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1.  The psmα Locus Regulates Production of Staphylococcus aureus Alpha-Toxin during Infection 
Infection and Immunity  2014;82(8):3350-3358.
Staphylococcus aureus is a leading cause of human bacterial infection, causing a wide spectrum of disease ranging from skin and soft tissue infections to life-threatening pneumonia and sepsis. S. aureus toxins play an essential role in disease pathogenesis, contributing to both immunomodulation and host tissue injury. Prominent among these toxins are the membrane-active pore-forming cytolysin alpha-toxin (Hla) and the amphipathic α-helical phenol-soluble modulin (PSM) peptides. As deletion of either the hla or psm locus leads to a phenotypically similar virulence defect in skin and soft tissue infection, we sought to determine the relative contribution of each locus to disease pathogenesis. Here we show that production of Hla can be modulated by PSM expression. An S. aureus mutant lacking PSM expression exhibits a transcriptional delay in hla mRNA production and therefore fails to secrete normal levels of Hla at early phases of growth. This leads to attenuation of virulence in vitro and in murine skin and lung models of infection, correlating with reduced recovery of Hla from host tissues. Production of Hla and restoration of staphylococcal virulence can be achieved in the psm mutant by plasmid-driven overexpression of hla. Our study suggests the coordinated action of Hla and PSMs in host tissue during early pathogenesis, confirming a major role for Hla in epithelial injury during S. aureus infection. These findings highlight the possibility that therapeutics targeting PSM production may simultaneously prevent Hla-mediated tissue injury.
doi:10.1128/IAI.00089-14
PMCID: PMC4136214  PMID: 24866799
2.  Accessibility and Affordability of Alcohol Dependency Medical Care in Serbia 
doi:10.3389/fpsyt.2014.00192
PMCID: PMC4290475  PMID: 25628574
alcohol; dependency; addiction; affordability; economics; medical care; Serbia; access
3.  Evolution of community- and healthcare-associated methicillin-resistant Staphylococcus aureus☆ 
Staphylococcus aureus is a prominent cause of human infections globally. The high prevalence of infections is compounded by antibiotic resistance—a significant problem for treatment. Methicillin-resistant S. aureus (MRSA) is endemic in hospitals and healthcare facilities worldwide, and is an increasingly common cause of community-associated bacterial infections in industrialized countries. Although much focus is placed on the role of S. aureus as a human pathogen, it is in fact a human commensal organism that has had a relatively long coexistence with the human host. Many S. aureus infections can be explained by host susceptibility or other predisposing risk factors. On the other hand, the emergence/re-emergence of successful S. aureus clones (referred to as epidemic waves) suggests a rapid bacterial adaption and evolution, which includes the emergence of antibiotic resistance and increased virulence and/or transmissibility. It is within this context that we review our understanding of selected S. aureus epidemic waves, and highlight the use of genome sequencing as a means to better understand the evolution of each lineage.
doi:10.1016/j.meegid.2013.04.030
PMCID: PMC3884050  PMID: 23648426
Staphylococcus aureus; MRSA; Epidemic; Genome sequencing; Antimicrobial resistance
4.  A Spaetzle-like role for Nerve Growth Factor β in vertebrate immunity to Staphylococcus aureus 
Science (New York, N.Y.)  2014;346(6209):641-646.
Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, Nerve Growth Factor β (NGFβ), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFβ or its high-affinity receptor TRKA were associated with severe S. aureus infections. NGFβ was released by macrophages in response to S. aureus exoproteins through activation of NLRP3 and NLRP4, and enhanced phagocytosis and superoxide-dependent killing, stimulated pro-inflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFβ-TRKA signaling in pathogen-specific host immunity.
doi:10.1126/science.1258705
PMCID: PMC4255479  PMID: 25359976
5.  D-Cycloserine Augmentation of Cognitive Behavioral Group Therapy of Social Anxiety Disorder: Prognostic and Prescriptive Variables 
Objective
The aim of the current study was to identify individual characteristics that (1) predict symptom improvement with group cognitive behavioral therapy (CBT) for social anxiety disorder (SAD; i.e., prognostic variables) or (2) moderate the effects of d-cycloserine vs. placebo augmentation of CBT for SAD (i.e., prescriptive variables).
Method
Adults with SAD (N=169) provided Liebowitz Social Anxiety Scale (LSAS) scores in a trial evaluating DCS augmentation of group CBT. Rate of symptom improvement during therapy and posttreatment symptom severity were evaluated using multilevel modeling. As predictors of these two parameters, we selected the range of variables assessed at baseline (demographic characteristics, clinical characteristics, personality traits). Using step-wise analyses, we first identified prognostic and prescriptive variables within each of these domains and then entered these significant predictors simultaneously in one final model.
Results
African American ethnicity and cohabitation status were associated with greater overall rates of improvement during therapy and lower posttreatment severity. Higher initial severity was associated with a greater improvement during therapy, but also higher posttreatment severity (the greater improvement was not enough to overcome the initial higher severity). D-cycloserine augmentation was evident only among individuals low in conscientiousness and high in agreeableness.
