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Biomedical subjects

T A Brown

Publications and source records attributed to T A Brown.

At least 19 recordsLinked to original sources
PubMed1995

Diagnostic comorbidity in panic disorder: effect on treatment outcome and course of comorbid diagnoses following treatment.

The impact and course of additional diagnoses was examined in 126 patients undergoing cognitive-behavioral treatment for panic disorder. With the Anxiety Disorders Interview Schedule--Revised, a high comorbidity rate (51%) was observed at pretreatment. Pretreatment comorbidity was not predictive of premature termination, nor did it have a substantial impact on short-term treatment outcome. However, patients with comorbidity at posttreatment were more likely to have sought additional treatment over the follow-up interval. Although a significant and dramatic decline in the overall comorbidity rate was found at posttreatment (17%), at 24-month follow-up this rate had increased to a level (30.2%) that was no longer significantly different from pretreatment. This was despite the fact that patients maintained or improved on treatment gains for panic disorder over this interval. The implications of these findings for the treatment, conceptualization, and classification of emotional disorders are discussed.

Adolescent↗
PubMed1995

Long-term outcome in cognitive-behavioral treatment of panic disorder: clinical predictors and alternative strategies for assessment.

Long-term outcome (24-month follow-up; 24MFU) of cognitive-behavioral treatment was examined in 63 patients with panic disorder. When the traditional methods of cross-sectional assessment were used (e.g., panic frequency during past month), long-term outcome findings paralleled those of earlier studies. However, assessments of idiographic response and those that examined longer time periods revealed that a large proportion of the sample experienced a fluctuating symptom course of panic-related symptomatology that was not captured by the cross-sectional method. Many (27%) patients sought further treatment for panic during the follow-up period because of a less-than-adequate response to treatment; nevertheless, additional treatment did not result in further clinical improvement. Pretreatment severity of panic disorder was associated with poorer outcome at 24MFU. Use of psychotropic medication during treatment was associated with poorer outcome, although to a weaker degree when pretreatment responding was controlled. Findings are discussed in the context of how the outcome of treatments for panic disorder should be evaluated and interpreted.

Adult↗
PubMed1995

Regulation of nuclear genes encoding mitochondrial proteins in Saccharomyces cerevisiae.

Selection for mutants which release glucose repression of the CYB2 gene was used to identify genes which regulate repression of mitochondrial biogenesis. We have identified two of these as the previously described GRR1/CAT80 and ROX3 genes. Mutations in these genes not only release glucose repression of CYB2 but also generally release respiration of the mutants from glucose repression. In addition, both mutants are partially defective in CYB2 expression when grown on nonfermentable carbon sources, indicating a positive regulatory role as well. ROX3 was cloned by complementation of a glucose-inducible flocculating phenotype of an amber mutant and has been mapped as a new leftmost marker on chromosome 2. The ROX3 mutant has only a modest defect in glucose repression of GAL1 but is substantially compromised in galactose induction of GAL1 expression. This mutant also has increased SUC2 expression on nonrepressing carbon sources. We have also characterized the regulation of CYB2 in strains carrying null mutation in two other glucose repression genes, HXK2 and SSN6, and show that HXK2 is a negative regulator of CYB2, whereas SSN6 appears to be a positive effector of CYB2 expression.

Base Sequence↗
PubMed1995

Metabolic and pharmacokinetic studies following oral administration of famciclovir to the rat and dog.

