Examining predictors of help-seeking behaviours in patients with mood and anxiety symptoms.

Relatively little is known about individual characteristics that factor into the decision to seek help for mood and anxiety symptoms. The current study was undertaken in order to examine factors that predict the likelihood of seeking help for mood and anxiety symptoms amongst a clinical population. Patients (N = 278) referred to a tertiary care clinic in Toronto, Canada were asked about their help-seeking behaviours (HSB) through initial intake assessments and self-administered questionnaires, including the Beck Anxiety Inventory, Anxiety Sensitivity Index, Intolerance of Uncertainty Scale, and Beck Depression Inventory-II. Correlates of anxiety and depression were examined to determine whether they could predict HSB amongst individuals with Generalized Anxiety Disorder with or without comorbid Major Depressive Disorder, as well as Panic Disorder and Social Anxiety Disorder. Psychiatric diagnoses were then examined to determine whether comorbidity and demographic factors impacted HSB. Results indicated that there were significant differences in anxiety and depression correlating mainly with anxiety sensitivity, as a predictor of HSB, and that there is a complex relationship between disorder type and demographic variables. The implications of these findings and suggested targeted interventions are discussed.

Compliance with Clostridium difficile treatment guidelines: effect on patient outcomes.

Guidelines for the severity classification and treatment of Clostridium difficile infection (CDI) were published by Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) in 2010; however, compliance and efficacy of these guidelines has not been widely investigated. This present study assessed compliance with guidelines and its effect on CDI patient outcomes as compared with before these recommendations. A retrospective study included all adult inpatients with an initial episode of CDI treated in a single academic center from January 2009 to August 2014. Patients after guideline publication were compared with patients treated in 2009-2010. Demographic, clinical, and laboratory data were collected to stratify for disease severity. Outcome measures included compliance with guidelines, mortality, length of stay (LOS), and surgical intervention for CDI. A total of 1021 patients with CDI were included. Based upon the 2010 guidelines, 42 (28·8%) of 146 patients treated in 2009 would have been considered undertreated, and treatment progressively improved over time, as inadequate treatment decreased to 10·0% (15/148 patients) in 2014 (P = 0·0005). Overall, patient outcomes with guideline-adherent treatment decreased CDI attributable mortality twofold (P = 0·006) and CDI-related LOS by 1·9 days (P = 0·0009) when compared with undertreated patients. Compliance with IDSA/SHEA guidelines was associated with a decreased risk of mortality and LOS in hospitalized patients with CDI.

Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexible-dose, open-label pilot trial.

BACKGROUND: Generalized anxiety disorder (GAD) is a chronic disorder associated with significant morbidity and disability. Traditional therapies are associated with poor levels of remission, and often result in troublesome side effects. METHODS: This was a 12-week, open-label, flexible-dose study to assess the efficacy and tolerability of quetiapine as an adjunctive treatment to traditional medication. 40 outpatients with GAD who had not achieved remission following at least 8 weeks of an adequate dose of traditional therapy were enrolled. The primary endpoint was the mean change from pre-treatment to week 12 in the Hamilton Anxiety Rating Scale (HAM-A) total scores. Secondary endpoints included: the proportion of patients achieving remission (HAM-A total score of < or =10 at week 12), Clinical Global Impressions-Severity of Illness (CGI-S), Clinical Global Impressions-Global Improvement (CGI-I), Pittsburgh Sleep Quality Index (PSQI) and Penn State Worry Questionnaire (PSWQ). RESULTS: Adjunctive quetiapine (mean dose 386mg/day at week 12) significantly reduced the HAM-A total scores from pre-treatment (29.8+/-9.0) to week 12 (9.0+/-10.2) (-20.6; p<0.001). The HAM-A remission rate was 72.1% at week 12. Adjunctive quetiapine resulted in a significant reduction in all efficacy measures by study end. Quetiapine was well tolerated: the most common adverse event (AE) was sedation, with no incidence of serious AEs and no clinically significant changes in vital signs, weight (mean gain 0.5kg at week 12) or laboratory assessments. CONCLUSION: The results of this small pilot trial suggest that quetiapine adjunctive to traditional therapy may be a useful treatment in patients with GAD or treatment-resistant GAD, and warrant further investigation.