Conclusions
African American ethnicity, cohabitation status, and initial severity are prognostic of favorable CBT outcomes in SAD. D-cycloserine augmentation appears particularly useful for patients low in conscientiousness and high in agreeableness. These findings can guide clinicians in making decisions about treatment strategies and can help direct research on the mechanisms of these treatments.
doi:10.1037/a0034120
PMCID: PMC4241751  PMID: 23937345
Cognitive-behavioral therapy; d-cycloserine; CBT; social anxiety disorder; social phobia; randomized controlled trial; predictors; moderators; personality traits
6.  Seasonal H3N2 influenza A virus fails to enhance Staphylococcus aureus co-infection in a non-human primate respiratory tract infection model 
Virulence  2013;4(8):707-715.
Staphylococcus aureus community-acquired pneumonia is often associated with influenza or an influenza-like syndrome. Morbidity and mortality due to methicillin-resistant S. aureus (MRSA) or influenza and pneumonia, which includes bacterial co-infection, are among the top causes of death by infectious diseases in the United States. We developed a non-lethal influenza A virus (IAV) (H3N2)/S. aureus co-infection model in cynomolgus macaques (Macaca fascicularis) to test the hypothesis that seasonal IAV infection predisposes non-human primates to severe S. aureus pneumonia. Infection and disease progression were monitored by clinical assessment of animal health; analysis of blood chemistry, nasal swabs, and X-rays; and gross pathology and histopathology of lungs from infected animals. Seasonal IAV infection in healthy cynomolgus macaques caused mild pneumonia, but unexpectedly, did not predispose these animals to subsequent severe infection with the community-associated MRSA clone USA300. We conclude that in our co-infection model, seasonal IAV infection alone is not sufficient to promote severe S. aureus pneumonia in otherwise healthy non-human primates. The implication of these findings is that comorbidity factors in addition to IAV infection are required to predispose individuals to secondary S. aureus pneumonia.
doi:10.4161/viru.26572
PMCID: PMC3925702  PMID: 24104465
Staphylococcus aureus; influenza a virus; coinfection; USA300; MRSA; pneumonia
7.  SLEEP QUALITY PREDICTS TREATMENT OUTCOME IN CBT FOR SOCIAL ANXIETY DISORDER 
Depression and anxiety  2013;30(11):1114-1120.
Background
Sleep quality may be an important, yet relatively neglected, predictor of treatment outcome in cognitive-behavioral therapy (CBT) for anxiety disorders. Specifically, poor sleep quality may impair memory consolidation of in-session extinction learning. We therefore examined sleep quality as a predictor of treatment outcome in CBT for social anxiety disorder and the impact of d-cycloserine (DCS) on this relationship.
Methods
One hundred sixty-nine participants with a primary diagnosis of DSM-IV generalized social anxiety disorder were recruited across three sites. Participants were enrolled in 12 weeks of group CBT. Participants randomly received 50 mg of DCS (n = 87) or pill placebo (n = 82) 1 hr prior to sessions 3–7. Participants completed a baseline measure of self-reported sleep quality and daily diaries recording subjective feelings of being rested upon wakening. Outcome measures including social anxiety symptoms and global severity scores were assessed at each session.
Results
Poorer baseline sleep quality was associated with slower improvement and higher posttreatment social anxiety symptom and severity scores. Moreover, patients who felt more “rested” after sleeping the night following a treatment session had lower levels of symptoms and global severity at the next session, controlling for their symptoms and severity scores the previous session. Neither of these effects were moderated by DCS condition.
Conclusions
Our findings suggest that poor sleep quality diminishes the effects of CBT for social anxiety disorder and this relation is not attenuated by DCS administration. Therapeutic attention to sleep quality prior to initiation of CBT and during the acute treatment phase may be clinically indicated.
doi:10.1002/da.22170
PMCID: PMC4043139  PMID: 24038728
sleep quality; cognitive behavioral therapy; psychotherapy; social anxiety disorder; social phobia; d-cycloserine
8.  Extreme Attributions Predict Transition from Depression to Mania or Hypomania in Bipolar Disorder 
Journal of psychiatric research  2013;47(10):1329-1336.
Background
Relatively little is known about psychological predictors of the onset of mania among individuals with bipolar disorder, particularly during episodes of depression. In the present study we investigated attributional style as a predictor of onset of hypomanic, manic or mixed episodes among bipolar adults receiving psychosocial treatment for depression. We hypothesized that “extreme” (i.e., excessively pessimistic or optimistic) attributions would predict a greater likelihood of developing an episode of mood elevation.
Method
Outpatients with DSM-IV bipolar I or II disorder (N=105) enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomly allocated to one of three types of intensive psychotherapy for depression or a brief psychoeducational intervention. Patients completed a measure of attributional style at baseline and were followed prospectively for up to one year. All analyses were by intent to treat.
