Examining the relationship of concurrent obesity and tobacco use disorder on the development of substance use disorders and psychiatric conditions: Findings from the NESARC-III.

Background: Multimorbidity is linked to worse health outcomes than single health conditions. However, recent studies show that obesity may reduce the risk of developing substance use disorders (SUDs), particularly in vulnerable populations. We investigated how comorbid obesity and tobacco use disorder (TUD) relate to the risk of SUDs and psychiatric conditions. Methods: Data was used from 36,309 individuals who completed the National Epidemiological Survey on Alcohol and Related Conditions - Wave III. Individuals who met the DSM-5 criteria for TUD in the last year were defined as the TUD group. Obesity was defined as having a body mass index (BMI) greater than 30 kg/m2. Using this information, individuals were grouped into categories, with people being identified as either having obesity, TUD, both obesity and TUD, or not having either obesity or TUD (comparison). Groups were compared against their comorbid diagnoses of either an additional SUD or psychiatric conditions. Results: Controlling for demographic characteristics, we found that individuals with obesity including those individuals with TUD, had lower rates of comorbid SUD diagnosis than individuals with TUD alone. Additionally, individuals with combined TUD and obesity, and those with TUD alone, had the highest rates of comorbid psychiatric disorder diagnosis. Conclusions: The current study aligns with previous research suggesting that obesity may reduce risk of substance use disorders, even in individuals who have other risk factors promoting harmful substance use (e.g., tobacco use). These findings may inform targeted intervention strategies for this clinically relevant subpopulation.

Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis.

We investigated the hypothesis that low-penetrance mutations in genes (TNFRSF1A, MEFV and NALP3/CIAS1) associated with hereditary periodic fever syndromes (HPFs) might be risk factors for AA amyloidosis among patients with chronic inflammatory disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Crohn's disease, undiagnosed recurrent fevers and HPFs themselves. Four of 67 patients with RA plus amyloidosis had MEFV variants compared with none of 34 RA patients without amyloid (P value=0.03). The E148Q variant of MEFV was present in two of the three patients with TNF receptor-associated periodic syndrome (TRAPS) complicated by amyloid in two separate multiplex TRAPS families containing 5 and 16 affected members respectively, and the single patient with Muckle-Wells syndrome who had amyloidosis was homozygous for this variant. The R92Q variant of TNFRSF1A was present in two of 61 JIA patients with amyloidosis, and none of 31 nonamyloidotic JIA patients. No HPF gene mutations were found in 130 healthy control subjects. Although allelic variants in HPFs genes are not major susceptibility factors for AA amyloidosis in chronic inflammatory disease, low-penetrance variants of MEFV and TNFRSF1A may have clinically significant proinflammatory effects.

Examining alcohol outcome expectancies in laboratory and naturalistic bar settings: a within-subject experimental analysis.

Using a within-subject design, this study investigated the situational-specificity hypothesis, namely that alcohol outcome expectancies (AOEs), subjective evaluations of AOEs, and the speed with which AOEs are accessed from memory vary as a function of environmental setting. Thirty-nine undergraduates (20 women), of legal drinking age, responded to the Comprehensive Effects of Alcohol questionnaire (K. Fromme, E. Stroot, & D. Kaplan, 1993) that was presented on a laptop computer in 2 counterbalanced contexts: a laboratory setting and an on-campus bar. Response latencies served as dependent measures for memory accessibility. Consistent with previous research (A.-M. Wall, S. A. McKee, & R. E. Hinson, 2000), evidence in support of the situational-specificity hypothesis was found. Specifically, environmental context influenced undergraduates' expectations concerning alcohol's effects and subjective evaluations of AOEs, as well as the speed with which specific AOEs were accessed from memory. Overall, these findings suggest the need for greater attention to situational variation in AOEs.

Joint and skin laxity with Dandy-Walker malformation and contractures: a distinct recessive syndrome?

We report the case of a girl who has joint and skin laxity with atrophic scarring, and was diagnosed at birth with a Dandy-Walker malformation. She subsequently developed joint contractures, hydrocephalus and syringomyelia. This case shows some similarities to Ehlers-Danlos syndrome type VI, but with no evidence of lysyl hydroxylase deficiency or ocular fragility. It is likely that she represents a distinct and recognizable syndrome. There was parental consanguinity and a subsequent pregnancy resulted in a similarly affected fetus, suggesting autosomal recessive inheritance.