Characteristics of bulimic patients whose parents do or do not abuse alcohol.

OBJECTIVES: This study attempts to understand the effects of a parental history of alcohol abuse on the psychopathology and symptoms of bulimia nervosa (BN). METHOD: The study involved 121 female BN patients consecutively admitted to the Eating Disorders Unit of the University Hospital of Bellvitge. The sample was divided post hoc into two subgroups on the basis of the presence (PAA, n=25) or not of parental abuse of alcohol (NPAA, n=96). All of the patients fulfilled the DSM-IV criteria for BN. EVALUATION: The assessment measures were the Eating Attitudes Test (EAT-40), the Eating Disorders Inventory (EDI), the Bulimic Investigatory Test Edinburgh (BITE), the Body Shape Questionnaire (BSQ) and Beck Depression Inventory (BDI), as well as clinical and psychopathological variables. RESULTS AND CONCLUSIONS: Only 7.4% of the patients reported current alcohol abuse and this correlated positively with the presence of other impulsive behaviours (p<0.001). Furthermore, PAA was observed in 20.7% of cases. When the PAA and NPAA subgroups were compared, no significant differences were found in the symptomatological or psychopathological variables, but the PAA group showed more frequent parental obesity (p<0.001) and its members lived less frequently with their parents (p<0.001). The results of this study suggest that there is little correlation between parental abuse of alcohol and the severity of BN.

The ventilatory response to cholecystokinin tetrapeptide in healthy volunteers.

The cholecystokinin (CCK) system, which has been shown to interact with both the panicogenic and respiratory systems, provides an interesting mechanism to further evaluate the central chemoreceptor and its effect on panic attack sensitivity. Intravenous CCK, a naturally occurring neuropeptide in the brain, has been found to induce the emotional and somatic symptoms of panic in both Panic Disorder (PD) and Normal Control (NC) subjects in a dose-dependent and reproducible fashion. To induce these effects, lower doses of intravenous CCK are required in the PD patients, relative to the NC subjects potentially suggesting that endogenous alterations in the CCK system may be contributing to the development of PD. Intravenous administration of CCK-4 in association with panic also results in subjective dyspnea, that is, diminution in vital capacity without an effect on the respiratory resistance. CCK-4 also causes a significant increase in tidal volume and minute ventilation but has no effect on breathing frequency. These observations suggest that a CCK-B receptor agonist may be acting as a respiratory stimulant, exerting its effect on anxiety through a direct effect on respiration. This study represents an examination of the specific effects of CCK-4 on the central chemoreceptor response. The study used a modified rebreathing technique, which accurately measures the ventilatory response to carbon dioxide in terms of both threshold and sensitivity. This technique requires the subject to rebreathe from a bag containing a hyperoxic and hypercapnic gas mixture resulting in rapid equilibration between alveolar gas and arterial blood. Use of a hyperoxic gas allows for the preferential examination of the central chemoreflexes (sensitive to CO(2)) with little if any effect of the peripheral (oxygen sensitive) chemoreflexes. After significant training, 15 healthy control subjects were assigned via a double blind procedure to receive an intravenous injection of placebo or CCK-4, using a between-subjects design. A between-subjects comparison was undertaken for the injection run (run #3) between subjects receiving the CCK-4 injection and those receiving the placebo injection. As well, a within-subject comparison was undertaken to compare the results of the run following the injection (run #3) vs. the previous run when no injection took place (run #2). No significant differences were noted between subjects who received CCK-4 as compared with placebo for: basal or sub-threshold ventilation, threshold CO(2) resulting in a change in ventilation, or sensitivity of the central chemoreflex, regardless of whether a panic attack did or did not take place. In addition, within the group receiving the CCK-4 challenge, no significant differences were noted during run #3 (received the CCK-4 injection) and a prior run where no injection took place (run #2). We conclude that CCK-4 does not act to induce panic by altering the central (CO(2) sensitive) chemoreceptor.

Activity of HIV-1 integrases recovered from subjects with varied rates of disease progression.

