Bt toxin resistance from loss of a putative carbohydrate-modifying enzyme.

The development of resistance is the main threat to the long-term use of toxins from Bacillus thuringiensis (Bt) in transgenic plants. Here we report the cloning of a Bt toxin resistance gene, Caenorhabditis elegans bre-5, which encodes a putative beta-1,3-galactosyltransferase. Lack of bre-5 in the intestine led to resistance to the Bt toxin Cry5B. Wild-type but not bre-5 mutant animals were found to uptake toxin into their gut cells, consistent with bre-5 mutants lacking toxin-binding sites on their apical gut. bre-5 mutants displayed resistance to Cry14A, a Bt toxin lethal to both nematodes and insects; this indicates that resistance by loss of carbohydrate modification is relevant to multiple Bt toxins.

Familial relationship between mood disorders and alcoholism.

Clinical and epidemiological studies have consistently revealed an association between alcohol use disorders and both bipolar and nonbipolar mood disorders. However, the evidence regarding the nature of these associations is unclear. The familial patterns of alcohol and affective disorders were examined using data from a controlled family study of probands with alcohol and anxiety disorders who were sampled from treatment settings and the community. The substantial degree of comorbidity between mood and anxiety disorders among probands allowed for the examination of comorbidity and familial aggregation of alcohol and mood disorders. The major findings are that (1) alcoholism was associated with bipolar and nonbipolar mood disorders in the relatives; (2) there was a strong degree of familial aggregation of alcohol dependence and both types of mood disorders were observed; and (3) there was no evidence of cross-aggregation (i.e., increase in mood disorders among probands with alcohol dependence, and vice versa) between alcoholism and mood disorders. The independent familial aggregation of bipolar disorder and alcoholism and the finding that the onset of bipolar disorder tended to precede that of alcoholism are compatible with a self-medication hypothesis as the explanation for the frequent co-occurrence of these disorders. In contrast, the independent familial aggregation and the tendency of an earlier onset of alcoholism than that of nonbipolar depression suggest that unipolar mood disorders are frequently secondary to alcoholism.

A quantitative assay for the non-covalent association between apolipoprotein[a] and apolipoprotein B: an alternative measure of Lp[a] assembly.

Increasing evidence suggests that the assembly of lipoprotein[a] (Lp[a]) proceeds in two steps. In the first step, non-covalent interactions between apolipoprotein[a] (apo[a]) and apolipoprotein B (apoB) of low density lipoprotein (LDL) form a dissociable apo[a]:LDL complex. In the second step, a covalent disulfide linkage forms the stable Lp[a] particle. Several methods are currently used to study the assembly of Lp[a], however, these methods are laborious, time-consuming, and not suitable for a high throughput screening. We report here the development of a rapid and simple assay based on the binding of labeled LDL to a Lp[a]/apo[a] substrate which is immobilized on the surface of a microtiter plate. Quantification of bound LDL provides a measure of the extent of complex formation. Labeled LDL bound to both Lp[a] and apo[a] substrates with similar affinity. Plasma lipoproteins containing apoB as well as free apo[a] were capable of competing with LDL binding. The binding of LDL to Lp[a]/apo[a] was inhibited by L-proline and lysine analogs, which are known to inhibit the non-covalent association between apo[a] and apoB. Using this method we have found that nicotinic acid and captopril are able to inhibit the association of apo[a] with apoB. This method is compatible with automation and can be applied to a high throughput screening of inhibitors of Lp[a] formation.

Familial transmission of substance use disorders.

BACKGROUND: There is increasing evidence that substance use disorders are familial and that genetic factors explain a substantial degree of their familial aggregation. To perform a controlled family study of probands with several different predominant drugs of abuse, including opioids, cocaine, cannabis, and/or alcohol. METHODS: The subjects for the present study included 231 probands with dependence on opioids, cocaine, cannabis, and/or alcohol and 61 control probands, and their 1267 adult first-degree relatives. Diagnostic estimates were based on semistructured diagnostic interviews and/or structured family history interviews regarding each proband, spouse, and adult first-degree relative. The interview data were reviewed blindly and independently by clinicians with extensive experience in the evaluation and treatment of substance use disorders. RESULTS: There was an 8-fold increased risk of drug disorders among the relatives of probands with drug disorders across a wide range of specific substances, including opioids, cocaine, cannabis, and alcohol, which is largely independent from the familial aggregation of both alcoholism and antisocial personality disorder. There was also evidence of specificity of familial aggregation of the predominant drug of abuse. CONCLUSIONS: Elevation in risk of this magnitude places a family history of drug disorder as one of the most potent risk factors for the development of drug disorders. These results suggest that there may be risk factors that are specific to particular classes of drugs as well as risk factors that underlie substance disorders in general.

Co-morbidity and familial aggregation of alcoholism and anxiety disorders.

