Lithium-associated transcriptional regulation of CRMP1 in patient-derived olfactory neurons and symptom changes in bipolar disorder.

There is growing evidence that lithium used in the treatment of bipolar disorder (BD) affects molecular targets that are involved in neuronal growth, survival, and maturation, but it remains unclear if neuronal alterations in any of these molecules predict specific symptom changes in BD patients undergoing lithium monotherapy. The goals of this study were to (a) determine which molecular changes in the olfactory neurons of symptomatic patients receiving lithium are associated with antimanic or antidepressant response, and (b) uncover novel intraneuronal regulatory mechanisms of lithium therapy. Twenty-two treatment-naïve non-smoking patients, with symptomatic BD underwent nasal biopsies for collection of olfactory tissues, prior to their treatment and following a 6-week course of lithium monotherapy. Sixteen healthy controls were also biopsied. Combining laser capture microdissection with real-time polymerase chain reaction, we investigated baseline and treatment-associated transcriptional changes in candidate molecular targets of lithium action in the olfactory neuroepithelium. Baseline mRNA levels of glycogen synthase kinase 3 beta (GSK3ß) and collapsin response mediator protein 1 (CRMP1) genes were significantly associated with BD status and with severity of mood symptoms. Among BD subjects, treatment-associated downregulation of CRMP1 expression was most predictive of decreases in both manic and depressive symptoms. This study provides a novel insight into the relevance of CRMP1, a key molecule in semaphorin-3A signaling during neurodevelopment, in the molecular mechanism of action of lithium, and in the pathophysiology of BD. It supports the use of human-derived olfactory neuronal tissues in the evaluation of treatment response of psychiatric disorders.

Overlapping Risky Decision-Making and Olfactory Processing Ability in HIV-Infected Individuals.

OBJECTIVE: Given neuroimaging evidences of overlap in the circuitries for decision-making and olfactory processing, we examined the hypothesis that impairment in psychophysical tasks of olfaction would independently predict poor performances on Iowa Gambling Task (IGT), a laboratory task that closely mimics real-life decision-making, in a US cohort of HIV-infected (HIV+) individuals. METHOD: IGT and psychophysical tasks of olfaction were administered to a Washington DC-based cohort of largely African American HIV+ subjects (N=100), and to a small number of demographically-matched non-HIV healthy controls (N=43) from a different study. Constructs of olfactory ability and decision-making were examined through confirmatory factor analysis (CFA). Structural equation models (SEMs) were used to evaluate the validity of the path relationship between these two constructs. RESULT: The 100 HIV+ participants (56% female; 96% African Americans; median age = 48 years) had median CD4 count of 576 cells/µl and median HIV RNA viral load <48 copies per milliliter. Majority of HIV+ participants performed randomly throughout the course of IGT tasks, and failed to demonstrate a learning curve. Confirmatory factor analysis provided support for a unidimensional factor underlying poor performances on IGT. Nomological validity for correlations between olfactory ability and IGT performance was confirmed through SEM. Finally, factor scores of olfactory ability and IGT performance strongly predicted 6 months history of drug use, while olfaction additionally predicted hallucinogen use. CONCLUSION: This study suggests that combination of simple, office-based tasks of olfaction and decision-making may identify those HIV+ individuals who are more prone to risky decision-making. This finding may have significant clinical, public health value if joint impairments in olfaction and IGT task correlates with more decreased activity in brain regions relevant to decision-making.

A Pilot Study of Reduced Olfactory Bulb Volume as a Marker of PTSD in Childhood Trauma-Exposed Adult HIV-Infected Patients.

Evidence suggests that olfactory bulb (OB), a key structure in odor processing, may also be involved in mechanisms of traumatic stress. In animals, chronic stress reduces OB plasticity, and olfactory bulbectomy results in stress-enhanced startle reflex and autonomic dysregulation. However, OB morphometry has not been adequately studied in the development of stress disorders following childhood trauma in humans. The researchers conducted a pilot study evaluating the relationships between OB volume, childhood trauma, and lifetime posttraumatic stress disorder (PTSD) in a sample of 16 HIV-positive individuals, 13 of whom were exposed to childhood trauma of 9 developed PTSD. Participants were recruited from a larger cohort of inner city-dwelling HIV-positive populations in Washington, DC. Mean OB volumes were significantly reduced when PTSD and non-PTSD groups were compared, p = .019, as well as when trauma-exposed PTSD-positive and trauma-exposed PTSD-negative groups were compared, p = .008. No significant difference was observed when trauma-exposed and nonexposed participants were compared. The association between PTSD and right OB volume remained strong p = 0.002 after adjusting for group differences in sex, age, depression, hippocampal volume, and total intracranial volume. Because this study is limited by small sample size, further elucidation of relationships between OB, trauma, and PTSD should be investigated in larger cross-sectional and prospective studies and in diverse cohorts.