We recently described 102 HIV-1 integrase sequences that were amplified from blood cells or plasma obtained up to 18 years ago from 5 hemophiliacs who later died of AIDS and 5 hemophiliacs subsequently classified as slow or nonprogressors ( J Acquir Immune Defic Syndr Hum Retrovirol 1998;19:99-110). Although the region of the HIV-1 genome that encodes integrase was highly conserved, none of the deduced protein sequences of the patient-derived enzymes matched that of the clade B consensus or standard laboratory integrases. To test the hypothesis that the activity of HIV-1 integrases prevalent within an infected person contributes to the rate of disease progression, we have now expressed and purified these proteins and compared them in various assays. Most of the 75 unique full-length integrase proteins from the 102 clones were enzymatically active. Comparison of proteins derived from samples obtained soon after infection showed that the specificity and extent of viral DNA processing and the amount of DNA joining (the two biologically relevant activities of integrase) did not differ between the two groups of patients. In addition, the relative usage of alternative nucleophiles for processing and the amount of nonspecific nicking catalyzed by the proteins were indistinguishable between the patient groups. Although the patient-derived enzymes often exhibited different patterns of target site preferences compared with the laboratory integrase, there was no correlation with clinical course. Thus, the activities of HIV-1 integrases prevalent within these infected individuals, at least as reflected by standard assays, did not influence or predict the rate of disease progression.

Use of patient-derived human immunodeficiency virus type 1 integrases to identify a protein residue that affects target site selection.

To identify parts of retroviral integrase that interact with cellular DNA, we tested patient-derived human immunodeficiency virus type 1 (HIV-1) integrases for alterations in the choice of nonviral target DNA sites. This strategy took advantage of the genetic diversity of HIV-1, which provided 75 integrase variants that differed by a small number of amino acids. Moreover, our hypothesis that biological pressures on the choice of nonviral sites would be minimal was validated when most of the proteins that catalyzed DNA joining exhibited altered target site preferences. Comparison of the sequences of proteins with the same preferences then guided mutagenesis of a laboratory integrase. The results showed that single amino acid substitutions at one particular residue yielded the same target site patterns as naturally occurring integrases that included these substitutions. Similar results were found with DNA joining reactions conducted with Mn(2+) or with Mg(2+) and were confirmed with a nonspecific alcoholysis assay. Other amino acid changes at this position also affected target site preferences. Thus, this novel approach has identified a residue in the central domain of HIV-1 integrase that interacts with or influences interactions with cellular DNA. The data also support a model in which integrase has distinct sites for viral and cellular DNA.

Nucleophile selection for the endonuclease activities of human, ovine, and avian retroviral integrases.

Retroviral integrases catalyze four endonuclease reactions (processing, joining, disintegration, and nonspecific alcoholysis) that differ in specificity for the attacking nucleophile and target DNA sites. To assess how the two substrates of this enzyme affect each other, we performed quantitative analyses, in three retroviral systems, of the two reactions that use a variety of nucleophiles. The integrase proteins of human immuno- deficiency virus type 1, visna virus, and Rous sarcoma virus exhibited distinct preferences for water or other nucleophiles during site-specific processing of viral DNA and during nonspecific alcoholysis of nonviral DNA. Although exogenous alcohols competed with water as the nucleophile for processing, the alcohols stimulated nicking of nonviral DNA. Moreover, different nucleophiles were preferred when the various integrases acted on different DNA targets. In contrast, the nicking patterns were independent of whether integrase was catalyzing hydrolysis or alcoholysis and were not influenced by the particular exogenous alcohol. Thus, although the target DNA influenced the choice of nucleophile, the nucleophile did not affect the choice of target sites. These results indicate that interaction with target DNA is the critical step before catalysis and suggest that integrase does not reach an active conformation until target DNA has bound to the enzyme.

Mapping target site selection for the non-specific nuclease activities of retroviral integrase.

