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Biomedical subjects

B Grant

Publications and source records attributed to B Grant.

At least 37 records · Page 2Linked to original sources
PubMed1999

Factor structures for DSM-IV substance disorder criteria endorsed by alcohol, cannabis, cocaine and opiate users: results from the WHO reliability and validity study.

AIMS: The factor structure of DSM-IV substance disorder criteria is examined among alcohol, cannabis, cocaine and opiate users to determine the dimensionality of abuse and dependence criteria within each of these drug classes and whether a common construct can be generalized across drug classes. DESIGN: 12-month criterion prevalence was assessed as part of the World Health Organization's Study on the Reliability and Validity of the Alcohol and Drug Use Disorder Instruments in various settings at eight sites around the world using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). A majority of respondents were recruited from non-treatment settings. In addition to exploratory factor analysis, confirmatory factor analysis was used to analyse factor structures using weighted least square methods and tetrachoric correlation matrices. Multi-sample analysis techniques were used to model differences between drug-classes. FINDINGS: In the full data analyses identified a single factor solution for each user population and across user populations. However, analyses of data from users reporting low to moderate symptomatology identified a two-dimensional construct among alcohol, cannabis and opiate users consisting of a major "dependence" factor and a lesser "abuse" factor. In addition, results showed that neither the abuse criterion "(A2) use in physical hazardous situations" or the dependence criterion "(D7) use despite knowledge of psychological/physical problems" were central to the latent construct in any of the user populations, except for D7 among alcohol users. CONCLUSIONS: The multi-dimensional results found among users with low to moderate symptomatology indicate that: (1) previous results from relatively homogeneous populations may have been biased towards lesser order solutions, and that (2) the DSM-IV substance disorder criteria describe at least two distinct phenomena, supporting the current DSM-IV organization of substance disorder criteria. Further work needs to evaluate whether prevalent symptoms are present in random or predictable combinations, whether combinations reflecting a specific hierarchy of severity can be identified, and whether incident symptoms are accumulated in a predictable pattern, within specific user populations and across user populations.

Alcoholism↗
PubMed1999

Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte.

The Caenorhabditis elegans oocyte is a highly amenable system for forward and reverse genetic analysis of receptor-mediated endocytosis. We describe the use of transgenic strains expressing a vitellogenin::green fluorescent protein (YP170::GFP) fusion to monitor yolk endocytosis by the C. elegans oocyte in vivo. This YP170::GFP reporter was used to assay the functions of C. elegans predicted proteins homologous to vertebrate endocytosis factors using RNA-mediated interference. We show that the basic components and pathways of endocytic trafficking are conserved between C. elegans and vertebrates, and that this system can be used to test the endocytic functions of any new gene. We also used the YP170::GFP assay to identify rme (receptor-mediated endocytosis) mutants. We describe a new member of the low-density lipoprotein receptor superfamily, RME-2, identified in our screens for endocytosis defective mutants. We show that RME-2 is the C. elegans yolk receptor.

Animals↗
PubMed1999

The validity of DSM-IV alcohol abuse: drunk drivers versus all others.

OBJECTIVE: Prior research in a community sample indicated that almost half the individuals receiving a diagnosis of DSM-IV alcohol abuse did so on the basis of only one symptom, driving after drinking too much. While this is certainly unwise behavior, it may not be a psychiatric disorder. Therefore, we investigated the differential validity of this subgroup of abuse cases by testing the association of a set of external validating criterion variables with three groups: those who met criteria for abuse just for drinking-driving, those who met criteria by other means and those with no alcohol diagnosis. Present status of past cases of abuse was also investigated. METHOD: Subjects were 22,204 U.S. household residents (a subset of a national probability sample) interviewed in 1992 with the Alcohol Use Disorders and Associated Disabilities Interview Schedule. The generalized logit model was the principal means of analysis. RESULTS: Subjects who met criteria for DSM-IV alcohol abuse just for drinking-driving differed from subjects with no diagnosis on about half the variables tested, while those who met criteria for abuse in other ways differed from subjects with no diagnosis on all variables tested. The two abuse groups differed from each other on some but not all variables. Past cases of abuse for drinking-driving and past cases of other abuse were equally likely to have remitted in the last 12 months, and slightly less likely to meet criteria for current dependence. CONCLUSIONS: Further conceptual and empirical work is needed to resolve the difficulties with the DSM-IV alcohol abuse category.

Adolescent↗
PubMed1997

Prevalence and demographic correlates of symptoms of last year dependence on alcohol, nicotine, marijuana and cocaine in the U.S. population.