Results
Logistic regressions and Cox proportional hazards models indicated that extreme (both positively- and negatively-valenced) attributions predicted a higher likelihood of (and shorter time until) transition from depression to a (hypo)manic or mixed episode (ps < .04), independent of the effects of manic or depressive symptom severity at baseline. Extreme attributions were also retrospectively associated with more lifetime episodes of (hypo)mania and depression (ps < .05).
Conclusions
Evaluating extreme attributions may help clinicians to identify patients who are at risk for experiencing a more severe course of bipolar illness, and who may benefit from treatments that introduce greater cognitive flexibility.
doi:10.1016/j.jpsychires.2013.05.016
PMCID: PMC3743936  PMID: 23791456
attributional style; cognitive style; cognitive vulnerability; mania; hypomania; manic switch
9.  D-cycloserine Enhancement of Exposure Therapy for Social Anxiety Disorder Depends on the Success of Exposure Sessions 
Journal of psychiatric research  2013;47(10):1455-1461.
Objective
The evidence for the efficacy of D-cycloserine (DCS) for augmenting cognitive behavioral therapy (CBT) for anxiety disorders has been mixed. Guided by preclinical research and initial findings from a small-scale study involving humans, we tested the hypothesis that DCS enhancement of exposure therapy would be specific to successful exposure sessions.
Method
Medication-free adults with generalized social anxiety disorder (N = 145) received 50 mg of DCS or placebo 1 hour before each of 5 exposure sessions that were part of a standardized 12-session group CBT protocol. Participants provided fear ratings at the beginning and just before the end of exposure exercises. Independent raters, blind to group assignment, administered the clinical global impression improvement and severity scales at each session and at posttreatment.
Results
Mixed-effects analyses revealed that, among patients who reported low fear at the end of an exposure session, those who had received DCS evidenced significantly greater clinical improvement at the next session, relative to those who had received placebo. In contrast, when exposure end fear was high, patients receiving DCS exhibited less clinical improvement at the following session than patients receiving placebo. Similarly, patients who had received DCS evidenced lower clinical severity at posttreatment, relative to patients who had received placebo, only when their average end fear for medication-augmented sessions had been in the low to moderate range. Finally, these moderating effects of exposure success as indexed by end fear were not better accounted for by within-session extinction.
Conclusions
The efficacy of DCS for augmenting exposure-based CBT depends on the success of exposure sessions. These findings may help guide the development of an algorithm for the effective use of DCS for augmenting exposure-based CBT.
Trial Registry
http://www.ClinicalTrials.gov, ID# NCT00633984, http://www.clinicaltrials.gov/ct2/show/NCT00633984
doi:10.1016/j.jpsychires.2013.06.020
PMCID: PMC3747985  PMID: 23870811
CBT; Cognitive Behavioral Therapy; Exposure therapy; Fear extinction; D-cycloserine; Moderators; Social Anxiety Disorder; Social Phobia
10.  Combination Prophylactic Therapy with Rifampin Increases Efficacy against an Experimental Staphylococcus epidermidis Subcutaneous Implant-Related Infection 
The incidence of infections related to cardiac devices (such as permanent pacemakers) has been increasing out of proportion to implantation rates. As management of device infections typically requires explantation of the device, optimal prophylactic strategies are needed. Cefazolin and vancomycin are widely used as single agents for surgical prophylaxis against cardiac device-related infections. However, combination antibiotic prophylaxis may further reduce infectious complications. To model a localized subcutaneous implant-related infection, a bioluminescent strain of Staphylococcus epidermidis was inoculated onto a medical-procedure-grade titanium disc, which was placed into a subcutaneous pocket in the backs of mice. In vivo bioluminescence imaging, quantification of ex vivo CFU from the capsules and implants, variable-pressure scanning electron microscopy (VP-SEM), and neutrophil enhanced green fluorescent protein (EGFP) fluorescence in LysEGFP mice were employed to monitor the infection. This model was used to evaluate the efficacies of low- and high-dose cefazolin (50 and 200 mg/kg of body weight) and vancomycin (10 and 110 mg/kg) intravenous prophylaxis with or without rifampin (25 mg/kg). High-dose cefazolin and high-dose vancomycin treatment resulted in almost complete bacterial clearance, whereas both low-dose cefazolin and low-dose vancomycin reduced the in vivo and ex vivo bacterial burden only moderately. The addition of rifampin to low-dose cefazolin and vancomycin was highly effective in further reducing the CFU harvested from the implants. However, vancomycin-rifampin was more effective than cefazolin-rifampin in further reducing the CFU harvested from the surrounding tissue capsules. Future studies in humans will be required to determine whether the addition of rifampin has improved efficacy in preventing device-related infections in clinical practice.
doi:10.1128/AAC.01943-13
PMCID: PMC4023771  PMID: 24514089
11.  Patient Preference for Psychological vs. Pharmacological Treatment of Psychiatric Disorders: A Meta-Analytic Review 
Objective
Models of evidence-based practice emphasize the consideration of treatment efficacy/effectiveness, clinical expertise, and patient preference in treatment selection and implementation. However, patient preference for psychiatric treatment has been understudied. The aim of this meta-analytic review was to provide an estimate of the proportion of patients preferring psychological treatment relative to medication for psychiatric disorders.