To identify the parts of retroviral integrase that interact with its DNA substrates, we compared the patterns of target site usage by chimeric enzymes and protein fragments in assays that reveal integrase's non-specific nuclease activities. The central region of 12 chimeric proteins between the human immunodeficiency virus type 1 and visna virus integrases was found to be responsible for selecting non-viral target DNA sites when small alcohols provide the attacking nucleophilic OH group during non-specific alcoholysis assays. Testing deletion derivatives of the integrase protein in this assay, which has similarities to the DNA joining reaction that occurs during retroviral integration, defined a smaller central domain that is sufficient for activity. Thus, this core domain likely contains both the host DNA site and the nucleophile site. Surprisingly, the region of integrase responsible for selecting non-viral target DNA sites when the viral DNA end is the attacking nucleophile could not similarly be mapped with the standard oligonucleotide joining assay. We therefore tested the proteins in a more sensitive assay that displays preferred sites of viral DNA insertion in a plasmid DNA target. All 12 chimeras yielded novel patterns compared with the wild-type enzymes in this assay, although local insertion patterns indicated that the central domain plays an important role in target site selection. Together, these data suggest that other protein regions must be involved when the attacking nucleophilic group is provided by viral DNA. Because specific recognition of viral DNA ends was previously mapped to the central domain, two different regions of integrase must interact with retroviral DNA.

Subterminal viral DNA nucleotides as specific recognition signals for human immunodeficiency virus type 1 and visna virus integrases under magnesium-dependent conditions.

Many reports describe the characteristics of susceptible viral DNA substrates to various retroviral integrases during in vitro reactions in which manganese serves as the divalent cation cofactor for site-specific nicking. However, manganese is known to alter the specificity of some endonucleases and magnesium may be the divalent cation used during retroviral integration in vivo. To address these concerns, we identified conditions under which the integrases of human immunodeficiency virus type 1 and visna virus were optimally active with magnesium (the first time such activity was shown for visna virus integrase) and used these conditions to test the susceptibility of a series of oligodeoxynucleotide substrates. The data show that two base pairs immediately internal to the conserved CA dinucleotide near the termini of retroviral DNA are selectively recognized by the two integrases and that the final six base pairs of viral DNA contain sufficient sequence information for specific recognition and cleavage by each enzyme. The results validate the importance of the subterminal viral DNA positions even in the presence of magnesium and identify viral DNA positions that functionally interact with integrase. The data obtained under magnesium-dependent conditions, which were obtained with substrates containing single and multiple base-pair substitutions and two different retroviral integrases, are consistent with those previously obtained with manganese. Thus, the large body of manganese-dependent data identifying terminal viral DNA positions that are important in substrate recognition by various integrases likely reflects interactions that are biologically relevant.

Seasonal affective symptoms in adults with residual attention-deficit hyperactivity disorder.

There is evidence from clinical, epidemiological, and neuroimaging studies that attention-deficit hyperactivity disorder (ADHD) and seasonal affective disorder (SAD) may have several features in common. To assess seasonal affective symptoms in adults with ADHD, 115 individuals attending an adult ADHD clinic in Toronto, Ontario, Canada were asked to complete the Seasonal Pattern Assessment Questionnaire (SPAQ). From this clinic population of 115, a total of 56 completed SPAQs were returned. Assuming that all individuals failing to complete the SPAQ were nonseasonal and depending on which case-finding criteria were used, the rate of SAD in the overall clinic sample was estimated at either 10.4% (Terman criteria) or 19.1% (criteria of Kasper et al.). These prevalence rates are significantly greater than the rates reported in large population surveys at similar latitudes. There was an apparent relationship between female gender, impulsive-subtype ADHD, and seasonality. Future studies to examine whether core symptoms of ADHD fluctuate across the seasons and to assess the efficacy of light therapy in "seasonal" ADHD patients would be of great theoretical and clinical interest.

Substrate recognition by retroviral integrases.

Substrate recognition by the retroviral IN enzyme is critical for retroviral integration. To catalyze this recombination event, IN must recognize and act on two types of substrates, viral DNA and host DNA, yet the necessary interactions exhibit markedly different degrees of specificity. Although particular sequences at the viral DNA termini are recognized by IN, many host DNA sequences can serve as the target for integration. Over the last decade, both in vitro and in vivo data have contributed to our understanding of how IN recognizes its substrates. This review provides an overview of the sequence and structure requirements for recognition of viral and host DNA by different retroviral INs and discusses recent progress in mapping protein domains involved in these interactions.