The prevalence of last year use of alcohol, cigarettes, marijuana and cocaine in the U.S. population and conditional prevalence of a proxy measure of last year dependence among last year users of each drug class were assessed as a function of age, gender and ethnicity. Analyses were based on three aggregated waves (1991, 1992 and 1993) of the nationally representative samples of the general population aged > or = 12 interviewed in the National Household Surveys on Drug Abuse (n = 87915). An approximation of DSM-IV drug-specific last year dependence for each drug class was derived from self-reported symptoms of dependence, data on frequency and quantity of use and drug-related problems reported for the last year. Descriptive and multivariate analyses were conducted. The inclusion of cigarettes among the drugs, the large number of cases and the wide age range of respondents (> or = 12) enable us to make drug, age, gender and ethnic comparisons not otherwise possible in any other data set. The proxy measure of dependence, however, has limitations. The five major findings are that: (1) nicotine is the most addictive of the four drugs we examined; (2) among female last year users of alcohol and marijuana, adolescents are significantly more at risk for dependence than any other age group of women; (3) conditional prevalences of last year dependence on alcohol, marijuana and cocaine are higher among adolescent females than adolescent males but significantly different only for cocaine; (4) among adults, the rates of dependence are higher among males than among females for alcohol and marijuana, but lower for nicotine; and (5) among last year users, whites are more likely than any other ethnic group to be dependent on nicotine and blacks to be dependent on cocaine.

Adolescent↗
PubMed1997

Engraftment and outcomes of patients receiving myeloablative therapy followed by autologous peripheral blood stem cells with a low CD34+ cell content.

Engraftment kinetics after high-dose chemotherapy (HDC) were evaluated in patients receiving autologous peripheral blood stem cell (PBSC) infusions with a low CD34+ cell content. Forty-eight patients were infused with < 2.5 x 10(6) CD34+ cells/kg; 36 because of poor harvests and 12 because they electively received only a fraction of their harvested cells. A median of 2.12 x 10(6) CD34+ cells/kg (range, 1.17-2.48) were infused following one of seven different HDC regimens. All patients achieved absolute neutrophil counts > or = 0.5 x 10(9)/l at a median of day 11 (range, 9-16). Forty-seven patients achieved platelet counts > or = 20 x 10(9)/l at a median of day 14 (range, 8-250). Nine of 47 (19%) had platelet recovery after day 21, 4/47 (9%) after day 100 and one died on day 240 without platelet recovery. Twenty-six patients (54%) died of progressive disease in 51-762 days; 22 (46%) are alive at a median of 450 days (range, 94-1844), 17 (35%) of whom are surviving disease-free at a median of 494 days (range, 55-1263). No patient died as a direct consequence of low blood cell counts. These data demonstrate that PBSC products containing 1.17-2.48 x 10(6) CD34+ cells/kg resulted in relatively prompt neutrophil recovery in all patients but approximately 10% had delayed platelet recovery.

Antigens, CD34↗
PubMed1997

Autophosphorylation of the catalytic subunit of cAMP-dependent protein kinase in Escherichia coli.

When the catalytic (rC) subunit of cAMP-dependent protein kinase (cAPK) is expressed in Escherichia coli, it is autophosphorylated at four sites, Ser10, Ser139, Ser338 and Thr197 (49). Three of these sites, Ser10, Ser338 and Thr197, are also found in the mammalian enzyme. To understand the functional importance of these phosphorylation sites, each was replaced with Ala, Glu or Asp. The expression, solubility and phosphorylation state of each mutant protein was characterized by immunoprecipitation following in vivo labeling with 32Pi. When possible, isoforms were resolved and kinetic properties were measured. The two stable phosphorylation sites in the mammalian enzyme, Ser338 and Thr197, were shown to play different roles. Ser338, which stabilizes a turn near the C-terminus, is important for stability. Both rC(S338A) and rC(S338E) were very labile; however, the kinetic properties of rC(S338E) were similar to the wild-type catalytic subunit (C-subunit). Ser338 most likely helps to anchor the C-terminus to the surface of the small lobe. Thr197 is in the activation loop near the cleft interface. Mutagenesis of T197 caused a significant loss of catalytic activity with increases in Kms for both peptide and MgATP, as well as a small decrease in k(cat) indicating that this phosphate is important for the correct orientation of catalytic residues at the active site. Replacement of Ser139, positioned at the beginning of the E-helix, with Ala had no effect on the kinetic parameters, stability or phosphorylation at the remaining sites. In contrast, mutation of Ser10, located at the beginning of the A-helix, produced mostly insoluble, inactive, unphosphorylated protein, suggesting that this region, though far removed from the active site, is structurally important at least for the expression of soluble phosphoprotein in E.coli. Since the mutation of active site residues as well as deletion mutants generate underphosphorylated proteins, these phosphorylations in E.coli all result from autophosphorylation.

