Human papillomavirus (HPV) status of non-tobacco related squamous cell carcinomas of the lateral tongue.

OBJECTIVES: The human papillomavirus (HPV) is an important cause of some head and neck squamous cell carcinomas (HNSCCs), but its role in cancer of the lateral tongue is debatable. Suspicion of HPV causation is heightened when these lateral tongue carcinomas arise in patients that are young and/or have never smoked. The purpose of this study was to determine the incidence of transcriptionally active high risk HPV in these tumors, with a particular emphasis on non-smoking patients who are often presumed to have HPV-positive tumors. METHODS: We evaluated 78 HNSCCs of the lateral tongue for the presence of HPV using p16 immunohistochemistry and an RNA in situ hybridization assay targeting HPV E6/E7 mRNA. The study population was enriched for patients without traditional risk factors such as smoking and drinking. RESULTS: P16 overexpression was detected in 9 (11.5%) of 78 cases, but HPV E6/E7 mRNA transcripts were detected in only 1 (1.3%) case (positive predictive value of p16 staining for the presence of transcriptionally active HPV=0.12). HPV mRNA transcripts were not detected in any patient under 40 (n=11), or in patients who had never smoked (n=44), had quit smoking (n=15), and/or were only light consumers of alcohol (n=57). CONCLUSIONS: HPV is not detected in the vast majority of lateral tongue carcinomas. In light of the observation that HPV plays little if any role in the development of these cancers, routine HPV testing is unwarranted , even for patients without traditional risk factors. P16 staining is not a reliable marker for the presence of transcriptionally active HPV at this particular anatomic site.

Myocardial metabolic monitoring with the microdialysis technique during and after open heart surgery.

BACKGROUND: Post-operative ischemia after coronary artery bypass grafting (CABG) is well described but effective intervention requires immediate diagnosis. One possible way of increasing efficacy of peri-operative myocardial monitoring is using the microdialysis technique. METHODS: In 30 patients undergoing routine CABG, a microdialysis catheter was inserted in the left heart in an area of abnormal ventricular contraction. A second catheter was placed in normal tissue of the right ventricle. Microdialysis measurements were performed at time intervals before, during and 24 h after cardiopulmonary bypass (CPB) and retrospectively compared with standard clinical monitoring and clinical course. RESULTS: During CPB, both ventricles showed signs of poor tissue oxygenation. Glycerol was significantly higher in the left myocardium (146 +/- 67 vs. 72 +/- 36 micromol/l) and the glucose/lactate ratio (GLR), as a marker of nutritional disorder of the right ventricle (41 +/- 15% vs. 67 +/- 17%, P < 0.05), had significantly better values at this time point. Myocardial lactate concentrations were significantly higher in the dyskinetic segments (2.82 +/- 0.81 vs. 1.5 +/- 0.81 microM). During this period, no abnormal clinical standard monitoring results were observed. Post-operative significantly increased lactate/pyruvate ratios of three patients were clinically associated with peri-operative myocardial infarction (108 +/- 67 vs. 38 +/- 9, P < 0.05). The lactate/pyruvate ratio started rising before any other standard monitoring tools showed abnormal values. CONCLUSIONS: Peri-operative microdialytic measurements of parameters related to ischemia can be safely performed in a clinical setting, resulting in faster and more reliable detection of ongoing or new ischemia.

Clonidine and yohimbine in opioid-dependent humans responding under a naloxone novel-response discrimination procedure.

Opioid-maintained volunteers were trained to distinguish between a low dose of the opioid antagonist naloxone (0.15 mg/70 kg, i.m.; i.e. Drug A) and placebo (i.e. Drug B), under an instructed novel-response drug discrimination procedure in which subjects identify the drug condition as 'A', 'B', or 'N' (neither A nor B - 'novel'). Once the discrimination was acquired, doses of naloxone, the alpha2-adrenergic antagonist yohimbine, the alpha2-adrenergic agonist clonidine, and the training dose of naloxone in combination with clonidine were tested. Naloxone and yohimbine each produced a dose-related increase and decrease in naloxone- and 'novel'-appropriate responding, respectively, with the naloxone stimulus partially generalizing to yohimbine. Clonidine produced primarily placebo-appropriate responding. Naloxone produced expected changes in self-reports, but effects of yohimbine and clonidine were unremarkable, and yohimbine was never identified as an opioid antagonist. Clonidine partially attenuated naloxone-occasioned responding in a non-dose-related manner, and attenuated some, but not all, naloxone-induced changes in self-report measures. Naloxone attenuated or enhanced several clonidine-induced changes in self-report and physiological measures. These findings indicate that adrenergic mechanisms are involved in the expression of opioid withdrawal, but the involvement is indirect.