Engagement and outcome in the treatment of bulimia nervosa: first phase of a sequential design comparing motivation enhancement therapy and cognitive behavioural therapy.

Despite the major advances in the development of treatments for bulimia nervosa, drop-outs and a lack of engagement in treatment, continue to be problems. Recent studies suggest that the transtheoretical model of change may be applicable to bulimia nervosa. The aim of this study was to examine the roles of readiness to change and therapeutic alliance in determining engagement and outcome in the first phase of treatment. One hundred and twenty five consecutive female patients meeting DSM-IV criteria for bulimia nervosa took part in a randomised controlled treatment trial. The first phase of the sequential treatment compared four sessions of either cognitive behavioural therapy (CBT) or motivational enhancement therapy (MET) in engaging patients in treatment and reducing symptoms. Patients in the action stage showed greater improvement in symptoms of binge eating than did patients in the contemplation stage. Higher pretreatment scores on action were also related to the development of a better therapeutic alliance (as perceived by patients) after four weeks. However, pretreatment stage of change did not predict who dropped out of treatment. There were no differences between MET and CBT in terms of reducing bulimic symptoms or in terms of developing a therapeutic alliance or increasing readiness to change. The results suggest that the transtheoretical model of change may have some validity in the treatment of bulimia nervosa although current measures of readiness to change may require modification. Overall, readiness to change is more strongly related to improvement and the development of a therapeutic alliance than the specific type of treatment.

Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans.

The influence of single and multiple oral doses of ondansetron, a selective 5-HT3 receptor antagonist, was evaluated against placebo on cholecystokinin tetrapeptide (CCK-4)-induced behavioral and neuroendocrine changes in humans. As compared to placebo, subjects receiving acute ondansetron treatment showed a significant decrease in the sum intensity of CCK-4-induced-panic symptoms (iPSS). Pre-CCK-4 neuropeptide Y (NPY) plasma levels were significantly higher and maximal changes in cortisol, growth hormone, and prolactin secretion from baseline (delta max) were significantly lower in the ondansetron group. After ondansetron and placebo chronic administration, there were no statistical differences in the iPSS between groups. Pre-CCK-4 NPY plasma levels were significantly higher; whereas, delta max for NPY significantly lower in the ondansetron group as compared to placebo. These results suggest a role for the 5-HT3 receptor in the neurobiology of panic disorder through a possible interaction with CCK and NPY systems. Ondansetron chronic effect on CCK-4-induced behavioral changes needs further exploration.

Perfection as acculturation: psychological correlates of eating problems in Chinese male and female students living in the United States.

OBJECTIVE: The purpose of this study was to assess the relationship between acculturation, self-esteem, depression, and characteristics associated with eating disorders among Chinese university students in the United States. METHOD: A self-report questionnaire which included an acculturation scale (SL-ASIA), Center for Epidemiologic Studies of Depression (CES-D), Index of Self Esteem (ISE), and the Eating Disorders Inventory (EDI) was administered to 197 Chinese university students in the United States (93 females and 104 males). RESULTS: Highly acculturated females reported significantly higher EDI total scores, more maturity fears, and a greater sense of ineffectiveness. Males who were less acculturated also reported high ineffectiveness while high male scores on acculturation were associated with greater perfectionism. Overall, females reported more body dissatisfaction and drive for thinness, and respondents with high acculturation reported more perfectionism and interoceptive awareness. DISCUSSION: The impact of perfecting onself or one's body as a means of acculturating is discussed along with potential gender differences in perceived efficacy in a new culture.

Analysis of a large collection of natural HIV-1 integrase sequences, including those from long-term nonprogressors.