Assessing variation in alcohol outcome expectancies across environmental context: an examination of the situational-specificity hypothesis.

Using an in vivo manipulation, this study examined whether alcohol outcome expectancies (AOEs) vary across environmental settings. Two hundred twenty-one undergraduates were randomly assigned to 1 of 4 conditions in which environmental context (an on-campus bar vs. a laboratory) and instructed phase of intoxication ("just enough to begin to feel intoxicated" vs. "too much to drink") were manipulated. AOEs were assessed with a revised version of the Effects of Alcohol Scale (L. Southwick, C. Steele, A. Marlatt, & M. Lindell, 1981). Compared with participants tested in the laboratory, individuals exposed to the on-campus bar expected greater alcohol-related stimulation/perceived dominance and pleasurable disinhibition. Women expected more behavioral impairment during the latter stage of intoxication. These findings highlight the importance of ecologically valid research in this area, as well as cue-exposure assessment and treatment approaches.

Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease.

BACKGROUND: Patients with von Hippel-Lindau disease (VHL) may develop pancreatic neuroendocrine tumors (PNETs), which can behave in a malignant fashion. We prospectively evaluated size criteria for resection of lesions and the role of genotype/phenotype analysis of germline VHL mutations in predicting clinical course. METHODS: From December 1988 through December 1999 we screened 389 patients with VHL. The diagnosis of PNET was made by pathologic analysis of tissues or by radiographic appearance. Germline mutations were determined by quantitative Southern blotting, fluorescence in situ hybridization and complete gene sequencing. RESULTS: Forty-four patients with PNETs have been identified; 25 have undergone surgical resection, 5 had metastatic disease, and 14 are being monitored. No patient who has undergone resection based on tumor size criteria has developed metastases. Patients with PNETs were more likely to have missense mutations (58%), and 4 of 5 patients (80%) with metastatic disease had mutations in exon 3 compared with 18 of 39 (46%) patients without metastatic disease. CONCLUSIONS: Imaging for detection and surgical resection based on size criteria have resulted in the successful management of VHL patients with PNETs. Analysis of germline mutations may help identify patients at risk for PNET and which patients may benefit from surgical intervention.

Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.

Inherited mutations in the E-cadherin gene ( CDH1 ) were described recently in three Maori kindreds with familial gastric cancer. Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer. Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.

Alcohol outcome expectancies, attitudes toward drinking and the theory of planned behavior.

OBJECTIVE: The present study investigated whether alcohol outcome expectancies are empirically distinguishable from attitudes toward drinking. Specifically, the contribution of expectancies and attitudes to the Theory of Planned Behavior was assessed. METHOD: Undergraduates (N = 316; 170 male), of legal drinking age, who drank at least once a month participated. Intentions to drink "too much" and self-report excessive consumption episodes served as criterion measures, and attitudes, subjective norm, perceived behavioral control and alcohol outcome expectancies were employed as predictor variables. Stepwise regression analyses were performed separately for men and women. RESULTS: The Theory of Planned Behavior appeared to be a valid framework for predicting excessive alcohol consumption among undergraduates. The predictive power of the model, however, was enhanced through the inclusion of gender-specific alcohol outcome expectancies. Specifically, in addition to attitudes and perceived behavioral control, women's expectancies for sociability enhanced the prediction of intentions to drink "too much." Expectancies for sexual functioning (male) and assertiveness (female) improved the prediction of excessive consumption, over and above intentions and perceived behavioral control. CONCLUSIONS: Alcohol outcome expectancies, unlike attitudes, are proximal predictors of excessive alcohol consumption among undergraduates.

Alcohol outcome expectancies and coping styles as predictors of alcohol use in young adults.

