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1.
Neuropsychopharmacology ; 48(7): 991-999, 2023 06.
Article in English | MEDLINE | ID: mdl-36804489

ABSTRACT

This study is the first randomized controlled trial to test the effects of ketamine in Borderline Personality Disorder (BPD). BPD remains undertreated in the community and no medication has FDA approval for this indication. People with BPD experience chronic mood disturbances with depressed mood, suicidal ideation, and severe social difficulties. In this double-blind, randomized controlled pilot study, we tested the effects of one infusion of ketamine (0.5 mg/kg, n = 10) or the psychoactive comparator drug midazolam (0.04 mg/kg, n = 12) in adults with BPD. Infusions were well tolerated in both groups. Dissociative symptoms during infusion were more intense with ketamine than midazolam (t(12.3) = 3.61, p = 0.01), but they resolved by 40 min after infusion in both groups. Post-infusion adverse events were at the expected low levels in both groups. For our primary outcome measure of suicidal ideation and our secondary outcome measure of depression, we found numerical reduction but not significant group or group x timepoint difference (p > 0.05). For our secondary outcome measures of anxiety and BPD symptoms, we did not observe group or group x timepoint differences. There was a group x timepoint effect for socio-occupational functioning (F(1,20.12) = 5.16, p = 0.03, at Day 14, ketamine group showed more improvement than midazolam group). An exploratory analysis revealed that improvement in socio-occupational functioning was correlated with improvement in depression in the ketamine group (r(8) = 0.65, p = 0.04) but not midazolam group (r(9) = 0.41, p = 0.216). This pilot study provides the first randomized controlled evidence of the effects of antidepressant-dosed ketamine in people with BPD. Our results provide reason for optimism that antidepressant-dosed ketamine will be well-tolerated in larger studies and may provide clinical benefit for mood symptoms and related impairments in people with BPD.


Subject(s)
Borderline Personality Disorder , Ketamine , Adult , Humans , Pilot Projects , Borderline Personality Disorder/drug therapy , Midazolam/therapeutic use , Antidepressive Agents/therapeutic use , Double-Blind Method
2.
Chronic Stress (Thousand Oaks) ; 4: 2470547020912504, 2020.
Article in English | MEDLINE | ID: mdl-32518886

ABSTRACT

Borderline personality disorder is an often misunderstood and underdiagnosed mental illness characterized in part by affective lability. Clinicians' unique understanding of the disorder has allowed them to develop disorder-specific approaches to treatment. In this review, we highlight how borderline personality disorder research can benefit from greater engagement with key disorder-specific features, including symptom variability and interpersonal sensitivity. In addition, we propose that research which employs interactive tasks will be more reflective of the kinds of volatility found in the real-life situations. Finally, we discuss how mixed-methodology can serve as a way for recovery-oriented research to practice the very ideals and recommendations it suggests. We use a patient case to contextualize each section. As interest in borderline personality disorder continues to grow, an intentional emphasis on a person-centered, recovery-focused, and disorder-specific approach to research is needed.

3.
Sci Signal ; 12(605)2019 10 29.
Article in English | MEDLINE | ID: mdl-31662487

ABSTRACT

Human blood CD14+ monocytes are bone marrow-derived white blood cells that sense and respond to pathogens. Although innate immune activation by RNA viruses preferentially occurs through intracellular RIG-I-like receptors, other nucleic acid recognition receptors, such as Toll-like receptors (TLRs), play a role in finely programming the final outcome of virus infection. Here, we dissected how human monocytes respond to infection with either Coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), or vesicular stomatitis (VSV) virus. We found that in monocytes, type I interferon (IFN) and cytokine responses to infection were RNA virus specific and differentially involved TLR7 and TLR8, which sense single-stranded RNA. These TLRs activated distinct signaling cascades in monocytes, which correlated with differences in the production of cytokines involved in the polarization of CD4+ T helper cells. Furthermore, we found that TLR7 signaling specifically increased expression of the transcription factor FOSL1, which reduced IL-27 and TNFα production by monocytes. TLR7, but not TLR8, activation of monocytes also stimulated Ca2+ flux that prevented type I IFN responses. Our work demonstrates that in human monocytes, TLR7 and TLR8 triggered different signaling pathways that contribute to distinct phenotypes during RNA virus infection. In addition, we defined individual targets within these pathways that promoted specific T helper and antiviral responses.