A large collection of natural HIV-1 integrase (IN) sequences has not previously been described. We reasoned that analysis of such sequences would address whether natural variation of HIV-1 IN contributes to the pathogenesis of AIDS and might also identify amino acid residues important for IN function. Sequences encoding HIV-1 IN were amplified from cryopreserved lymphocytes or plasma obtained at different times from 10 hemophilia patients who had been observed for up to 17 years. The region of the HIV-1 genome that encodes the 288-amino acid IN protein was sequenced from a total of 102 clones; information was obtained for 99.97% of 29,478 amino acid positions. Phylogenetic analysis indicated that patient samples were unique. Interpatient nucleic acid distances ranged from 0.8% to 4.9%, highlighting the tight conservation of this genomic region. No major differences were found between DNA and RNA or between early and late time points from the same patient. Significantly, no amino acid changes that might account for the variable rate of disease progression between patients were evident. Only one amino acid substitution involved a highly conserved residue known to be important for enzymatic activity. However, several interesting amino acid substitutions were noted, including residues within the C-terminal region of the protein for which sequence comparisons between animal retroviruses have not been very informative. These results should encourage the pursuit of anti-integrase therapies, especially inasmuch as the apparent biologic constraints on the IN sequence may deter the development of drug resistance.

Female or male therapists for women with eating disorders? A pilot study of experts' opinions.

OBJECTIVE: This study assessed the client and clinician characteristics associated with choosing a male or a female therapist for eating-disordered individuals. METHOD: Participants were 27 clinicians who worked in the field of eating disorders. They were asked to judge whether they would be more likely to recommend a male or a female therapist for an adolescent client presenting with eating problems, given different clinical features. RESULTS: Considering the group as a whole, the client characteristics that were associated with a preference for a female therapist included a history of paternal sexual abuse, body image issues, and an overprotective mother. The recommendation of a female therapist was more likely if the participants were older, and less likely if they were medically qualified. However, duration of experience with eating-disordered patients was not a relevant factor. DISCUSSION: Future research into the appropriateness of male or female therapists for eating-disordered clients should attend to the complex contribution of both therapists' and clients' characteristics.

Mapping viral DNA specificity to the central region of integrase by using functional human immunodeficiency virus type 1/visna virus chimeric proteins.

We previously described the construction and analysis of the first set of functional chimeric lentivirus integrases, involving exchange of the N-terminal, central, and C-terminal regions of the human immunodeficiency virus type 1 (HIV-1) and visna virus integrase (IN) proteins. Based on those results, additional HIV-1/visna virus chimeric integrases were designed and purified. Each of the chimeric enzymes was functional in at least one oligonucleotide-based IN assay. Of a total of 12 chimeric IN proteins, 3 exhibit specific viral DNA processing, 9 catalyze insertion of viral DNA ends, 12 can reverse that reaction, and 11 are active for nonspecific alcoholysis. Functional data obtained with the processing assay indicate that the central region of the protein is responsible for viral DNA specificity. Target site selection for nonspecific alcoholysis again mapped to the central domain of IN, confirming our previous data indicating that this region can position nonviral DNA for nucleophilic attack. However, the chimeric proteins created patterns of viral DNA insertion distinct from that of either wild-type IN, suggesting that interactions between regions of IN influence target site selection for viral DNA integration. The results support a new model for the functional organization of IN in which viral DNA initially binds nonspecifically to the C-terminal portion of IN but the catalytic central region of the enzyme has a prominent role both in specific recognition of viral DNA ends and in positioning the host DNA for viral DNA integration.

Chinese men and women in the United States and Hong Kong: body and self-esteem ratings as a prelude to dieting and exercise.

OBJECTIVE: The present study compared the body and weight satisfaction, self-esteem, and depression of Chinese male and female university students in Hong Kong and the United States and assessed the impact of these ratings on compensatory behavior such as dieting and exercise. METHOD: Self-report measures were administered to 501 Chinese participants in the language of their university's locale. RESULTS: Females reported significantly more body dissatisfaction and depression, and males reported greater weight dissatisfaction (the majority of men wishing to be larger). Overall, Chinese subjects in Hong Kong reported significantly more body and weight dissatisfaction, lower self-esteem, higher depression, more dieting, and less exercise as compared to their counterparts in the United States. DISCUSSION: Asian students in this study mirrored gendered patterns previously reported in Caucasian samples with respect to the relation of body image, self-esteem, and mood. For both sexes, there appeared to be a caricatured mimicking of the bodies perceived to be associated with the dominant culture--men wanted to be larger while the women wanted to be even more petite.