The carbohydrate structure of DEFB126, the major component of the cynomolgus Macaque sperm plasma membrane glycocalyx.

Based on the amino-acid sequence of the macaque epididymal secretory protein, ESP 13.2 (Q9BEE3/AJ236909), it has now been classified as beta-defensin DEFB126. DEFB126 is one of the five beta-defensins with genes that are clustered along chromosome 20pl3, and all five proteins have an extended carboxy terminus that continues beyond the 6-cysteine beta-defensin core region. This 60-amino acid carboxyl tail extension of the DEFB126 molecule is extraordinarily rich in threonine and serine (40%), many of which appear to be likely candidates for having O-glycosylation. DEFB126 has been shown to coat the entire surface of cynomolgus macaque sperm as they move through the corpus/caudal region of the epididymis. It is a major glycocalyx barrier to the external environment and is retained until the completion of capacitation. Sperm exposed to fluorescein-conjugated poly-L-lysine or Alexa488-histone showed a very uniform fluorescent labeling pattern over the entire sperm surface, almost identical to that observed with anti-DEFB126 Ig label. Sperm surface components that were released following treatment with caffeine/cAMP (in vitro capacitation) were blotted and probed with three different lectins which are known to recognize terminal sialic acid residues, and all three recognized the 35 kDa DEFB126 band. Neuraminidase treatment of sperm shifted the molecular weight of DEFB126 from 34-36 kDa to approximately 38-40 kDa and removed or greatly inhibited sialic acid-specific lectin recognition. O-Glycanase treatment alone was ineffective at removal of the oligosaccharides, but prior treatment with neuraminidase was sufficient to enable the O-glycanase treatment to effectively change the apparent molecular weight to 10 kDa, confirming that a major portion of the molecular mass is associated with the carbohydrate portion. Western blots of neuraminidase-treated DEFB126 showed strong recognition with a number of lectins that identify beta-galactose and also lectins that recognize the N-acetylgalactosamine-serine/threonine, the proposed connection site of O-glycosylation. All of the lectins that recognized DEFB126 on Western blots were used to fluorescently probe sperm. The fluorescent patterns that were observed with poly-L-lysine, Alexa488-histone, sialic acid-specific lectins, and galactose-specific lectins showed even distributions over the entire sperm surface and the patterns were identical to sperm labeled with anti-DEFB126 Ig, and all but the antibody did not recognize neuraminidase-treated sperm.

Disposition of valproic acid in a case of fatal intoxication.

The case history and toxicological findings of a fatal suicidal valproic acid overdose are presented. Valproic acid concentrations were determined in body tissues and fluids by gas-liquid chromatography (GLC) following both direct extraction and the method of standards addition and quantitative fluorescence polarization immunoassay. The quantitative results obtained by the three procedures were in good agreement. Qualitative identification of valproic acid as its methylated derivative was by ion-trap gas chromatography-mass spectrometry. Toxicological analysis by direct extraction GLC yielded the following valproate concentrations (mg/mL or mg/kg): blood, 1050; bile, 713; brain, 510; heart, 670; kidney, 1580; liver, 985; and vitreous, 516. A total of 15.1 g of valproate was recovered in the stomach contents. These findings far exceed those associated with valproate therapy and are similar to the limited valproate disposition data reported in prior fatal overdoses.

Predicting adolescent problem use of marijuana: development and testing of a Bayesian model.

This paper reports on the development and testing of a risk assessment index for problem marijuana use designed to guide teenagers through an extensive computer-based support system intended to help them improve marijuana-related behaviors. Bayesian decision theory, used as the basis of the index development process, offers the advantage of building the index on subjective judgments of experts and does not require a large empirical data base. The index was found to predict an independent panel's ratings of teenager risk, and predict the marijuana use of 10th graders using self-reports of their profiles in the 7th grade. Implications for future risk assessment developments are discussed.

Effect of axis II diagnoses on treatment outcome with clomipramine in 55 patients with obsessive-compulsive disorder.

We used the Structured Interview for DSM-III Personality Disorders to diagnose DSM-III personality disorders systematically in 55 patients with obsessive-compulsive disorder in the active-treatment cell of a controlled trial of clomipramine hydrochloride. Patients with a cluster A personality disorder had significantly higher obsessive-compulsive disorder severity scores at baseline, and the number of personality disorders was strongly related to baseline severity of obsessive-compulsive disorder symptoms. At the conclusion of the 12-week study, we found no significant difference in treatment outcome with clomipramine between those patients with at least one personality disorder and those with no personality disorders. However, the presence of schizotypal, borderline, and avoidant personality disorders, along with total number of personality disorders, did predict poorer treatment outcome. These variables were strongly related to having at least one cluster A personality disorder diagnosis, which was also a strong predictor of poorer outcome. Implications of these findings are discussed.