Data Sources
A literature search was conducted using PubMed, PsycINFO, and the Cochrane Collaboration Library through August, 2011 for studies written in English that assessed patient preferences for the treatment of psychiatric disorders.
Study Selection
Studies assessing the preferred type of treatment including at least one psychological treatment and one pharmacological treatment were included. Of the 641 articles initially identified, 34 met criteria for inclusion.
Data Extraction
Authors extracted relevant data including the proportion of participants reporting preference for psychological and pharmacological treatment.
Results
Across studies, the proportion preferring psychological treatment was 0.75 (95% CI: 0.69 to 0.80), which was significantly higher than equivalent preference (i.e., higher than 0.50, p < .001). Sensitivity analyses suggested that younger patients (p < .05) and women (p < .01) were significantly more like to choose psychological treatment. A preference for psychological treatment was consistently evident in both treatment-seeking and unselected samples (ps < .05), but was somewhat stronger for the unselected samples.
Conclusions
Aggregation of patient preferences across diverse settings yielded a significant three-fold preference for psychological treatment relative to medication. Given the similar efficacy of these treatments for depression and anxiety, improving access to evidence-based psychological treatment is needed to connect more patients to their preferred treatment.
doi:10.4088/JCP.12r07757
PMCID: PMC4156137  PMID: 23842011
12.  Production of an Attenuated Phenol-Soluble Modulin Variant Unique to the MRSA Clonal Complex 30 Increases Severity of Bloodstream Infection 
PLoS Pathogens  2014;10(8):e1004298.
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms.
Author Summary
Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of morbidity and mortality and a great concern for public health. The CC30 MRSA lineage is especially notorious for causing bloodstream infections with complications such as seeding into organs. In our study, we show that this lineage produces an attenuated form of a key S. aureus toxin with decreased pro-inflammatory features. Our results suggest that attenuation of this toxin allows the bacteria to evade recognition and subsequent elimination by host defenses, thereby increasing pathogen success during blood infection.
doi:10.1371/journal.ppat.1004298
PMCID: PMC4140855  PMID: 25144687
13.  Oxacillin Alters the Toxin Expression Profile of Community-Associated Methicillin-Resistant Staphylococcus aureus 
The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a growing cause for concern. These strains are more virulent than health care-associated MRSA (HA-MRSA) due to higher levels of toxin expression. In a previous study, we showed that the high-level expression of PBP2a, the alternative penicillin binding protein encoded by the mecA gene on type II staphylococcal cassette chromosome mec (SCCmec) elements, reduced toxicity by interfering with the Agr quorum sensing system. This was not seen in strains carrying the CA-MRSA-associated type IV SCCmec element. These strains express significantly lower levels of PBP2a than the other MRSA type, which may explain their relatively high toxicity. We hypothesized that as oxacillin is known to increase mecA expression levels, it may be possible to attenuate the toxicity of CA-MRSA by using this antibiotic. Subinhibitory oxacillin concentrations induced PBP2a expression, repressed Agr activity, and, as a consequence, decreased phenol-soluble modulin (PSM) secretion by CA-MRSA strains. However, consistent with other studies, oxacillin also increased the expression levels of alpha-toxin and Panton-Valentine leucocidin (PVL). The net effect of these changes on the ability to lyse diverse cell types was tested, and we found that where the PSMs and alpha-toxin are important, oxacillin reduced overall lytic activity, but where PVL is important, it increased lytic activity, demonstrating the pleiotropic effect of oxacillin on toxin expression by CA-MRSA.
doi:10.1128/AAC.01618-13
PMCID: PMC3910814  PMID: 24295979
14.  Community-associated MRSA: what makes them special? 
Summary
While infections with methicillin-resistant Staphylococcus aureus (MRSA) were traditionally restricted to the hospital setting, novel MRSA strains emerged over the last two decades that have the capacity to infect otherwise healthy people outside of the hospital setting. These communityassociated (CA-) MRSA strains combine methicillin resistance with enhanced virulence and fitness. Interestingly, CA-MRSA strains emerged globally and from different backgrounds, indicating that the “trade-off” between maintaining sufficient levels of methicillin resistance and obtaining enhanced virulence at a low fitness cost was achieved on several occasions in convergent evolution. However, frequently this process comprised similar changes. First and foremost, all CA-MRSA strains typically carry a novel type of methicillin resistance locus that appears to cause less of a fitness burden. Additionally, acquisition of specific toxin genes, most notably that encoding Panton-Valentine leukocidin (PVL), and adaptation of gene expression of genome-encoded toxins, such as alpha-toxin and phenol-soluble modulins (PSMs), further contributed to the evolution of CA-MRSA. Finally, the exceptional epidemiological success of the USA300 CA-MRSA clone in particular may have been due to yet another gene acquisition, namely that of the speG gene, which is located on the arginine catabolic mobile element (ACME) and involved in detoxifying harmful host-derived polyamines.
doi:10.1016/j.ijmm.2013.02.007
PMCID: PMC3729626  PMID: 23517691
Staphylococcus aureus; MRSA; community-associated MRSA; alpha-toxin; Panton-Valentine leukocidin; phenol-soluble modulin
15.  Staphylococcus δ-toxin promotes mouse allergic skin disease by inducing mast cell degranulation 
Nature  2013;503(7476):397-401.
Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15 to 30% of children and ~5% of adults in industrialized countries1. Although the pathogenesis of AD is not fully understood, the disease is mediated by an abnormal immunoglobulin E (IgE) immune response in the setting of skin barrier dysfunction2. Mast cells (MCs) contribute to IgE-mediated allergic disorders including AD3. Upon activation, MCs release their membrane-bound cytosolic granules leading to the release of multiple molecules that are important in the pathogenesis of AD and host defense4. More than 90% of AD patients are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbor the pathogen5. Several Staphylococcal exotoxins (SEs) can act as superantigens and/or antigens in models of AD6. However, the role of these SEs in disease pathogenesis remains unclear. Here, we report that culture supernatants of S. aureus contain potent MC degranulation activity. Biochemical analysis identified δ-toxin as the MC degranulation-inducing factor produced by S. aureus. MC degranulation induced by δ-toxin depended on phosphoinositide 3-kinase (PI3K) and calcium (Ca2+) influx, but unlike that mediated by IgE crosslinking, it did not require the spleen tyrosine kinase (Syk). In addition, IgE enhanced δ-toxin-induced MC degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from AD patients produced high levels of δ-toxin. Importantly, skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted IgE and IL-4 production, as well as inflammatory skin disease. Furthermore, enhancement of IgE production and dermatitis by δ-toxin was abrogated in KitW-sh/W-sh MC-deficient mice and restored by MC reconstitution. These studies identify δ-toxin as a potent inducer of MC degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.
doi:10.1038/nature12655
PMCID: PMC4090780  PMID: 24172897
16.  Mood regulation and quality of life in social anxiety disorder: An examination of generalized expectancies for negative mood regulation 
Journal of anxiety disorders  2012;26(3):435-441.
The present study examined negative mood regulation expectancies, anxiety symptom severity, and quality of life in a sample of 167 patients with social anxiety disorder (SAD) and 165 healthy controls with no DSM-IV Axis I disorders. Participants completed the Generalized Expectancies for Negative Mood Regulation Scale (NMR), the Beck Anxiety Inventory, and the Quality of Life Enjoyment and Satisfaction Questionnaire. SAD symptom severity was assessed using the Liebowitz Social Anxiety Scale. Individuals with SAD scored significantly lower than controls on the NMR. Among SAD participants, NMR scores were negatively correlated with anxiety symptoms and SAD severity, and positively correlated with quality of life. NMR expectancies positively predicted quality of life even after controlling for demographic variables, comorbid diagnoses, anxiety symptoms, and SAD severity. Individuals with SAD may be less likely to engage in emotion regulating strategies due to negative beliefs regarding their effectiveness, thereby contributing to poorer quality of life.
doi:10.1016/j.janxdis.2012.01.004
PMCID: PMC4090049  PMID: 22343166
Social anxiety disorder; Social phobia; Emotion regulation; Generalized expectancies for mood; regulation
17.  D-cycloserine as an augmentation strategy of cognitive behavioral therapy for social anxiety disorder 
The American journal of psychiatry  2013;170(7):751-758.
OBJECTIVE
To test whether d-cycloserine, a partial agonist at the glutamatergic N-methyl-D-aspartate receptor, augments and accelerates a full course of comprehensive cognitive behavioral therapy (CBT) in medication-free adults with generalized social anxiety disorder.
METHOD
A randomized placebo-controlled efficacy-study conducted at Boston University, Massachusetts General Hospital, and Southern Methodist University between 9/2007 and 12/2011 of 169 medication-free adults with generalized social anxiety disorder; 144 completed treatment, and 131 completed the follow-up assessments. Patients were randomized to receive 50 mg of d-cycloserine or placebo 1 hour before each of 5 exposure sessions that were part of a 12-session cognitive behavioral group treatment. Response and remission status was determined at baseline, throughout treatment, post-treatment, and at 1, 3, and 6-month follow-up assessments rated by assessors who were blind to treatment condition.
RESULTS
D-cycloserine-augmented and placebo-augmented CBT were associated with similar completion rates (87% and 82%), response rates (79.3% and 73.3%), and remission rates (34.5% and 24.4%) at post-treatment that were largely maintained at follow-up. Although d-cycloserine was associated with a 24–33% faster rate of improvement in symptom severity and remission rates relative to placebo during the 12-week treatment phase, the groups did not differ in response and remission rates.
CONCLUSIONS
D-cycloserine did not augment a full course of comprehensive CBT for social anxiety disorder.