1. Drug-related material was well absorbed following oral administration of 14C-famciclovir to the male rat at doses up to 4000 mg/kg and to the male dog at doses up to 250 mg/kg, as judged by the early onset of the peak blood or plasma concentrations of radioactivity (usually < or = 1.5h) and the rapid extensive excretion of radioactivity in the urine (57-76 and 86-89% of dose in rat and dog respectively). 2. Famciclovir underwent extensive first-pass metabolism in both species. In rat, following dosing at 40 mg/kg, famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma (mean 3.5 micrograms/ml) at 0.5 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other major metabolite detected in rat plasma. Cmax values for BRL 42359 (mean 2.2 micrograms/ml) were also achieved at 0.5 h. In dog, extensive conversion of famciclovir to penciclovir, via BRL 42359, also occurred, but its rate of formation from BRL 42359 was somewhat slower than in rat. In dog, following dosing at 25 mg/kg, Cmax values for penciclovir (mean 4.4 micrograms/ml) occurred at 3 h and were lower than the Cmax values for BRL 42359 (mean 10.0 micrograms/ml) which were achieved at 1h. 3. A dose-dependent decrease in the conversion of BRL 42359 to penciclovir occurred in both species, resulting a changes in the ratios of the plasma concentrations of the two metabolites with increasing dose. In rat, the urinary excretion of penciclovir decreased from 36% of dose at 40 mg/kg to 21% at 4000 mg/kg, and was accompanied by a corresponding increase in the urinary excretion of BRL 42359. In dog, a similar decrease in the urinary excretion of penciclovir occurred on increasing the dose of famciclovir from 25 to 250 mg/kg. 4. Penciclovir and BRL 42359 were the major metabolites detected in urine and faeces. In rat, following dosing at 40 mg/kg, 54 and 22% of dose were recovered in the excreta as penciclovir and BRL 42359 respectively. Corresponding recoveries of the two metabolites in the dog were 34 and 50% of dose. The metabolic fate of famciclovir in these animal species is, therefore, similar to that reported previously in man.

2-Aminopurine↗
PubMed1992

Psychometric properties of the Penn State Worry Questionnaire in a clinical anxiety disorders sample.

With the advent of DSM-III-R, the diagnostic criteria for generalized anxiety disorder (GAD) shifted in emphasis from the autonomic arousal to the cognitive component of the disorder, namely worry. The Penn State Worry Questionnaire was developed to assess the trait of worry and has proven to be a reliable and valid measure in a series of studies largely based on college student samples. The purpose of the present study was to assess the psychometric properties and utility of the PSWQ in a clinical sample of 436 anxiety disorder patients and 32 normal controls. Factor analysis indicated that the PSWQ assesses a unidimensional construct. Furthermore, the PSWQ evidenced quite favorable internal consistency using GAD patients and each of the other anxiety disorder groups and normal controls. The validity of the PSWQ was supported by an analysis indicating that the measure distinguished. GADs from each of the other anxiety disorder groups including those with obsessive-compulsive disorder. Moreover, correlations between the PSWQ and measures of anxiety, depression, and emotional control supported the convergent and discriminant validity of the measure. Collectively, the findings speak favorably to the use of the PSWQ in research examining the nature and treatment of GAD and the processes of normal and pathological worry.

Agoraphobia↗
PubMed1992

Reactivity to alcohol-relevant beverage and imaginal cues in alcoholics.

This study was designed to explore three primary facets of reactivity to alcohol-relevant stimuli among alcoholics: (a) comparison of exposure to an alcohol-containing beverage vs. an appropriate, standardized control beverage; (b) efficacy of imaginally presented cues to elicit reactivity, alone and in combination with beverage cues; and (c) examination of the recovery process. Forty-eight male veterans attending an inpatient alcohol treatment program served as participants and were randomly assigned to one of four groups in a 2 (Alcohol vs. Lemonade Beverage) X 2 (High-Risk vs. Low-Risk Imagery) design. Heart rate reactivity to Beverage cues was consistent with previous research. An interaction of Beverage and Imagery manipulations during recovery revealed both experimental manipulations influenced heart rate, although the Alcohol/High-Risk Imagery exposure group did not demonstrate enhanced effects. Both manipulations also had an impact on ratings of desire to consume alcohol. These findings provide further support for the reliability of cue reactivity effects, and suggest the utility of imaginal exposure procedures as a component of a comprehensive cue reactivity assessment.

Adult↗
PubMed1992

Response to hyperventilation and inhalation of 5.5% carbon dioxide-enriched air across the DSM-III-R anxiety disorders.