Psychodynamic factors in the development of drug dependence.

In this article we have brought to bear on the complex problem of substance dependency the psychodynamic perspective: a model that views the problem from the inner experience and psychological structure of the individual drug user. Chronic drug dependence has been associated with a range of personality styles and psychopathologic conditions but most frequently with character disorder and vulnerability to depression. Regardless of specific symptoms or personality styles, certain characterologic features are repeatedly observed to characterize substance-dependent individuals. These include problems in affect management, narcissism, object relations, judgment, and self-care. These developmentally and structurally determined problems generally predispose individuals to drug dependence because they are the basis of the distresses that are relieved by drug-taking; they specifically predispose to drug dependence because, in various ways, the taking of drugs and the experience of their effects are syntonic with existing modes of defense, adaptation, and self-concept. The actual vulnerability to substance dependency can vary considerably both between individuals and for the same individual at different times. For many, a necessary precipitating event involves a severe crisis in which usual adaptive capacities are diminished and narcissistic vulnerability is intense. Once drug taking is initiated in a susceptible state and the user has experienced adaptive benefit from the experience, a variety of other processes are set in motion that often lead to the state of dependency. These processes include both regressive effects that can exacerbate the original character problem and progressive effects that promote stable functioning. In both cases, however, this may interfere with further maturation of character, particularly when onset of use occurs in adolescence. Dependency involves the gradual incorporation of the drug effects and their experienced need into the defensive structure building activity of the ego itself. Undoing a dependency involves dealing with the unconscious and conscious components of this outcome. The user must be able to relinquish behaviors and drug effects that have come to be experienced as a valued (even if also hated) part of the self-capacity to function, cope, and be comforted in distress.

DSM-III psychiatric diagnosis of narcotic addicts. Recent findings.

We diagnosed and classified a diverse sample of 133 narcotic addicts using DSM-III criteria. Seventy-seven percent of the sample met criteria for one or more diagnoses on axis I, and 65% met criteria for a personality disorder on axis II. In total, 93% met the criteria for one or more psychiatric disorders other than substance abuse. Although heterogeneity of diagnosis is noted, depressions and personality disorders, often in combination, were most prominent. Several factors related to specific diagnostic groupings are analyzed and their significance for the psychopathology of narcotic addiction is discussed.

DSM-III as a research tool.

The author describes the use of the DSM-III's diagnostic criteria and classification system as a research instrument and discusses some of the advantages and drawbacks of DMS-III for a specific type of study. A rearrangement of the hierarchical order of the DSM-III diagnostic classes is suggested. This rearrangement provides for levels of certainty in analyzing interrater reliability and offers a simplified framework for summarizing group data. When this approach is combined with a structured interview and response format, it provides a flexible way of managing a large classification system for a smaller study without sacrificing standardization.

Object relations and differential treatment response to methadone maintenance.

The authors report results from a psychiatric study of narcotic addicts in which the relationship between specified aspects of object relations development and treatment response to methadone maintenance was examined. Two groups were defined as high and low drug users (in addition to the prescribed methadone dose) depending upon the frequency and intensity of additional drug use; a middle group was excluded. Thirty subjects participated. The dimensions of separation/individuation, narcissistic development, and self and object representations were measured by 12 scaled variables; scores of the high and low drug users were compared by t-test. In all cases, the high use group was found to be more impaired than the low use group. However, the dimensions differed greatly in their ability to differentiate the groups. The strongest group differences were found in the area of narcissistic development, with the high user group significantly more impaired than the low user group. The strength of these findings lends empirical support to the notion that an addict population can be differentiated on diagnostic and ego psychological measures. This has important implications for methadone maintenance treatment programs, and, possibly, for drug programs in general.

DSM-III personality type and dose levels in methadone maintenance patients.

The authors report results from a psychiatric study of narcotic addicts using diagnostic criteria from DSM-III and other clinical data. Evidence is presented for a strong relationship between personality disorder and methadone dose, in which patients with schizoid-like disorders had significantly higher stabilization doses than patients with other types of diagnoses. The treatment implications of individual differences in drug and personality interaction are noted, and the findings are discussed in terms of a psychodynamic understanding of addiction.