TRIAL REGISTRATION
http://www.ClinicalTrials.gov, ID# NCT00633984, http://www.clinicaltrials.gov/ct2/show/NCT00633984
doi:10.1176/appi.ajp.2013.12070974
PMCID: PMC4058999  PMID: 23599046
Cognitive behavioral therapy; d-cycloserine; N-methyl-D-aspartate receptor agonist; CBT; social anxiety disorder; social phobia; randomized controlled trial
18.  Selective Chemical Inhibition of agr Quorum Sensing in Staphylococcus aureus Promotes Host Defense with Minimal Impact on Resistance 
PLoS Pathogens  2014;10(6):e1004174.
Bacterial signaling systems are prime drug targets for combating the global health threat of antibiotic resistant bacterial infections including those caused by Staphylococcus aureus. S. aureus is the primary cause of acute bacterial skin and soft tissue infections (SSTIs) and the quorum sensing operon agr is causally associated with these. Whether efficacious chemical inhibitors of agr signaling can be developed that promote host defense against SSTIs while sparing the normal microbiota of the skin is unknown. In a high throughput screen, we identified a small molecule inhibitor (SMI), savirin (S. aureus virulence inhibitor) that disrupted agr-mediated quorum sensing in this pathogen but not in the important skin commensal Staphylococcus epidermidis. Mechanistic studies employing electrophoretic mobility shift assays and a novel AgrA activation reporter strain revealed the transcriptional regulator AgrA as the target of inhibition within the pathogen, preventing virulence gene upregulation. Consistent with its minimal impact on exponential phase growth, including skin microbiota members, savirin did not provoke stress responses or membrane dysfunction induced by conventional antibiotics as determined by transcriptional profiling and membrane potential and integrity studies. Importantly, savirin was efficacious in two murine skin infection models, abating tissue injury and selectively promoting clearance of agr+ but not Δagr bacteria when administered at the time of infection or delayed until maximal abscess development. The mechanism of enhanced host defense involved in part enhanced intracellular killing of agr+ but not Δagr in macrophages and by low pH. Notably, resistance or tolerance to savirin inhibition of agr was not observed after multiple passages either in vivo or in vitro where under the same conditions resistance to growth inhibition was induced after passage with conventional antibiotics. Therefore, chemical inhibitors can selectively target AgrA in S. aureus to promote host defense while sparing agr signaling in S. epidermidis and limiting resistance development.
Author Summary
New approaches are needed to lessen the burden of antibiotic resistant bacterial infections. One strategy is to develop therapies that target virulence which rely on host defense elements to clear the bacteria rather than direct antimicrobial killing. Quorum sensing is a bacterial signaling mechanism that often regulates virulence in medically relevant bacterial pathogens. Therefore, drugs that inhibit quorum sensing can promote host defense by rendering the pathogenic bacteria avirulent and/or less fit for survival within the host. Our work addressed this strategy in the pathogen Staphylococcus aureus which is the major cause of acute bacterial skin and soft tissue infections. We conducted a high throughput screen to identify compounds that could inhibit signaling by the quorum sensing operon, agr. We found a compound that we termed savirin (S. aureus virulence inhibitor) that could inhibit signaling by this operon. The drug helped the innate immune system in animals to clear bacteria that express this operon without affecting clearance of bacteria that do not have this operon. We addressed the mechanism of action of this compound and whether resistance or tolerance to this compound would likely develop. Our data indicate for the first time that host defense against S. aureus skin infections can be enhanced by chemical inhibition of agr-mediated quorum sensing.
doi:10.1371/journal.ppat.1004174
PMCID: PMC4055767  PMID: 24945495
19.  d-cycloserine Enhancement of Fear Extinction is Specific to Successful Exposure Sessions: Evidence from the Treatment of Height Phobia 
Biological psychiatry  2013;73(11):1054-1058.
Background
Whereas some studies have shown clear evidence for an augmentation effect of d-cycloserine (DCS) on exposure therapy for anxiety disorders, other studies have shown weak effects or no effect at all. Some preclinical data suggest that the DCS augmentation effect is moderated by the success of the extinction trials. Therefore, we conducted a re-analysis of existing data to examine whether the effects of DCS on clinical outcome would vary as a function of response to the exposure session (i.e. exposure success).
Methods
In a clinical trial, patients with height phobia received two sessions involving 30 minutes of virtual reality exposure therapy and were randomly assigned to a pill placebo (N=14) or 50 mg of DCS (N=15) immediately after each session.
Results
Mixed-effects regression analysis showed that the effects of DCS administration on clinical improvement was moderated by the level of fear experienced just prior to concluding exposure sessions. Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when subjective fear was low at the end of the exposure. In contrast, when end fear was still elevated, patients receiving DCS improved less compared to those receiving placebo.
Conclusions
DCS appears to enhance the benefits of exposure treatment when applied after a successful session, but it seems to have detrimental effects when administered after inadequate/unsuccessful exposures.
Trial Registry
The Trial is registered at ClinicalTrials.gov (NCT01102803).
doi:10.1016/j.biopsych.2012.12.009
PMCID: PMC3636175  PMID: 23332511
CBT; Cognitive Behavioral Therapy; Exposure therapy; Fear extinction; d-cycloserine; Moderators; Acrophobia
20.  Disparate Rates of New-Onset Depression During the Menopausal Transition in 2 Community-based Populations: Real, or Really Wrong? 