BACKGROUND: This study examined the patterns of familial aggregation and co-morbidity of alcoholism and anxiety disorders in the relatives of 165 probands selected for alcoholism and/or anxiety disorders compared to those of 61 unaffected controls. METHODS: Probands were either selected from treatment settings or at random from the community. DSM-III-R diagnoses were obtained for all probands and their 1053 first-degree relatives, based on direct interview or family history information. RESULTS: The findings indicate that: (1) alcoholism was associated with anxiety disorders in the relatives, particularly among females; (2) both alcoholism and anxiety disorders were highly familial; (3) the familial aggregation of alcoholism was attributable to alcohol dependence rather than to alcohol abuse, particularly among male relatives; and (4) the the pattern of co-aggregation of alcohol dependence and anxiety disorders in families differed according to the subtype of anxiety disorder; there was evidence of a partly shared diathesis underlying panic and alcoholism, whereas social phobia and alcoholism tended to aggregate independently. CONCLUSIONS: The finding that the onset of social phobia tended to precede that of alcoholism, when taken together with the independence of familial aggregation of social phobia and alcoholism support a self-medication hypothesis as the explanation for the co-occurrence of social phobia and alcoholism. In contrast, the lack of a systematic pattern in the order of onset of panic and alcoholism among subjects with both disorders as well as evidence for shared underlying familial risk factors suggests that co-morbidity between panic disorder and alcoholism is not a consequence of self-medication of panic symptoms. The results of this study emphasize the importance of examining co-morbid disorders and subtypes thereof in identifying sources of heterogeneity in the pathogenesis of alcoholism.

Comorbidity of migraine and psychiatric disorders.

This article reviews the evidence for comorbidity of migraine with psychiatric disorders, particularly the affective and anxiety disorders. Studies of the association between migraine and depression in both clinical and community studies have provided consistent evidence regarding a substantial degree of comorbidity between these disorders, regardless of the index disorder for which the subject sought treatment in the clinical settings. Methodologic issues, possible mechanisms, and implications of comorbidity for clinical practice and future research are discussed.

Substance abuse, comorbidity, and sensation seeking: gender differences.

Two hundred sixty-two probands and 261 of their relatives with DSM-III-R diagnoses of drug and alcohol abuse and/or anxiety disorders completed the Zuckerman Sensation Seeking Scale. It was hypothesised that subjects with both substance abuse disorders and comorbid anxiety disorders would have lower sensation-seeking profiles than subjects with substance abuse alone. This was confirmed in women, with thrill- and adventure-seeking scores showing significant differences between pure substance abusers and those with a comorbid anxiety disorder, lending support to theories that substance abusers are a heterogeneous group. In men, there were fewer significant differences between diagnostic groups. If substance abusers are indeed a heterogeneous group, with some motivated by high sensation-seeking needs, a better understanding of these motivations can lead to more effective strategies of prevention and treatment, according to etiology.

Tyramine conjugation deficit in migraine, tension-type headache, and depression.

This study was designed to investigate tyramine sulfate conjugation in patients with migraine or tension-type headache, as defined by the newly introduced International Headache Society (IHS) criteria and to examine whether this relationship is mediated by major depression. A total of 62 subjects completed the study: 38 with migraine (22 with aura and 16 without aura), 12 with tension-type headache, and 12 controls. Patients with migraine had significantly lower urinary tyramine sulfate excretion following oral tyramine challenge than normal control. Tension-type headache was also associated with low tyramine conjugation, but only when comorbid with depression. Although mean tyramine sulfate output was lower among subjects with major depression within each of the subtypes of headache, no significant main effect emerged for depression or major subtype thereof. The lower tyramine sulfate excretion values among patients with both migraine and depression compared to those of migraine alone or depression alone in our data and those of others suggests that comorbid migraine with depression may represent a more severe form of migraine than migraine alone. The findings underscore the importance of comorbidity in clinical and epidemiological studies of migraine.

Psychopathology and headache syndromes in the community.

The present study investigated the association between psychopathology and headache in a prospective longitudinal epidemiologic study of a cohort of 19- and 20-year-olds in Zurich, Switzerland. Prevalence rates of psychopathology by headache subtype were examined both cross-sectionally and longitudinally. Psychiatric disorders were evaluated using a direct interview administered by experienced clinicians. Personality was assessed using the Freiburg Personality Inventory and the Symptom Checklist 90. In general, subjects with migraine had more affective and anxiety disorders and exhibited elevated rates of neuroticism and somatization compared to nonmigraine subjects. When examined by headache subtype, migraineurs with aura exhibited greater rates of psychopathology and more personality abnormalities than any of the other headache subtypes or controls. In contrast to clinical wisdom, subjects with tension-type headache did not differ from controls in rates of psychopathology or on any of the personality or symptom factors.

Headache and personality: results of a community sample of young adults.

The present study investigated the association between personality, symptoms and headache subtypes in a prospective longitudinal epidemiologic study of a cohort of 19- and 20-year-olds in Zurich, Switzerland. Personality was assessed by the Freiburg Personality Inventory (FPI), a standardized self-report personality instrument, which yields nine primary factors and three secondary factors. The Symptom Checklist 90 (SCL-90) was employed to examine somatic and psychological symptoms. Subjects with migraine exhibited elevated rates of neuroticism compared to non-migraine subjects on FPI. Somatization was the only primary symptom factor on the SCL-90 which discriminated between subjects with migraine and those without migraine. Persons with migraine with aura exhibited greater impairment than any of the other headache subtypes or controls on both the FPI and SCL-90. Subjects with tension-type headache did not differ from controls on any of the personality or symptom factors.