Biomedical subjects

C A Ross

Publications and source records attributed to C A Ross.

At least 145 records · Page 8Linked to original sources

PubMed1996

Bacterial expression and characterization of an anti-desipramine single-chain antibody fragment.

Tricyclic antidepressant toxicity is a leading cause of death from intentional drug overdose. Monoclonal antibody Fab' fragments specific for the tricyclic antidepressant, desipramine, reverse acute drug toxicity but may themselves have adverse effects at therapeutic doses. To evaluate the characteristics of smaller antibody fragments, we cloned, expressed and characterized a 26 kD single chain Fv fragment (G5-sFv). A DNA sequence encoding VH-linker-V1 was constructed from hybridoma mRNA encoding a high affinity monoclonal desipramine specific IgG1 and expressed in E. coli. G5-sFv was produced at high levels as insoluble inclusion bodies. Single chain Fv was solubilized, folded in a redox buffer and affinity purified on desipramine-Sepharose. The affinity of G5-sFv for desipramine was similar to that of the corresponding monoclonal Fab' as measured by surface plasmon resonance (Fab' 5.5 +/- 0.5 x 10(8) M-1, sFv 2.3 +/- 0.5 x 10(8) M-1). G5-sFv administered to rats after a tracer dose of 3H-desipramine produced rapid and marked redistribution of drug from tissues into serum. G5-sFv was stable at 4 C for greater than 6 months but lost activity at higher temperatures. We conclude that desipramine-specific-single chain Fv expressed in E. coli retains the affinity of the parent antibody for desipramine. The pharmacokinetic effect of G5-sFv on desipramine distribution suggests that it may be useful as an antidote for desipramine overdose.

Amino Acid Sequence↗

PubMed1996

Schizophrenia: a disease of heteromodal association cortex?

There is considerable evidence of disturbances of multiple brain areas in schizophrenia. The clinical features and findings from pathologic and neuro-imaging studies suggest primary involvement of a system of parallel distributed networks within the neocortex--the phylogenetically recent heteromodal association cortex (HASC). There is evidence that HASC is a family of higher-order parallel distributed networks of circuits, mediating complex representationally guided behaviors. We argue that HASC regions are especially involved in schizophrenia. Lesions of HASC in the disease are likely to be neurodevelopmental in origin (as evidenced by such examples as reversed planum temporale asymmetry) which have been identified by magnetic resonance imaging as specific regions of disproportionately reduced local gray matter volumes, and by neuropathologic examination as cellular migration disruptions. We believe the hypothesis of preferential heteromodal cortical abnormalities has heuristic value, and briefly indicate how it opens new avenues for investigating this debilitating condition.

Cerebral Cortex↗

PubMed1996

The "equal environments assumption" in MZ-DZ twin comparisons: an untenable premise of psychiatric genetics?

The comparison of MZ-DZ twins in behavioral genetics has produced what seems like irrefutable evidence for the heritability of many psychiatric disorders. But such research depends on the validity of the EEA--the "equal environments assumption"--as an underlying premise. In this paper, several empirical studies which support the EEA are critically reviewed in terms of methodology and the way data has been processed in a mathematical model called "path analysis". It turns out that studies investigating the EEA appear to be largely inadequate in terms of technique, as well as biased in the inferences drawn. Further, the "heritability" estimate--often taken to mean the influence of trait-specific genes--is merely a statistical abstraction derived from a matrix of correlations; this estimate encompasses many buried environmental effects so that "heritability" does not correspond to any underlying DNA structure. In conclusion, many MZ-DZ pedigree studies have dubious scientific value, given the non-viable premise of the EEA, as well as the misleading operational definition of what has been called "heritability".

Humans↗

PubMed1996

Lifetime axis I and II comorbidity and childhood trauma history in dissociative identity disorder.

According to DSM-IV, dissociative identity disorder is characterized by the existence within the person of two or more distinctly different identities or personality states that from time to time take executive control of the person's body and behavior, with accompanying amnesia (American Psychiatric Association, 1994). By retrospective patient report, dissociative identity disorder usually occurs in conjunction with severe childhood trauma (Kluft 1985; Putnam et al. 1986; Ross 1989; Ross et al. 1989a, 1990a). The disorder appears to be the most severe form of disturbance on the dissociative disorders continuum (Boon and Draijer 1993; Coons 1992; Ross 1985; Ross et al. 1992). There is evidence that dissociative identity disorder may be more prevalent than once believed in the general population (Ross 1991) and among general adult psychiatric inpatients (Latz et al. 1995; Ross et al. 1991; Saxe et al. 1993).