Adenosine Triphosphate↗
PubMed1997

Structure, function, and expression of SEL-1, a negative regulator of LIN-12 and GLP-1 in C. elegans.

Previous work indicated that sel-1 functions as a negative regulator of lin-12 activity, and predicted that SEL-1 is a secreted or membrane associated protein. In this study, we describe cell ablation experiments that suggest sel-1 mutations elevate lin-12 activity cell autonomously. We also use transgenic approaches to demonstrate that the predicted signal sequence of SEL-1 can direct secretion and is important for function, while a C-terminal hydrophobic region is not required for SEL-1 function. In addition, by analyzing SEL-1 localization using specific antisera we find that SEL-1 is localized intracellularly, with a punctate staining pattern suggestive of membrane bound vesicles. We incorporate these observations, and new information about a related yeast gene, into a proposal for a possible mechanism for SEL-1 function in LIN-12 turnover.

Animals↗
PubMed1997

The NBS.

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Humans↗
PubMed1996

The Caenorhabditis elegans sel-1 gene, a negative regulator of lin-12 and glp-1, encodes a predicted extracellular protein.

The Caenorhabditis elegans lin-12 and glp-1 genes encode members of the LIN-12/NOTCH family of receptors. The sel-1 gene was identified as an extragenic suppressor of a lin-12 hypomorphic mutant. We show in this report that the sel-1 null phenotype is wild type, except for an apparent elevation in lin-12 and glp-1 activity in sensitized genetic backgrounds, and that this genetic interaction seems to be lin-12 and glp-1 specific. We also find that sel-1 encodes a predicted extracellular protein, with a domain sharing sequence similarity to predicted proteins from humans and yeast. SEL-1 may interact with the LIN-12 and GLP-1 receptors and/or their respective ligands to down-regulate signaling.

Alleles↗
PubMed1995

The thrombin receptor in human platelets is coupled to a GTP binding protein of the G alpha q family.

The thrombin receptor is a G protein-coupled receptor, but the G proteins functionally coupled to this receptor in human platelets are not yet definitively identified. Thrombin stimulation of platelets leads to phospholipase C-mediated increases in intracellular calcium, and previous studies have suggested that the thrombin receptor is coupled to members of the Gq family. We now demonstrate direct GTPase activation by thrombin receptor activation peptide (TRAP) in human platelet membranes, and specific inhibition of TRAP-activated GTPase by antibodies to Gq. These data demonstrate functional coupling of the thrombin receptor to a member of the Gq family.

Amino Acid Sequence↗
PubMed1994

Validity of the bi-axial dependence concept: a test in the US general population.

According to the "bi-axial" concept of alcohol dependence, the Alcohol Dependence Syndrome (ADS) constitutes an axis or dimension of alcohol difficulties, while other alcohol-related problems (social, legal, etc.) constitute one or more separate dimensions. The validity of the bi-axial distinction was investigated in a stratified probability sample of 3212 US current drinkers who were interviewed in their households. Indicators of the Alcohol Dependence Syndrome and potentially distinct alcohol-related problems were covered in a structured interview administered by carefully trained interviewers. This interview provided extensive coverage of drinking patterns and problems. Aspects of the ADS covered included narrowing, salience, tolerance, withdrawal, withdrawal relief/avoidance and compulsion/control. Other alcohol problems included difficulties with work, health, the law, general social difficulties and problems in marriage/home life. Confirmatory and exploratory factor analyses were used to determine whether a single factor (dimension) or two or more factors fit the data best. Using all methods, we found that one general factor explained the structure of the data better than a two-factor model or other models for males, females, blacks and whites. Thus, the utility of this approach to distinguishing between types of alcohol problems was challenged, raising some questions about abuse/dependence distinctions in various nomenclatures.

Adult↗
PubMed1994

Nosological comparisons of DSM-III-R and DSM-IV alcohol abuse and dependence in a clinical facility: comparison with the 1988 National Health Interview Survey results.

The purpose of this study was to compare DSM-III-R and proposed formulations of DSM-IV diagnoses of alcohol use disorders in a clinical sample with the same assessment methods used in a large national survey previously reported. Issues included the number of symptoms required for abuse and dependence diagnoses, the effects of requiring evidence of physiological dependence to make the dependence diagnosis (Option 1 vs. Option 2), whether to require a duration criterion, and the concept of alcohol abuse. The diagnostic criteria proposed in the 1991 DSM-IV options book were the criteria investigated in this study. Concordance between DSM-III-R and DSM-IV was closest when the form of DSM-IV used was most similar to DSM-III-R. The duration criterion had much less effect on a dependence diagnosis in this clinical sample than in the general population. DSM-IV Option 2 for alcohol dependence excluded a number of cases from the dependence diagnosis who received such a diagnosis under DSM-III-R and DSM-IV Option 1. Abuse continued to function as a residual category, especially noticeable under increasingly restrictive definitions of dependence, and was rare in both the clinical and general population sample. Implications of the findings for research and other purposes are discussed.