This study was designed to examine the pattern and strength of relationships among coping styles and alcohol outcome expectancies with regard to drinking behavior in young adult social drinkers. Quantity and frequency of weekly consumption were used as criterion measures, and alcohol outcome expectancies/valences (CEOA: Fromme, Stroot & Kaplan, 1993) and coping styles (COPE: Carver, Scheier, & Weintraub, 1989) were used as predictor variables. For males, the expectancy of risk and aggression, and the valence of cognitive and behavioral impairment, were predictive of drinking behavior. For females, sociability valence and the expectancy of negative self-evaluation positively predicted the alcohol-use measures. With regards to coping styles, alcohol and drug disengagement and suppression of competing activities uniquely predicted alcohol use in males, whereas alcohol and drug disengagement, turning to religion, and behavioral disengagement were predictive of female alcohol use. In general, coping styles were more predictive of the alcohol-use measures than were alcohol-outcome expectancies. Practical implications of these results are highlighted.

Varicella-zoster virus thymidine kinase. Characterization and substrate specificity.

The varicella-zoster virus (VZV) thymidine kinase (TK) EC 2.7.2.21) catalyzes the phosphorylation of many anti-VZV nucleosides. Purified, bacterially expressed VZV TK was characterized with regard to N-terminal amino acid sequence, pI value, pH optimum, metal ion requirement, phosphate donor and acceptor specificity, and inhibition by dTTP. Initial velocities of thymidine phosphorylation with variable MgATP concentrations fit a two-site model with apparent Km values for MgATP of 0.10 and 900 microM. dTTP was a noncompetitive inhibitor of thymidine phosphorylation but was competitive with MgATP. Phosphate donor and acceptor specificities of the bacterially expressed enzyme were indistinguishable from those of VZV TK purified from infected cells. Detailed studies of the nucleoside specificity with the bacterially expressed enzyme showed that, for a given sugar moiety, thymine nucleosides were the most efficient substrates followed by nucleosides of cytosine, uracil, adenine, and with some exceptions, guanine. For a given pyrimidine or purine (except guanine), 2'-deoxyribonucleosides were the most efficient substrates, followed by arabinosides, ribonucleosides, 2',3'-dideoxyribonucleosides, and the acyclic moiety of acyclovir.

The effect of the CS-UCS interval and extinction on place conditioning and analgesic tolerance with morphine.

In experiment 1, a CS-UCS interval study of place conditioning and analgesic tolerance with morphine was conducted. Morphine (10 mg/kg i.p.) was administered to separate groups of rats either 2 h prior to, 1 h prior to, immediately prior to, immediately after or 2 h after 30-min confinement in one end compartment of a place conditioning apparatus. A total of three choice tests was given, one after every six morphine injections. A preference for the end compartment contingent upon morphine injection was shown in groups that received morphine prior to end compartment placement. Groups that received morphine after end compartment placement were not different in their preference behavior from groups that received only saline during place conditioning training. A hot-plate test for tolerance to the analgesic effect of morphine was given at the end of all choice testing. All groups that had received morphine during place conditioning training were equally tolerant. These results indicate a dissociation between the analgesic effect of morphine and the effect that produces place preference, since the former was not affected by temporal parameters that did affect the latter. In the second experiment, the effect of extinction on a morphine-induced place preference was studied using extinction procedures that, in contrast to previous studies, equated exposure to both end compartments. Whereas the morphine-induced place preference was undiminished by a 10-day retention period in which animals received saline injections in the home cage, extinction trials during the same period eliminated the place preference. These results provide evidence that morphine-induced place preferences involve associative processes.

Cytoplasmic 5'-nucleotidase catalyzes acyclovir phosphorylation.

A cytoplasmic 5'-nucleotidase (EC 3.1.3.5) can catalyze the phosphorylation of inosine (Worku, Y., and Newby, A.C. (1982) Biochem. J. 205, 503-510). This enzyme was purified to determine whether it could catalyze the formation of trace levels of phosphorylated acyclovir (ACV), a nucleoside analog with antiherpes activity. Acyclovir phosphorylating activity from rat liver co-chromatographed with the enzyme throughout the 1200-fold purification and through size exclusion chromatography or polyacrylamide-gel electrophoresis. In addition, the pH optimum, ATP stimulation, and phosphate inhibition of the ACV phosphorylating activity paralleled those of the 5'-nucleotidase. Finally, ACV phosphorylation was competitively inhibited by inosine (Kis = 6.5 mM; K'm (inosine) = 5.0 mM). This was consistent with phosphorylation at a common catalytic site. In addition to inosine and ACV, the guanine derivatives Guo, dGuo, 9-beta-D-arabinofuranosylguanine, and 9-(1,3-dihydroxy-2-propoxymethyl)guanine were substrates for the enzyme. The relative phosphorylation rates were, respectively, 100, 0.7, 19, 4, 0.3, and 0.7, at 0.1 mM phosphate acceptor. Approximate K'm values were, respectively, 5, 90, 10, 10, greater than 100, and greater than 100 mM. Although the substrate activity of ACV with the 5'-nucleotidase was inefficient, it appeared to be sufficient to account for the small amounts of ACV phosphates formed in uninfected cells.