Adult↗

PubMed1996

Inositol 1,4,5-trisphosphate receptors in endocrine cells: localization and association in hetero- and homotetramers.

The inositol 1,4,5-trisphosphate receptor (IP3R) is an intracellular calcium channel involved in coupling cell membrane receptors to calcium signal transduction pathways within cells including endocrine cells. Several isoforms (I, II, and III) of IP3Rs have been identified, which are encoded by separate genes, and are expressed in many tissues with differing patterns of cellular expression. We have generated specific affinity-purified polyclonal anti-peptide antibodies to each of the three isoforms. Western blot analysis of RINm5F and ATt20 cells shows high levels of endogenously expressed type I and type III IP3R, but undetectable levels of type II. Immunofluorescence studies revealed an endoplasmic reticulum-like pattern similar to BiP, an ER marker. In contrast with previous claims, both type I and type III IP3Rs were absent from the secretory granules of ATt20 cells. Western blots of sucrose gradients and gel filtration probed with antibodies to either type I or type III showed a molecular weight of greater than 1,000 kDa consistent with a tetrameric structure. Co-immunoprecipitation experiments indicated that most of the receptors were present as heterotetramers. Homotetramers were identified for the type III IP3R; however, type I homotetramers were undetectable. These data suggest that molecular association of IP3Rs into heterotetrameric forms can contribute to the complexity of the regulation of Ca2+ release from ER by IP3Rs within cells.

Amino Acid Sequence↗

PubMed1996

Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript.

The mutation underlying Huntington disease (HD) is CAG expansion in the first exon of the HD gene. In order to investigate the role of CAG expansion in the pathogenesis of HD, we have produced transgenic mice containing the full length human HD cDNA with 44 CAG repeats. By 1 year, these mice have no behavioral abnormalities and morphometric analysis at 6 (one animal) and 9 (two animals) months age revealed no changes. Despite high levels of mRNA expression, there was no evidence of the HD gene product in any of these transgenic mice. In vitro transfection studies indicated that the inclusion of 120 bp of the 5' UTR in the cDNA construct and the presence of a frameshift mutation at nucleotide 2349 prevented expression of the HD cDNA. These findings suggest that the pathogenesis of HD is not mediated through DNA-protein interaction and that presence of the RNA transcript with an expanded CAG repeat is insufficient to cause the disease. Rather, translation of the CAG is crucial for the pathogenesis of HD. In contrast to that seen in humans, the CAG repeat in these mice was remarkably stable in 97 meioses. This suggests that genomic sequences may play a critical role in influencing repeat instability.

Animals↗

PubMed1996

cDNA cloning of a human homologue of the Caenorhabditis elegans cell fate-determining gene mab-21: expression, chromosomal localization and analysis of a highly polymorphic (CAG)n trinucleotide repeat.

The two most consistent features of the diseases caused by trinucleotide repeat expansion-neuropsychiatric symptoms and the phenomenon of genetic anticipation-may be present in forms of dementia, hereditary ataxia, Parkinsonism, bipolar affective disorder, schizophrenia and autism. To identify candidate genes for these disorders, we have screened human brain cDNA libraries for the presence of gene fragments containing polymorphic trinucleotide repeats. Here we report the cDNA cloning of CAGR1, originally detected in a retinal cDNA library. The 2743 bp cDNA contains a 1077 bp open reading frame encoding 359 amino acids. This amino acid sequence is homologous (56% amino acid identify and 81% amino acid conservation) to the Caenorhabditis elegans cell fate-determining protein mab-21. CAGR1 is expressed in several human tissues, most prominently in the cerebellum, as a message of approximately 3.0 kb. The gene was mapped to 13q13, just telomeric to D13S220. A 5'-untranslated CAG trinucleotide repeat is highly polymorphic, with repeat length ranging from six to 31 triplets and a heterozygosity of 87-88% in 684 chromosomes from several human populations. One allele from an individual with an atypical movement disorder and bipolar affective disorder type II contains 46 triplets, 15 triplets longer than any other allele detected. Though insufficient data are available to link the long repeat to this clinical phenotype, an expansion mutation of the CAGR1 repeat can be considered a candidate for the etiology of disorders with anticipation or developmental abnormalities, and particularly any such disorders linked to chromosome 13.