Personality and substance use disorders as predictors of criminality.

The study objective was to evaluate the relationship between a personality disorder (PD) diagnosis and criminal behavior among drug- and alcohol-dependent patients both retrospectively and prospectively. We examined 1-year pretreatment and 1-year post-treatment crime rates among 370 drug- and/or alcohol-dependent patients. Hierarchical logistic regression was used to examine the predictive value of DSM-III-R PD diagnoses after controlling for demographic features and type and severity of substance dependence. Patients with a diagnosis of antisocial PD (ASPD) were more likely to report having committed a variety of crimes, including violent crimes, during the pretreatment period. Individuals with more PD diagnoses or a diagnosis of borderline PD (BPD) or schizoid PD also reported a greater number of pretreatment violent crimes. In addition, the number of PD diagnoses was correlated with the number of crimes against property. During the pretreatment period, significant interactions were also found between PD measures and substance use in relation to both property crimes and violation of parole or probation. During the posttreatment period, a diagnosis of BPD predicted the commission of violent crimes. In contrast, a cluster A PD predicted a lower frequency of crimes against property. ASPD did not predict criminality during the 1-year follow-up period. In conclusion, a PD diagnosis, particularly ASPD, was associated with a variety of criminal behaviors during the 1-year period preceding substance abuse treatment. Following treatment, PD diagnosis had limited value in the prediction of criminal behavior. Possible explanations for these findings are discussed.

Co-occurrence of Axis I and Axis II disorders in substance abusers.

OBJECTIVE: This study examined the co-occurrence of anxiety/mood and personality disorders (PDs) in substance abusers, the impact of anxiety/ mood disorders on the symptom profiles of PDs, and the impact of anxiety/mood disorders and PDs on pre-treatment status. METHOD: Current anxiety/mood disorders and PDs and pre-treatment status were assessed using semi-structured interviews in 370 treated substance abusers. RESULTS: Anxiety/mood disorders and PDs frequently co-occurred, with the overall pattern of associations being non-specific. The strongest associations were of social phobia with avoidant and schizotypal PD, and of major depression with borderline PD. However, symptom profiles of PDs were not associated with anxiety/mood disorders. Finally, anxiety/mood disorders and PDs were both independently and differentially associated with poor pre-treatment characteristics. CONCLUSION: The findings suggest the clinical importance of obtaining both Axis I and Axis II diagnoses in treated substance abusers, and highlight the distinctiveness of the Axis I and Axis II disorders.

Axis I and Axis II disorders in alcoholics and drug addicts: fact or artifact?

OBJECTIVE: It has been argued that Axis I and Axis II disorders diagnosed in substance users refer to substance-induced conditions rather than to independent psychiatric conditions; this argument will be referred to as the substance-related artifact hypothesis. Furthermore, Axis II symptoms co-occurring with Axis I disorders have been attributed to the contamination of personality assessment by mood and/or anxiety state effects (the trait-state artifact hypothesis). The present study is the first to prospectively examine the validity of these two hypothesized "artifacts" in substance users. METHOD: In 276 individuals (57.6% female) applying for substance use treatment, current substance use disorders, mood/anxiety disorders and Axis II disorders were diagnosed using semistructured interviews both at baseline and at 1-year follow-up. The substance-related artifact hypothesis is tested by examining the covariation between recovery from substance use disorders on the one hand and recovery from and/or improvement of mood/anxiety and Axis II disorders on the other hand. The trait-state artifact hypothesis is tested by examining the covariation between recovery from mood/anxiety disorders on the one hand and recovery from and/or improvement of Axis II disorders on the other hand. RESULTS: Recovery from substance use disorders covaried with recovery from and improvement of mood/anxiety disorders, but not with recovery from or improvement of Axis II pathology. Furthermore, recovery from mood/anxiety disorders covaried with recovery from and improvement of personality disorders, in particular Cluster C disorders. CONCLUSIONS: Results from this study suggest that mood/anxiety disorders, but not personality disorders, diagnosed among people with substance use disorder may partly reflect substance-related artifacts. Furthermore, this study provides evidence for the contention that semistructured interview assessment of Axis II, at least without inquiry on an item-by-item basis, is susceptible to contamination by mood/anxiety state effects.