Orthophosphate determination in the presence of high concentrations of ATP.

A method to measure orthophosphate which contaminates samples of ATP was developed. Concentrations of orthophosphate as low as 0.4% of the ATP concentration were determined using a zinc-molybdate reagent [D. A. Bencini, J. R. Wild, and G. A. O'Donovan, Anal. Biochem. 132, 254-258 (1983)] and continuous spectrophotometric monitoring of chromophore formation. Since the rate of ATP hydrolysis was pseudo-first order and was slow compared to the rate of chromophore formation, the initial concentration of phosphate could be readily determined by extrapolation to zero time. The method is rapid and reproducible, and requires a single, stable reagent.

Altered thymidine-thymidylate kinases from strains of herpes simplex virus with modified drug sensitivities to acyclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine.

Virus-coded thymidine (dThd) kinases were purified by affinity chromatography from a parental strain (SC16) and two strains (SC16 B3 and SC16 S1) of herpes simplex virus, Type 1, with altered drug sensitivities. These latter two strains were less sensitive, respectively, to E-5-(2-bromovinyl)-2'-deoxyuridine (BrVdUrd) and to both BrVdUrd and 9-(2-hydroxyethoxymethyl)guanine (acyclovir). The enzymes were characterized with respect to physical and catalytic properties. The enzyme from SC16 B3 was very similar to the parental enzyme except in its substrate specificity and kinetic constants. It catalyzed the phosphorylation of BrVdUrd at a relative rate that was 110% of the rate with dThd versus a relative rate of 140% with the parental enzyme. The apparent Km value for BrVdUrd was 6 microM versus 0.1 microM for the parental enzyme. The reaction kinetics with acyclovir were similar for the two enzymes. The SC16 B3 enzyme catalyzed the phosphorylation of dTMP, but at only 2% the efficiency of the parental enzyme; phosphorylation of the monophosphate of BrVdUrd (BrVdUMP) was not detected with the SC16 B3 enzyme. The enzyme from the SC16 S1 variant had a much narrower phosphate acceptor specificity than the enzyme from the parental virus. BrVdUrd was a substrate but with a relative rate of 30% and an apparent Km value of 4 microM; acyclovir was neither detectably phosphorylated nor a good inhibitor. BrVdUMP was not detectably phosphorylated. The relative efficiencies of the two variant enzymes for acyclovir phosphorylation correlated well with the sensitivities of the viruses to this compound. In contrast, the relative efficiencies of the second phosphorylation step (BrVdUMP to BrVdUDP) were most consistent with the sensitivities of the viruses to BrVdUrd.

Activation and antiviral effect of acyclovir in cells infected with a varicella-like simian virus.

Acyclovir inhibited the replication of a varicella-like simian virus (DHV-1) in cell culture (Vero cells) with an ED50 of 38 +/- 2 microM. The activation of acyclovir in this cell culture system was compared with that in the cell system with human varicella zoster virus (VZV). Extracts of cells infected with DHV-1 catalyzed the phosphorylation of acyclovir. The phosphorylation was inhibited by dThd, suggesting the catalyst was a dThd kinase. Electrophoresis of cytosol fractions on polyacrylamide gels corroborated the existence of a virus-associated dThd kinase. This enzyme copurified with an acyclovir-phosphorylating activity. The enzyme catalyzed the phosphorylation of acyclovir at a greater relative rate than that with the VZV enzyme, but with a higher apparent Km value for acyclovir. The relative efficiencies for the two enzymes with acyclovir were similar. Anabolic studies with cells infected with DHV-1 and incubated with [14C]acyclovir indicated that triphosphate of acyclovir did accumulate. The results indicate that acyclovir is activated in cells infected with DHV-1 in a manner similar to that in cells infected with VZV.