Amino Acid Sequence↗

PubMed1996

Patterns of dissociation in clinical and nonclinical samples.

Research has consistently found elevated mean dissociation scores in particular diagnostic groups. In this study, we explored whether mean dissociation scores for different diagnostic groups resulted from uniform distributions of scores within the group or were a function of the proportion of highly dissociative patients that the diagnostic group contained. A total of 1566 subjects who were psychiatric patients, neurological patients, normal adolescents, or normal adult subjects completed the Dissociative Experience Scale (DES). An analysis of the percentage of subjects with high DES scores in each diagnostic group indicated that the diagnostic group's mean DES scores were a function of the proportion of subjects within the group who were high dissociators. The results contradict a continuum model of dissociation but are consistent with the existence of distinct dissociative types.

Adolescent↗

PubMed1996

Analysis of the DRPLA triplet repeat in brain tissue and leukocytes from schizophrenics.

An expansion of the CAG triplet in the human gene called atrophin-1 or CTG-B37 causes the neuropsychiatric disease known as dentatorubral-pallidoluysian atrophy (DRPLA). We have examined the genomic DNA from brains and peripheral blood leukocytes (PBLs) of schizophrenic and non-schizophrenic individuals and PBLs from a cohort of monozygotic twins discordant or concordant for schizophrenia, for expansions of the CTG-B37 region. All samples, including non-schizophrenic/normal controls, had 7-22 CAG repeats in this region. Thus we found no evidence for an expansion of the DRPLA triplet repeat associated with schizophrenia when compared to controls. Our data suggest that an expansion in the CTG-B37 gene is not linked to or responsible for the disease schizophrenia.

Alleles↗

PubMed1996

Childhood physical and sexual abuse in patients with anxiety disorders and in a community sample.

OBJECTIVE: The authors investigated whether histories of childhood physical or sexual abuse were reported more frequently in a clinical sample of patients with anxiety disorders than in a matched community comparison sample. METHOD: A standardized interview with an extensive series of trauma probes was administered to 125 patients with DSM-IV anxiety disorders (panic disorder, social phobia, or obsessive-compulsive disorder) and to 125 age- and gender-matched subjects drawn from a random community sample. RESULTS: Childhood physical abuse was higher among both men (15.5%) and women (33.3%) with anxiety disorders than among comparison subjects (8.1%). Childhood sexual abuse was higher among women with anxiety disorders (45.1%) than among comparison women (15.4%) and was higher among women with panic disorder (60.0%) than among women with other anxiety disorders (30.8%). CONCLUSIONS: These findings confirm the association between anxiety disorders and reported childhood physical and sexual abuse and extend earlier findings by pointing to a particular association between sexual abuse and panic disorder in women.

Adolescent↗

PubMed1996

Sertraline in the treatment of severe aggressiveness in Huntington's disease.

Sertraline, a selective serotonin reuptake inhibitor, was used to treat two consecutive cases of genetically confirmed Huntington's disease in which severe irritability and aggressiveness required inpatient admission. The complete cessation of aggressive behavior in both cases has been maintained on follow-up. This report adds to the literature implicating serotonergic mechanisms in irritability and aggressiveness in both neuropsychiatric and idiopathic psychiatric disorders.

1-Naphthylamine↗

PubMed1996

Trinucleotide repeat length and clinical progression in Huntington's disease.

We examined the relationship between length of the trinucleotide (CAG) repeat at IT-15 and clinical progression of Huntington's disease in 46 mildly to moderately affected patients over a 2-year interval. Patients were divided into those with short mutations (37 to 46 repeats; n = 25) and those with long mutations (> or = 47 repeats; n = 21). Patients with long repeat lengths had earlier age at onset and were younger and less functionally impaired than those with short repeats at the initial visit, but the groups did not differ in severity of neurologic or cognitive impairment. However, the long-repeat group displayed significantly greater decline in both neurologic and cognitive functioning over the 2-year follow-up period. The length of the CAG repeat correlated highly with age at onset (r = -0.72, p < 0.001) and was a strong predictor of decline in both neurologic and cognitive function. The mechanism of gene action, and the means by which longer expansions result in a more malignant disease process, remain to be elucidated.