Rates of personality disorders in substance abusers: a comparison between DSM-III-R and DSM-IV.

The publication of the DSM-IV represents the first revision in 7 years to the DSM-III-R diagnostic criteria. The purpose of the current study is to evaluate the impact of changes to the Axis II criteria on diagnostic rates in a substance abusing population. We interviewed 370 patients entering treatment using a modified version of the SCID-II, which allowed for the diagnosis of both DSM-III-R and DSM-IV Axis II diagnoses. Prevalence rates for each Axis II disorder are given, as well as kappa statistics showing diagnostic agreement between the two systems. The results of this study indicate good rates of diagnostic agreement between the two systems with a few notable exceptions. Poor rates of diagnostic agreement were obtained for the histrionic and dependent diagnostic categories. No single diagnostic change appears to be responsible for the prevalence rate differences between the two systems.

Personality disorder and dimension differences between type A and type B substance abusers.

Substance abuse subtype differences in DSM-IV personality disorders and normal personality dimensions were evaluated in 370 inpatient and outpatient alcohol, cocaine, and opiate abusers. The Type A/Type B distinction was replicated, with Type B substance abusers exhibiting more premorbid risk factors, more severe substance abuse, and greater psychosocial impairment. As predicted, compared to Type A, Type B were more commonly diagnosed with, and had more severe symptoms of, all personality disorders except Schizoid. With regard to normal personality dimensions, Type B scored higher on neuroticism, novelty seeking, and harm avoidance; Type A scored higher on agreeableness, conscientiousness, cooperativeness, and self-directedness. These subtype differences remained after controlling for the effects of antisocial personality and psychiatric symptoms.

Personality disorders in substance abusers: relation to substance use.

Previous studies have documented high but variable rates of DSM personality disorders (axis II) in clinical samples of substance abusers. Distinguishing between personality disorder symptoms that are independent versus substance-related (SR) is a particular challenge for diagnosing comorbid axis II disorders in substance abusers. DSM-IV guidelines currently recommend excluding axis II symptoms that are accounted for by an axis I disorder, including a substance use disorder. In this study, axis II diagnoses were made on a heterogenous clinical sample of 370 patients entering treatment for substance use disorders. Axis II diagnoses were made according to DSM-III-R criteria using the Structured Clinical Interview for DSM-III-R (SCID-II), which was modified to determine, on an item-by-item basis, whether symptoms were attributed to subjects' substance use disorders or independent of these disorders. The majority (57.0%) of substance use disorder patients met criteria for at least one comorbid axis II disorder, with cluster B (45.7%) being particularly prominent, especially antisocial personality disorder (ASP) (27.0%) and borderline personality disorder (BPD) (18.4%). Notably, inclusion of SR symptoms led to a substantial number of newly diagnosed cases, especially for ASP (19.2%) and BPD (11.4%). Including SR symptoms improved the reliability of ASP and did not change the reliability of BPD diagnoses. Generally, patients with SR and independent personality disorders had a similar clinical profile.

Personality, temperament, and character dimensions and the DSM-IV personality disorders in substance abusers.

The authors evaluated the relationship between P. T. Costa and R. R. McCrae's (1992) NEO 5-factor model, C. R. Cloninger's (1993) 7-factor Temperament and Character Inventory (TCI), and the American Psychiatric Association's (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th ed., personality disorders in 370 inpatient and outpatient alcohol, cocaine, and opiate abusers. NEO Neuroticism was associated with many disorders, and different patterns for Agreeableness, Conscientiousness, and Extraversion emerged for the different disorders. Several TCI scales were associated with different personality disorders, although not as strongly as the NEO dimensions. Results did not support most predictions made for the TCI. Normal personality dimensions contributed significantly to the prediction of personality disorder severity above and beyond substance abuse and depression symptoms.

Docosahexaenoic acid block of neuronal voltage-gated K+ channels: subunit selective antagonism by zinc.