American Journal of Epidemiology  2013;177(10):1148-1156.
This study took place in eastern Massachusetts and included respondents from the Harvard Study of Moods and Cycles Cohort 1, enrolled between 1995 and 1997, and the Harvard Study of Moods and Cycles Cohort 2, enrolled between 2005 and 2009. In prospectively assessing rates of new-onset depression in 2 populations of late-reproductive–aged women with no Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) lifetime history of depression, we were surprised to find far lower rates of depression in the population with greater racial diversity and lower socioeconomic status, contrary to what had been reported in the scientific literature. To better understand why these disparate results occurred, we assessed confounding and outcome misclassification as potential explanations for the discrepancy. After determining that these were unlikely explanations for the findings, we explored 2 potential sources of selection bias: one induced by self-referral of healthy participants into the study and the other induced by the design of the study itself. We concluded that both types of selection bias were likely to have occurred in this study and could account for the observed difference in rates.
doi:10.1093/aje/kws365
PMCID: PMC3649637  PMID: 23589585
bias; depression; prospective studies
21.  Staphylococcus aureus PSM peptides modulate dendritic cell functions and increase in vitro priming of regulatory T cells1 
The major human pathogen Staphylococcus aureus has very efficient strategies to subvert the human immune system. Virulence of the emerging community-associated methicillin-resistant S. aureus (CA-MRSA) depends on phenol-soluble modulin (PSM) peptide toxins, which are known to attract and lyse neutrophils. However, their influences on other immune cells remain elusive. Here, we analyzed the impact of PSMs on dendritic cells (DCs) playing an essential role in linking innate and adaptive immunity. In human neutrophils, PSMs exert their function by binding to the formyl peptide receptor (FPR) 2. We show that mouse DCs express the FPR2 homologue mFPR2 as well as its paralog mFPR1 and that PSMs are chemoattractants for DCs at non-cytotoxic concentrations. PSMs reduced clathrin-mediated endocytosis and inhibited TLR2 ligand-induced secretion of the proinflammatory cytokines TNF, IL-12 and IL-6 while inducing IL-10 secretion by DCs. As a consequence, treatment with PSMs impaired the capacity of DCs to induce activation and proliferation of CD4+ T cells, characterized by reduced Th1 but increased frequency of FOXP3+ regulatory T cells (Tregs). These Tregs secreted high amounts of IL-10 and their suppression capacity was dependent on IL-10 and TGF-β. Interestingly, the induction of tolerogenic DCs by PSMs appeared to be independent of mFPRs as shown by experiments with mice lacking mFPR2 (mFPR2−/−) and the cognate G protein (p110γ−/−). Thus, PSMs from highly virulent pathogens affect DC functions thereby modulating the adaptive immune response and probably increasing the tolerance towards the pathogen.
doi:10.4049/jimmunol.1202563
PMCID: PMC3608756  PMID: 23460735
22.  Do Comorbid Anxiety Disorders Moderate the Effects of Psychotherapy for Bipolar Disorder? Results From STEP-BD 
The American journal of psychiatry  2014;171(2):178-186.
Objective
At least 50% of individuals with bipolar disorder have a lifetime anxiety disorder. Individuals with both bipolar disorder and a co-occurring anxiety disorder experience longer illness duration, greater illness severity, and poorer treatment response. The study explored whether comorbid lifetime anxiety in bipolar patients moderates psychotherapy treatment outcome.
Method
In the Systematic Treatment Enhancement Program randomized controlled trial of psychotherapy for bipolar depression, participants received up to 30 sessions of intensive psychotherapy (family-focused therapy, interpersonal and social rhythm therapy, or cognitive-behavioral therapy) or collaborative care, a three-session comparison treatment, plus pharmacotherapy. Using the number needed to treat, we computed effect sizes to analyze the relationship between lifetime anxiety disorders and rates of recovery across treatment groups after 1 year.
Results
A total of 269 patients (113 women) with a comorbid lifetime anxiety disorder (N=177) or without a comorbid lifetime anxiety disorder (N=92) were included in the analysis. Participants with a lifetime anxiety disorder were more likely to recover with psychotherapy than with collaborative care (66% compared with 49% recovered over 1 year; number needed to treat=5.88, small to medium effect). For patients without a lifetime anxiety disorder, there was no difference between rates of recovery in psychotherapy compared with collaborative care (64% compared with 62% recovered; number needed to treat=50, small effect). Participants with one lifetime anxiety disorder were likely to benefit from intensive psychotherapy compared with collaborative care (84% compared with 53% recovered; number needed to treat=3.22, medium to large effect), whereas patients with multiple anxiety disorders exhibited no difference in response to the two treatments (54% compared with 46% recovered; number needed to treat=12.5, small effect).
Conclusions
Depressed patients with bipolar disorder and comorbid anxiety may be in particular need of additional psychotherapy for treating acute depression. These results need to be replicated in studies that stratify bipolar patients to treatments based on their anxiety comorbidity status.
doi:10.1176/appi.ajp.2013.13020225
PMCID: PMC3946300  PMID: 24077657
23.  Impulsivity as a moderator of the intention-behavior relationship for illicit drug use in patients undergoing treatment 
Addictive behaviors  2012;38(3):1651-1655.