Adolescent↗
PubMed1994

1994 draft DSM-IV criteria for alcohol use disorders: comparison to DSM-III-R and implications.

In 1994, DSM-IV will be published, with new criteria for alcohol abuse and dependence. Implications of the changes in criteria for alcohol use disorders were investigated by comparing the diagnoses made by the DSM-IV criteria and DSM-III-R criteria. The study was conducted in a sample of 424 patients in an inpatient alcohol rehabilitation unit in the New York metropolitan area. DSM-III-R and DSM-IV criteria showed similar results and high agreement for any alcohol use disorder (abuse and dependence combined). Alcohol dependence was also consistently diagnosed with DSM-III-R and DSM-IV criteria. Agreement between DSM-III-R and DSM-IV abuse diagnoses was very low. Compared with DSM-III-R, DSM-IV classified over three times as many patients as alcohol abusers, although those with alcohol dependence still overwhelmingly dominated the sample. With some fluctuations, the results were stable over Black, Hispanic, and White subgroups of patients. The direction of the findings was consistent with results from a national general population survey in that the prevalence of alcohol abuse increased in both studies. However, the clinical results alone would not have suggested the marked changes in relative prevalence of abuse and dependence that occurred in the general population when DSM-IV criteria were used in place of DSM-III-R. Research on diagnostic criteria limited to patient samples omits important information on the implications of changing aspects of the diagnostic criteria. The need for a coherent theory of alcohol abuse is highlighted.

Adolescent↗
PubMed1993

Doing the rumba.

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Medical Audit↗
PubMed1993

The dimensionality of alcohol abuse and dependence: factor analysis of DSM-III-R and proposed DSM-IV criteria in the 1988 National Health Interview Survey.

Decisions on the final version of the DSM-IV alcohol abuse and dependence criteria will be determined largely by the APA's substance abuse field trials, conducted primarily in treated, clinical samples. Among the major objectives of the field trials are to study the boundaries between abuse and dependence, and to identify specific criteria that define the abuse category. The decisions on revisions of the abuse and dependence criteria in DSM-IV should, however, be informed by data from non-treated or general population samples as well. The present study addresses the field trial objectives using recent data from a large general population survey, the 1988 National Health Interview Survey (NHIS88). The paper reports on factor analyses to assess the dimensions underlying the DSM-III-R and DSM-IV dependence and abuse criteria as operationalized in the NHIS88. The focus of the analyses is on whether models with more than one dimension are needed and if so, the correspondence of the dimensions to criteria sets defined in the DSM-III-R and DSM-IV. The analyses show that a two-dimensional model is required. The dimensions are interpreted as abuse and dependence, but the sets of criteria that define each of the dimensions show important deviations from the criteria sets used in the DSM definitions.

Ethanol↗
PubMed1992

Medical abortion.

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Abnormalities, Drug-Induced↗
PubMed1992

Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations.

This study investigates type II protein C deficiency in a family with manifestations of both arterial and venous thrombosis. Of 64 members of the kindred, 14 have been tested and 7 have PC deficiency. Among affected individuals (n = 7), mean protein C levels by different assays were as follows: enzyme-linked immunosorbent assay (ELISA), 3.8 micrograms/mL (2.1 to 4.3 micrograms/mL); amidolytic with venom activator, 115% (60% to 140%); clotting with venom activator, 42% (23% to 59%). The mean ratio of clotting to amidolytic assays for the affected individuals was 0.37 compared with a normal range of 0.8 to 1.2. Thus, the affected individuals have normal total protein C and their activated protein C has a normal active site assessed by chromogenic substrate; however, they have markedly diminished clotting activity. Immunoassay and chromatography data suggested an abnormality of carboxylation in the gamma carboxyglutamic acid (Gla) domain. Polymerase chain reaction amplification and direct DNA sequencing of exon 2 from genomic DNA of affected individuals showed two nucleotide substitutions. One of the mutations (A----C) results in Glu20----Ala, thereby eliminating a site for vitamin K-dependent gamma-carboxylation. The other substitution (G----A) results in a Val34----Met mutation. DNA sequencing of the other exons from affected individuals has shown no further difference from that of the wild-type gene. The former mutation also removes a Bgl II restriction endonuclease site, which has allowed us to confirm the mutation in affected individuals by direct digestion and Southern hybridization of genomic DNA from family members. This is the first reported family with documented Gla domain mutations in the protein C gene.

Adolescent↗