The omega-3 polyunsaturated fatty acid docosahexaenoic acid is highly enriched in neuronal membranes, and several studies suggest that DHA is critical for neuronal development. We have investigated the effects of exogenously applied DHA on voltage-gated K+ channels using patch-clamp techniques. DHA produced a concentration-dependent inhibition of the sustained outward current in isolated neocortical neurons. This blocking action was examined in more detail with two cloned neuronal K+ channels (Kv1.2 and Kv3.1a) expressed in mammalian fibroblasts. DHA produced a potent inhibition of depolarization-activated K+ currents from cells expressing these channels (Kd values, 1.8 +/- 0.1 muM and 690 +/- 60 nM, for Kv1.2 and Kv3.1a, respectively, at +40 mV). The DHA block of both channel types was rapidly reversed (approximately 2 sec) by bovine serum albumin, which binds the fatty acid. Micromolar concentrations of extracellular Zn2+ non-competitively antagonized DHA inhibition of Kv1.2 channels, whereas there was little effect on DHA block of Kv3.1a channels. Experiments with membrane patches from Kv1.2 transfected cells demonstrated that the DHA block occurred from the outside, suggesting that the fatty acid interacts directly with an external domain of the ion channel. DHA may serve as a local messenger molecule that selectively modulates the activity of certain voltage-gated K+ channels in a Zn2(+)-dependent fashion.

Anandamide, an endogenous cannabinoid, inhibits Shaker-related voltage-gated K+ channels.

Anandamide has been identified in porcine brain as an endogenous cannabinoid receptor ligand and is believed to be a counterpart to the psychoactive component of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC). Here we report that anandamide directly inhibits (IC50, 2.7 muM) Shaker-related Kv1.2 K+ channels that are found ubiquitously in the mammalian brain. Delta 9-THC also inhibited Kv1.2 channels with comparable potency (IC50, 2.4 muM), as did several N-acyl-ethanolamides with cannabinoid receptor binding activity. Potassium current inhibition occurred through a pertussis toxin-insensitive mechanism and was not prevented by the cannabinoid receptor antagonist SR141716A. Utilizing excised patches of Kv1.2 channel-rich membrane as a rapid and sensitive bioassay, we found that phospholipase D stimulated the release of an endogenous anandamide-like K+ channel blocker from rat brain slices. Structure-activity studies were consistent with the possibility that the released blocker was either anandamide or another N-acyl-ethanolamide.

Time- and voltage-dependent block of delayed rectifier potassium channels by docosahexaenoic acid.

Docosahexaenoic acid (22:6n3) acts at an extracellular site to produce a voltage- and time-dependent block of the delayed rectifier current (IK) similar to that classically described for intracellularly applied quaternary ammonia compounds. In dissociated cells from the pineal gland, some long-chain polyunsaturated fatty acids reduced both late sustained (IK) (for 22:6n3, IC50 = 2.5 +/- 0.3 microM) and early transient (IA) (IC50 = 2.0 +/- 0.1 microM) components of potassium current when applied extracellularly, whereas the monounsaturate oleic acid had minimal efficacy. From comparisons of other related fatty acids, it was determined that there is a structural requirement for polyunsaturation to block IK. In contrast, chain-elongated 22-carbon polyunsaturates acted similarly to their precursor 20-carbon fatty acids (arachidonic acid and eicosapentanoic acid). Block of IK by 22:6n3 was accompanied by a dose-dependent acceleration of the current decay in both whole-cell and outside-out membrane patches, and 22:6n3 increased the macroscopic inactivation rate of IA. The combined "eicosanoid" inhibitor eicosatetraenoic acid, when included in the patch pipette, did not antagonize the action of 22:6n3. Instead, eicosatetraenoic acid produced a direct block of IK when applied extracellularly at high concentrations (25 microM). Analyses of voltage- and time-dependent block by 22:6n3 support the hypothesis that certain fatty acids directly interact with and preferentially block the open state of some potassium channels. We also describe an interaction between fatty acid block and zinc; 22:6n3 failed to block either IA or IK in the presence of zinc or cadmium, whereas extracellular calcium did not affect the response. These studies suggest a possible biological function for 22:6n3 in the nervous system, which may underlie its essential role during neural development.

Using computers to enhance operational efficiency.

Computerization is not a simple process. It requires management's involvement and an understanding that long-term benefits should outweigh the short-term inconvenience. The agency is key to maximizing the benefits of the computerization process. Seldom does the reduction of office staff salaries make the system acquisition cost beneficial. Improved operational efficiency, increased cash flow, and availability of information represent the cost benefits of the installation. Cost benefits are maximized by seizing the opportunity to improve all systems and procedures.