Activities of Daily Living↗

PubMed1996

Millon Clinical Multiaxial Inventory--II. Follow-up of patients with dissociative identity disorder.

This study is part of a two-year follow-up assessment of 35 out of 96 patients clinically diagnosed with Dissociative Identity Disorder, who were administered the Millon Clinical Multiaxial Inventory-II. Eight subjects achieved integration during the two-year follow-up period. Significant improvement was evident for raw scores on the Self-defeating, Borderline, Paranoid, Anxiety, Somatoform, Dysthymia, Alcohol Dependence, and Drug Dependent scales among both the integrated and nonintegrated patients, with clinically meaningful Base Rate reductions occurring on Self-defeating, Borderline, Avoidant, Passive-Aggressive, Anxiety, Dysthymia, and Major Depression scales following integration. Although Dissociative Identity Disorder presents with polysymptomatology, much treatment progress can be achieved during pre-integration and dramatic improvement follows integration.

Adult↗

PubMed1996

Axis I and II comorbidity and childhood trauma history in chemical dependency.

The authors replicated and extended two former studies on Axis I and II comorbidity and childhood trauma histories in 106 patients admitted to a chemical dependency treatment unit. Sixty-nine subjects reported a history of physical and/or sexual abuse during childhood and 26.4% met criteria for posttraumaic stress disorder. Patients who reported a history of childhood abuse showed more symptoms of depression, dissociation, and borderline personality disorder than those who denied childhood trauma. Dissociative disorders, mood and anxiety disorders, personality disorders, and histories of childhood trauma appear to be common in chemical dependency subjects, and should be inquired about routinely.

Adult↗

PubMed1996

The role of prostate-specific antigen in the chemoprevention of prostate cancer.

An understanding of the natural history of changes in prostate-specific antigen (PSA) may be valuable as a surrogate view of prostate dynamics, as a method to differentiate between benign and malignant growth, and as a means to assess the use of PSA as a tool for monitoring activity of chemoprevention agents. Although PSA appears to be useful as a noninvasive marker of prostatic growth, PSA changes should not be confused with a direct measure of tumor growth. Serum PSA levels are a function of tumor volume but are also influenced by the volume of benign epithelium, grade of carcinoma (if any), inflammation, androgen levels, growth factors, and the extracellular matrix. The biological functions of PSA in the prostate and in its secretions need to be more completely elucidated in order that PSA measurements may more accurately describe prostate dynamics. The expression of PSA is androgen-regulated. It is one of the most abundant prostate-derived proteins in the seminal fluid. Seminogelin, a major protein in seminal fluid, is cleaved by PSA, and this cleavage is important in the liquefaction of semen. Less is known about other PSA substrates. Current PSA studies indicate that cancer cases exhibit an early slow linear PSA phase followed by a rapid exponential phase, and that PSA levels begin to increase exponentially approximately 7-9 years before diagnosis. The establishment of age-specific PSA reference ranges (ASRR) and of PSA velocity (PSAV) rates provide elements of a baseline from which prediction models could measure malignant potential of a prostatic carcinoma. Moreover, recent discoveries of different molecular forms of PSA in serum may allow a much more accurate differentiation of benign and malignant growth as well as a more potent measure of the impact of chemoprevention agents. If PSA doubling time is approximately 2.4-3.0 years and accurately reflects tumor doubling time, and if the average man has less than 0.5 ml of latent prostatic tumor tissue and the average stage T2 cancer is approximately 4 ml when detected, then the available PSA data suggest that the 3 doublings necessary to change from 0.5-4.0 ml, would take 7-12 years for a typical small volume tumor to reach the size of most stage T2 tumors. The findings that histologic cancers appear at much younger ages than previously known is disturbing. It indicates that disease initiation may begin sooner than ever thought likely. "Normal" PSA levels for younger men (< 40 years of age) may need to be studied, and an emphasis upon premalignant lesions in this age group may be necessary. Younger men may represent the most appropriate population and premalignant lesions the most relevant clinical factor for prostate cancer chemoprevention studies and trials. The molecular composition and molecular changes of PSA derived from premalignant lesions have yet to be elucidated, but such investigations may lead to a more complete understanding of the possible progression or transformation of normal prostate cells to premalignancy and subsequently to carcinoma. High grade prostatic intraepithelial neoplasia (PIN) in and of itself does not account for elevated serum PSA levels, but subtle changes in the molecular dynamics of PSA may reveal the influence of androgens and the impact of chemopreventive agents.