Subject(s)
Monocytes/immunology , RNA Viruses/immunology , Signal Transduction/immunology , Toll-Like Receptor 7/immunology , Toll-Like Receptor 8/immunology , Calcium/immunology , Calcium/metabolism , Cells, Cultured , Cytokines/genetics , Cytokines/immunology , Cytokines/metabolism , Gene Expression Regulation/immunology , Host-Pathogen Interactions/immunology , Humans , Interferon Type I/genetics , Interferon Type I/immunology , Interferon Type I/metabolism , Monocytes/metabolism , Monocytes/virology , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/immunology , Proto-Oncogene Proteins c-fos/metabolism , RNA Interference , RNA Viruses/classification , RNA Viruses/physiology , Signal Transduction/genetics , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/genetics , Toll-Like Receptor 8/metabolism
4.
J Virol ; 93(13)2019 07 01.
Article in English | MEDLINE | ID: mdl-30971475

ABSTRACT

Saliva from the mosquito vector of flaviviruses is capable of changing the local immune environment, leading to an increase in flavivirus-susceptible cells at the infected bite site. In addition, an antibody response to specific salivary gland (SG) components changes the pathogenesis of flaviviruses in human populations. To investigate whether antigenic SG proteins are capable of enhancing infection with Zika virus (ZIKV), a reemerging flavivirus primarily transmitted by the Aedes aegypti mosquito, we screened for antigenic SG proteins using a yeast display library and demonstrate that a previously undescribed SG protein we term neutrophil stimulating factor 1 (NeSt1) activates primary mouse neutrophils ex vivo Passive immunization against NeSt1 decreases pro-interleukin-1ß and CXCL2 expression, prevents macrophages from infiltrating the bite site, protects susceptible IFNAR-/- IFNGR-/- (AG129) mice from early ZIKV replication, and ameliorates virus-induced pathogenesis. These findings indicate that NeSt1 stimulates neutrophils at the mosquito bite site to change the immune microenvironment, allowing a higher level of early viral replication and enhancing ZIKV pathogenesis.IMPORTANCE When a Zika virus-infected mosquito bites a person, mosquito saliva is injected into the skin along with the virus. Molecules in this saliva can make virus infection more severe by changing the immune system to make the skin a better place for the virus to replicate. We identified a molecule that activates immune cells, called neutrophils, to recruit other immune cells, called macrophages, that the virus can infect. We named this molecule neutrophil-stimulating factor 1 (NeSt1). When we used antibodies to block NeSt1 in mice and then allowed Zika virus-infected mosquitoes to feed on these mice, they survived much better than mice that do not have antibodies against NeSt1. These findings give us more information about how mosquito saliva enhances virus infection, and it is possible that a vaccine against NeSt1 might protect people against severe Zika virus infection.


Subject(s)
Aedes/virology , Neutrophils/metabolism , Neutrophils/virology , Zika Virus Infection/immunology , Zika Virus/immunology , Aedes/immunology , Animals , Arboviruses , Chemokine CCL2 , Chemokine CXCL2/metabolism , Disease Models, Animal , Female , Immunity , Interleukin-1/metabolism , Male , Mice , Mice, Inbred C57BL , Mosquito Vectors/virology , Protein Precursors/metabolism , RAW 264.7 Cells , Saliva/virology , Salivary Glands/virology , Virus Replication , Zika Virus/pathogenicity , Zika Virus Infection/virology
5.
iScience ; 13: 339-350, 2019 Mar 29.
Article in English | MEDLINE | ID: mdl-30884311

ABSTRACT

The TAM receptor, Axl, has been implicated as a candidate entry receptor for Zika virus (ZIKV) infection but has been shown as inessential for virus infection in mice. To probe the role of Axl in murine ZIKV infection, we developed a mouse model lacking the Axl receptor and the interferon alpha/beta receptor (Ifnar-/-Axl-/-), conferring susceptibility to ZIKV. This model validated that Axl is not required for murine ZIKV infection and that mice lacking Axl are resistant to ZIKV pathogenesis. This resistance correlates to lower pro-interleukin-1ß production and less apoptosis in microglia of ZIKV-infected mice. This apoptosis occurs through both intrinsic (caspase 9) and extrinsic (caspase 8) manners, and is age dependent, as younger Axl-deficient mice are susceptible to ZIKV pathogenesis. These findings suggest that Axl plays an important role in pathogenesis in the brain during ZIKV infection and indicates a potential role for Axl inhibitors as therapeutics during viral infection.

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