Anxiety disorder patients (n = 198; under criteria of the Diagnostic and Statistical Manual of Mental Disorders; rev. 3rd ed.; American Psychiatric Association, 1987) and nonanxious control subjects (n = 25) underwent challenges of 90 s of voluntary hyperventilation and 15 min of 5.5% carbon dioxide in air. Panic disorder subjects showed a greater subjective response to both challenges than did subjects with other anxiety disorders, who in turn responded more than did control subjects. Furthermore, subjects with panic disorder as an additional diagnosis tended to report more subjective response than did anxiety disorder subjects without panic disorder. The best prechallenge predictor of response to each procedure was a measure of fear of physical symptoms. The findings support previous results that have pointed to a greater fear or anxiety-inducing effect of these challenge procedures in panic disorder patients, as compared with other subjects.

Adult↗
PubMed1992

Comorbidity among anxiety disorders: implications for treatment and DSM-IV.

Research on comorbidity among psychological disorders is relatively new. Yet, comorbidity data have fundamental significance for classification and treatment. This significance is particularly apparent in the anxiety disorders, which, prior to DSM-III-R, were subsumed under disorders considered more significant (e.g., psychotic and depressive disorders). After considering definitional, methodological, and theoretical issues of comorbidity, data on comorbidity among the anxiety disorders are reviewed as well as data on comorbidity of anxiety disorders with the depressive, personality, and substance use disorders. Treatment implications are presented with preliminary data on the effects of psychosocial treatment of panic disorder on co-morbid generalized anxiety disorder. Implications of comorbidity for research on the nature of psychopathology and the ultimate integration of dimensional and categorical features in our nosology are considered.

Anxiety Disorders↗
PubMed1992

Specificities of protein-protein and protein-DNA interaction of GABP alpha and two newly defined ets-related proteins.

The ets-related protein GABP alpha interacts with the four ankyrin-type (ANK) repeats of GABP beta to form a high-affinity DNA-binding complex that recognizes a site important for herpes simplex virus type I immediate early gene activation. To investigate the selectivity and specificity of the GABP complex, we have isolated two new ETS family members, termed ER81 and ER71. ER81 and GABP alpha were present in most tissues of adult mice, whereas ER71 was restricted to testis. We have compared the DNA-binding specificities of these proteins by binding site selection. GABP alpha, ER71, and ER81 recognized the common pentanucleotide DNA sequence 5'-CGGAA/T-3'. Although subtle differences were observed for nucleotide preferences flanking this pentanucleotide core, the overall similarity of the selected sequences was most striking. Given the observation that GABP alpha interaction with GABP beta requires its intact ETS domain, we further compared the ability of GABP beta to interact with other ETS proteins. GABP beta did not augment the DNA-binding activity of the highly similar ETS domains of ER81, ER71, or Ets-1. Moreover, probing of total tissue extracts with radiolabeled GABP beta demonstrated its exceedingly stringent specificity for GABP alpha. Given that the DNA-binding specificities of these ETS proteins are similar and that the protein-protein interactions between GABP beta and GABP alpha are highly specific, we conclude that the protein interactions determine the target site selection by GABP alpha.

Amino Acid Sequence↗
PubMed1991

Gadolinium block of calcium channels: influence of bicarbonate.

The selectivity of block of voltage-activated barium (Ba2+) currents by lanthanide ions was studied in a rat dorsal root ganglion (DRG) cell line (F11-B9), rat and frog peripheral neurons, and rat cardiac myocytes using the whole-cell patch clamp technique. Gadolinium (Gd3+) produced a dose-dependent and complete inhibition of whole-cell Ba2+ current in all cells studied, including cells expressing identified dihydropyridine-sensitive L-type currents and omega-conotoxin-sensitive N-type currents. Like Gd3+, lutetium (Lu3+) and lanthanum (La3+) blocked all Ba2+ current with little selectivity for different components of the whole-cell current. Gd3+ block of Ba2+ currents was incomplete, however, when sodium bicarbonate (5-22.6 mM) was added to the standard HEPES-buffered external Ba2+ solution. In rat DRG neurons and F11-B9 cells, a fraction of the whole-cell Ba2+ current recorded in the presence of bicarbonate was resistant to block by saturating concentrations of Gd3+ (50-100 microM). The resistant current inactivated more rapidly than the original current giving the appearance that, under these conditions, Gd3+ block is more selective for the slowly inactivating component of the whole-cell current. Bicarbonate modification of Gd3+ block occurred both before and after omega-conotoxin block of N-type currents in rat DRG neurons, suggesting that even in the presence of bicarbonate, Gd3+ block was not selective for N-type currents.