Adult↗

PubMed1995

A huntingtin-associated protein enriched in brain with implications for pathology.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanding polyglutamine repeat in the IT15 or huntingtin gene. Although this gene is widely expressed and is required for normal development, the pathology of HD is restricted to the brain, for reasons that remain poorly understood. The huntingtin gene product is expressed at similar levels in patients and controls, and the genetics of the disorder suggest that the expansion of the polyglutamine repeat induces a toxic gain of function, perhaps through interactions with other cellular proteins. Here we report the identification of a protein (huntingtin-associated protein (HAP)-1) that binds to huntingtin. This binding is enhanced by an expanded polyglutamine repeat, the length of which is also known to correlate with the age of disease onset. The HAP-1 protein is enriched in the brain, suggesting a possible basis for the selective brain pathology of HD.

Amino Acid Sequence↗

PubMed1995

In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder.

BACKGROUND: A prior positron emission tomographic study from The Johns Hopkins University, Baltimore, Md, using N-methylspiperone labeled with carbon 11 reported elevated basal ganglia D2 dopamine receptor density (Bmax) values in neuroleptic-naive schizophrenic patients compared with controls. We have now extended these studies to include patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 14) either had never received neuroleptic medication or had been neuroleptic-free for more than 6 months, and they met DSM-III criteria for currently symptomatic affective disorder. Patients with bipolar disorder were compared with matched schizophrenic patients and normal controls. All received two positron emission tomographic scans, the second of which was preceded by oral administration of haloperidol lactate, to permit the calculation of D2 dopamine receptor Bmax. RESULTS: Diagnostic groups differed in Bmax by analysis of variance (P < .0001); post hoc tests showed higher Bmax values for psychotic patients with bipolar disorder and schizophrenic patients compared with normal controls and for schizophrenic patients and psychotic patients with bipolar disorder compared with nonpsychotic patients with bipolar disorder. Among patients with bipolar disorder, Bmax values correlated significantly with the severity of psychotic symptoms (r = .63) on the Present State Examination but not with the severity of nonpsychotic mood symptoms. CONCLUSIONS: We conclude that, like schizophrenic patients, patients with psychotic bipolar disorder have elevations of D2 dopamine receptor Bmax values and that such elevations in affective disorder are more closely associated with the presence of psychosis than with mood abnormality. Elevations in dopamine receptor values thus may occur in psychiatric states that are characterized by psychotic symptoms rather than being specific to schizophrenia.

Adult↗

PubMed1995

Cloning and expression of the rat atrophin-I (DRPLA disease gene) homologue.

Dentatorubral pallidoluysian atrophy (DRPLA) is a rare, progressive, fatal neuropsychiatric disorder similar to Huntington's disease, caused by an expansion of a CAG trinucleotide repeat encoding glutamine. We have cloned the cDNA of the rat homologue of this gene. The cDNA contains a 3549 base pair open reading frame that is 88.2% identical to the human cDNA, with a predicted amino acid sequence that is 93.6% identical to the human sequence. The consecutive glutamine repeat is only five residues in length (normal range in human: 7-35 glutamines) and is followed by a polymorphic region of alternating glutamine and proline residues (QQQQQPQPQPQPQQ). The sequence also includes a polymorphic proline repeat, a serine repeat, and a region of alternating acidic and basic residues. Northern analysis and in situ hybridization indicate that the gene is widely expressed as a 4.5 kb mRNA, with a neuronal distribution in the brain. The widespread expression of this gene is consistent with the possibility that DRPLA, like other glutamine repeat diseases, is a result of an abnormality at the protein level.

Animals↗