Culturally Sensitive Approaches to Identification and Treatment of Depression among HIV Infected African American Adults: A Qualitative Study of Primary Care Providers' Perspectives.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent among HIV-infected (HIV+) individuals, and is associated with non-adherence to antiretroviral therapy (ART), and accelerated disease progression. MDD is underdiagnosed and undertreated among low-income African Americans, who are disproportionately impacted by the HIV epidemic. To improve detection and treatment of depression among African Americans living with HIV/AIDS, it is important to understand culturally and contextually relevant aspects of MDD and attitudes about mental health treatment. METHODS: A focus group session was conducted with seven providers and staff at a primary care center that serves a largely African-American community heavily impacted by the HIV epidemic in Washington, DC. Data were analyzed using an inductive approach to distill prominent themes, perspectives, and experiences among participating providers. RESULTS: Five themes emerged to characterize the lived experiences of HIV+ African-American patients: (a) Changes in perceptions of HIV over time; (b) HIV is comorbid with mental illness, particularly depression and substance abuse; (c) Stigma is associated with both HIV and depression; (d) Existing mental health services vary and are insufficient and (e) Suggestions for optimal treatment for comorbid HIV and depression. LIMITATION: This study reflects the views of providers from one clinic in this community. CONCLUSION: Substantial economic disadvantage, pervasive childhood adversity, limited education and limited resources jointly put members of this community at risk for acquisition of HIV and for development of depression and addictions. These contextual factors provide an important reminder that any patient-level depression identification or intervention in this community will have to be mindful of such circumstances.

Poor CD4 count is a predictor of untreated depression in human immunodeficiency virus-positive African-Americans.

AIM: To determine if efforts to improve antiretroviral therapy (ART) adherence minimizes the negative impact of depression on human immunodeficiency virus (HIV) outcomes. METHODS: A cross-sectional study of a clinic-based cohort of 158 HIV seropositive (HIV+) African Americans screened for major depressive disorder (MDD) in 2012. CD4 T lymphocyte (CD4+) counts were obtained from these individuals. Self-report on adherence to ART was determined from questionnaire administered during clinic visits. The primary outcome measure was conditional odds of having a poorer CD4+ count (< 350 cells/mm(3)). Association between CD4+ count and antidepressant-treated or untreated MDD subjects was examined controlling for self-reported adherence and other potential confounders. RESULTS: Out of 147 individuals with available CD4+ T lymphocyte data, 31% hadCD4+ count < 350 cells/mm(3) and 28% reported poor ART adherence. As expected the group with > 350 cells/mm(3) CD4+ T lymphocyte endorsed significantly greater ART adherence compared to the group with < 350 cells/mm(3) CD4+ T lymphocyte count (P < 0.004). Prevalence of MDD was 39.5% and 66% of individuals with MDD took antidepressants. Poor CD4+ T lymphocyte count was associated with poor ART adherence and MDD. Adjusting for ART adherence, age, sex and education, which were potential confounders, the association between MDD and poor CD4+ T lymphocyte remained significant only in the untreated MDD group. CONCLUSION: Therefore, CD4+ count could be a clinical marker of untreated depression in HIV+. Also, mental health care may be relevant to primary care of HIV+ patients.

Inhibition of HIV-1 by curcumin A, a novel curcumin analog.

Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 µM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 µM) compared to curcumin (IC50=12 µM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities.

Olfactory neurons obtained through nasal biopsy combined with laser-capture microdissection: a potential approach to study treatment response in mental disorders.

Bipolar disorder (BD) is a severe neuropsychiatric disorder with poorly understood pathophysiology and typically treated with the mood stabilizer, lithium carbonate. Animal studies as well as human genetic studies indicate that lithium affects molecular targets that are involved in neuronal growth, survival and maturation, and notably molecules involved in Wnt signaling. Given the ethical challenge to obtaining brain biopsies for investigating dynamic molecular changes associated with lithium-response in the central nervous system (CNS), one may consider the use of neurons obtained from olfactory tissues to achieve this goal.The olfactory epithelium contains olfactory receptor neurons at different stages of development and glial-like supporting cells. This provides a unique opportunity to study dynamic changes in the CNS of patients with neuropsychiatric diseases, using olfactory tissue safely obtained from nasal biopsies. To overcome the drawback posed by substantial contamination of biopsied olfactory tissue with non-neuronal cells, a novel approach to obtain enriched neuronal cell populations was developed by combining nasal biopsies with laser-capture microdissection. In this study, a system for investigating treatment-associated dynamic molecular changes in neuronal tissue was developed and validated, using a small pilot sample of BD patients recruited for the study of the molecular mechanisms of lithium treatment response.

Microwave synthesis of cyanine dyes.

Heptamethine cyanine dyes are a class of near infrared (NIR) dyes that have captured the interest of the scientific community. Although applications that utilize NIR fluorescence technology are rapidly expanding, progress is limited by the lack of availability and cost of suitable compounds that can be utilized as labels and/or probes. Herein, we report the use of microwave assisted organic synthesis of five NIR cyanine dyes in yields ranging from 64-83% with a significant reduction in solvent use. Spectra characteristics including absorbance and emission spectra, molar absorptivity, quantum yield, fluorescence lifetime, and redox potentials were determined for each synthesized NIR cyanine dye.