Animals↗
PubMed1991

Convergence of Ets- and notch-related structural motifs in a heteromeric DNA binding complex.

Analysis of the heteromeric DNA binding protein GABP has revealed the interaction of two distinct peptide sequence motifs normally associated with proteins located in different cellular compartments. The alpha subunit of GABP contains an 85-amino acid segment related to the Ets family of DNA binding proteins. The ETS domain of GABP alpha facilitates weak binding to DNA and, together with an adjacent segment of 37 amino acids, mediates stable interaction with GABP beta. The beta subunit of GABP contains four imperfect repeats of a sequence present in several transmembrane proteins including the product of the Notch gene of Drosophila melanogaster. These amino-terminal repeats of GABP beta mediate stable interaction with GABP alpha and, when complexed with GABP alpha, directly contact DNA. These observations provide evidence for a distinct biochemical role for the 33-amino acid repeats, and suggest that they may serve as a module for the generation of specific dimerization interfaces.

Animals↗
PubMed1991

Use of exoglycosidases from Mercenaria mercenaria (hard shelled clam) as a tool for structural studies of glycosphingolipids and glycoproteins.

The hepatopancreatic extract of M. mercenaria (hard shelled clam) was found to be a rich source for at least 16 different glycosidases. These glycosidases were successfully employed for the degradation of oligosaccharides, glycolipids, and glycoproteins at analytical as well as preparative levels. The identified glycosidases differ considerably in their stability profiles with respect to time and temperature of storage and presence of glycerol. However, most of the enzymes show higher activity at pH 4.5 than at pH 7.0, and could be bound on a DEAE CL-6B Sepharose anion-exchange column suggesting similar charge characteristics on the protein surface. A Gal beta 1, 3R linkage-specific beta-galactosidase activity has also been detected in the glycosidase-enriched fraction and has been utilized to obtain quantitative conversion of the ganglioside GM1 to GM2 on a preparative scale. The glycosidase-rich extract does not have detectable protease activity at the pH of optimal glycosidase activity (pH 4.5) and, hence, can be safely used for specific hydrolysis of carbohydrate moieties of glycoproteins and glycopeptides. This is the first report to characterize a repertoire of glycosidases from an inexpensive, dependable and convenient source that can be easily employed for compositional studies involving glycoconjugates.

Animals↗
PubMed1991

Sites of phosphorylation and photoaffinity labeling of the 1,25-dihydroxyvitamin D3 receptor.

The 1,25-dihydroxyvitamin D3 receptor is a member of the steroid/thyroid hormone receptor gene family and is thought to act by regulating transcription of specific genes. In this report, we have used peptide mapping of porcine 1,25-dihydroxyvitamin D3 receptor to localize the sites of phosphorylation, photoaffinity labeling, and monoclonal antibody binding. Receptor was immunoprecipitated from [32P]orthophosphate-labeled pig kidney LLC-PK1 cells grown in the absence and presence of 1,25-dihydroxyvitamin D3. Phosphorylation of receptor was induced by 1,25-dihydroxyvitamin D3. The phosphorylated receptor was digested with Staph A V8 protease within Cleveland gels and the 32P label was found entirely in a 23-kDa fragment. Similarly, receptor that was photoaffinity labeled with 1,25-dihydroxy-[26,27-3H]vitamin D3 was subjected to peptide mapping by Cleveland gels. The primary site of photoaffinity label incorporation was in the same 23-kDa peptide. This peptide was localized to a region in the center of the receptor protein, spanning part of the previously designated hinge region and roughly one-half the proposed steroid binding domain. Because phosphorylation did not occur in the DNA binding domain, it may not be involved in the binding of receptor to DNA. The localization of phosphorylation sites to this 23-kDa peptide may suggest that phosphorylation is involved in steroid binding and/or activation of the receptor.

