the radioactive ligand.

An open trial of L-tyrosine in the treatment of attention deficit disorder, residual type.

To elucidate the role of catecholamines in attention deficit disorder, the authors conducted an open 8-week trial of L-tyrosine in 12 adults with attention deficit disorder, residual type. Eight showed marked to moderate clinical response in 2 weeks; at 6 weeks these eight developed tolerance, suggesting that L-tyrosine is not useful in attention deficit disorder, residual type.

Analysis of the phorbol ester pharmacophore on protein kinase C as a guide to the rational design of new classes of analogs.

The diterpene diester phorbol 12-myristate 13-acetate and the alkaloid teleocidin B are structurally unrelated natural products that display similar potent irritant and tumor-promoting activities. Computer modeling of these and other structural classes of tumor promoters show a marked similarity in the relative positions of certain heteroatoms and hydrophobic groups. For phorbol this mapping consists of the C-4, C-9, and C-20 hydroxyl groups as well as a hydrophobic region filled by a long-chain acyl functionality attached to either the C-12 or the C-13 positions.