Introduction
Evident across clinical practice and clinical trials is a divergence between stated intentions and subsequent drug-related behaviors in substance abuse treatment settings. Impulsivity, itself related to drug abuse, may be one variable which may moderate the degree of disconnect in the intention-behavior relationship. The present study examines the relationship between self-stated desire to quit, impulsivity, and drug use in a group of outpatients receiving methadone maintenance treatment. In particular, we examined the direct and moderating influence of different facets of impulsivity (urgency, lack of premeditation, sensation seeking, and lack of perseverance) on drug use in the context of a stated desire to abstain from drugs.
Method
84 opioid-dependent individuals undergoing counseling and methadone maintenance treatment completed a battery of self-report questionnaires including measures of impulsivity (UPPS Impulsivity Scale), stated desire to quit, and past 30-day drug use. We hypothesized that two facets of impulsivity, urgency and (lack of) premeditation, would moderate the relationship between desire to quit and past 30-day drug use, such that the relationship between intention and behavior would be weaker in those with high levels of these facets of impulsivity.
Results
Consistent with the disconnect between intentions and drug-use behaviors typical of treatment settings, desire to quit was not directly associated with self-reported past month drug use. However, in separate regression analyses, 2 facets of impulsivity, premeditation and sensation seeking, moderated the relationship between desire to quit and past month use. Whereas there was not a significant relationship between desire to quit and drug use in individuals high in sensation-seeking or lack of premeditation, the relationship between intention and drug use behaviors was preserved in those low in these facets of impulsivity.
Conclusion
These findings indicate that the relationship between desire to quit and self-reported past-month drug use is weak for those high in sensation seeking or low in premeditation. These results are discussed in the context of current interventions for substance dependence.
doi:10.1016/j.addbeh.2012.09.008
PMCID: PMC3558639  PMID: 23254213
24.  Whole Genome Analysis of a Community-Associated Methicillin-Resistant Staphylococcus aureus ST59 Isolate from a Case of Human Sepsis and Severe Pneumonia in China 
PLoS ONE  2014;9(2):e89235.
We report a case of necrotizing pneumonia in a young patient caused by community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) in a teaching hospital in the People’s Republic of China. The patient had a typical clinical presentation and was successfully treated with antibiotics and intravenous immunoglobulin. A CA-MRSA strain, named SA268, was isolated from the blood of the patient. The isolate was susceptible to most antimicrobial agents, except cephalosporins, penicillins, and β-lactamase inhibitor combinations. Multi-locus sequence typing (MLST) assigned SA268 to ST59, a clone widely spread in eastern Asia. The strain was positive for Panton Valentine Leukocidin (PVL)-encoding genes and SCCmec type V. We sequenced the complete genome of the SA268 isolate. The genome of SA268 was almost identical to that of the Taiwanese ST59 CA-MRSA strains M013 and SA957. However, we observed several differences in gene composition, which included differences in the SCCmec element and several lipoprotein genes that were present in the Taiwanese strains but absent from SA268.
doi:10.1371/journal.pone.0089235
PMCID: PMC3930696  PMID: 24586619
25.  Augmentation of exposure therapy with post-session administration of d-cycloserine 
Journal of psychiatric research  2012;47(2):168-174.
Background
Pre-session administration of d-cycloserine (DCS) has been found to augment exposure therapy outcomes in a variety of anxiety disorders. To be able to enhance learning only for successful exposure sessions, it would be beneficial to have the option of administering DCS after rather than before the session, a strategy encouraged by pre-clinical work. We believe the present study is the first published report on the efficacy of post-session administration of DCS in humans.
Method
Adults (N = 29) with a DSM-IV diagnosis of acrophobia were randomized to receive two sessions of virtual reality exposure therapy (VRE) in combination with placebo or 50 mg of DCS. Instead of administering the pill prior to each of the sessions, as has been done in extant work, we administered the pill immediately following each session. Measures of acrophobia severity were collected at baseline, at each treatment session, 1-week post-treatment, and at 1-month follow-up.
Results
Mixed-effects repeated-measures ANOVAs and GLMMs revealed significant improvement in all outcome measures over time, but no between-group differences were observed. At post-treatment, 63.5% of patients in the placebo condition vs. 60.0% of those in the DCS condition were in remission. At 1-month follow up, 63.4% of those in the placebo condition vs. 66.6% of those in the DCS condition were in remission.
Conclusions
These findings do not support the application of post-session DCS administration for augmenting the efficacy of exposure-based treatments. Possible reasons for these findings are discussed. Trial Registry: The Trial is registered at ClinicalTrials.gov (NCT01102803).
doi:10.1016/j.jpsychires.2012.09.024
PMCID: PMC3732105  PMID: 23098672
Augmentation; CBT; Cognitive behavioral therapy; d-cycloserine; Exposure treatment; Randomized controlled trial; Acrophobia

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