Affinity Labels↗
PubMed1991

Photoaffinity labeling of the 1,25-dihydroxyvitamin D-3 receptor.

Underivatized 1,25-dihydroxy[26,27-3H]vitamin D-3 was successfully used to photoaffinity label the 1,25-dihydroxyvitamin D-3 receptor. The covalent incorporation of tritium into the receptor protein was induced by ultraviolet irradiation of the receptor-1,25-dihydroxy[26,27-3H]vitamin D-3 complex in crude pig intestinal nuclear extract. The amount of incorporated label increased with increasing time of irradiation and was dependent on light of wavelengths 220-280 nm. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography were used to demonstrate that label was incorporated primarily into the 1,25-dihydroxyvitamin D-3 receptor. In addition, the label incorporation was eliminated by competition with a 100-fold excess nonradioactive 1,25-dihydroxyvitamin D-3, indicating that the label was specific for the steroid binding site. Since 1,25-(OH)2[26,27-3H]vitamin D-3 is readily available and requires no special precautions for its preparation and handling, it should be a useful photoaffinity label for future studies of the receptor.

Affinity Labels↗
PubMed1991

Human keratinocytes express a new CD44 core protein (CD44E) as a heparan-sulfate intrinsic membrane proteoglycan with additional exons.

We previously identified a 90-kD (GP90), collagen-binding, membrane glycoprotein, termed extracellular matrix receptor III (ECMR III), that is homologous to the lymphocyte homing receptor and CD44 antigen (Gallatin, W. M., E. A. Wayner, P. A. Hoffman, T. St. John, E. C. Butcher, and W. G. Carter. 1989. Proc. Natl. Acad. Sci. USA. 86:4654-4658). CD44 is abundantly expressed in many epithelial tissues, and is localized predominantly to filopodia in cultured keratinocytes. Here we establish CD44 as a polymorphic family of related membrane proteoglycans and glycoproteins possessing extensive diversity in both glycosylation and core protein sequence. Human neonatal foreskin keratinocytes (HFKs) and QG56 lung squamous carcinoma cells express an alternatively spliced form of the CD44 core protein (termed CD44E) that contains an additional 132 amino acids in the carbohydrate attachment region of the extracellular domain. HFKs, HT1080 fibrosarcoma and QG56 cells, as well as many other human cells, contain varying ratios of GP90 and structurally related, higher molecular mass forms of CD44 that express the following characteristics: (a) each form reacted with anti-CD44 (mAbs) P1G12, P3H9, and P3H5. Each of these mAbs recognized a distinct, nonoverlapping epitope present on each CD44 form. (b) Differences in mass were due primarily to variation in carbohydrate moieties, including sulfated aspargine-linked glycopeptides (GP), chondroitin sulfate (CS), and heparan sulfate (HS) glycosaminoglycans, as well as O-linked mucin and polylactosamine structure(s). The major polymorphic forms were designated HT1080 GP90 and CS180, QG56 GP230, and HFK HS/CS250, based on dominant carbohydrate moieties and relative mass. (c) The polymorphic forms use CD44 and CD44E core proteins, each containing a unique set of potential attachment sites for O- and N-glycosides and glycosaminoglycans. (d) Immunofluorescence microscopy, differential extraction with Triton-X-114 detergent, and incorporation into liposomes indicated that all the forms were membrane bound glycoconjugates. These results define CD44 as a structurally diverse, but immunologically related, set of intrinsic membrane macromolecules, and suggests that these structurally varied forms might be expected to manifest multiple functions.

Amino Acid Sequence↗