Papers by Barbara Lasater
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, Jan 15, 2009
Insomnia-pharmacology clinical trials routinely exclude primary sleep disorders, such as obstruct... more Insomnia-pharmacology clinical trials routinely exclude primary sleep disorders, such as obstructive sleep apnea (OSA) and periodic limb movement disorder (PLMD), with a single night of polysomnography (PSG). Given the expense of PSG, we examined whether a thorough clinical screening, combined with actigraphy, would successfully identify OSA and PLMD as part of baseline screening for a clinical trial of insomnia treatment in depressed patients. Of the 73 patients with a complete baseline dataset, 12 screened positive for OSA/PLMD (AHI > 15, or PLMAI > 15), while 61 "passed" the PSG screen. The OSA/PLMD+ patients were older (51.4 +/- 10.2 y) and took more naps (2.6 per week) than the OSA/PLMD- patients (41.3 +/- 12.8 y; and 1.1 naps per week). The combination of age and nap frequency produced a "good" receiver operating characteristic (ROC) model for predicting OSA/PLMD+, with the area under the curve of 0.82. There were no other demographic, sleep diary, or...
Journal of Clinical Sleep Medicine Jcsm Official Publication of the American Academy of Sleep Medicine, Aug 15, 2010
Study Objectives: Insomnia is associated with poor health related quality of life (HRQOL) in depr... more Study Objectives: Insomnia is associated with poor health related quality of life (HRQOL) in depressed patients. Prior clinical trials of hypnotic treatment of insomnia in depressed patients have shown improvement in HRQOL, but in these studies HRQOL was relegated to a secondary outcome, and objective measures of sleep were not undertaken. Design: Double-blind, randomized, placebo-controlled clinical trial Setting: Outpatient clinic and sleep laboratory Patients: 60 depressed, insomniac outpatients Interventions: one week of open-label fluoxetine (FLX), followed by 8 more weeks of FLX combined with either eszopiclone (ESZ) 3 mg or placebo at bedtime Measurements: The primary HRQOL measure was the daily living and role functioning subscale (DLRF) of the Basis-32. Other measures included the Q-LES-Q, self-reported sleep, PSG, actigraphy, depression severity (HRSD) Results: At the end of randomized treatment, patients receiving ESZ had lower (better) DLRF scores (0.81 ± 0.64) than those receiving placebo (1.2 ± 0.72), p = 0.01. The effect size for DLRF was 0.62, indicating a moderate effect. An advantage for ESZ was also seen in other measures of HRQOL, and most assessments of antidepressant efficacy and sleep. Women reported better end of treatment HRQOL scores than men. Conclusions: ESZ treatment of insomnia in depressed patients is associated with multiple favorable outcomes, including superior improvement in HRQOL, depression severity, and sleep. ClinicalTrials.gov Identifier: NCT00247624 Rosenquist PB. Treatment of insomnia in depressed insomniacs: effects on health-related quality of life, objective and self-reported sleep, and depression. J Clin Sleep Med 2010;6(4):322-329.
Sleep Medicine, 2010
Objective: Insomnia has been linked to suicidal ideas and suicide death in cross-sectional and lo... more Objective: Insomnia has been linked to suicidal ideas and suicide death in cross-sectional and longitudinal population-based studies. A link between insomnia and suicide has not been previously examined in the setting of a clinical trial. Herein we describe the relationship between insomnia and suicidal thinking during the course of a clinical trial for depression with insomnia. Methods: Sixty patients aged 41.5 ± 12.5 years (2/3 women) with major depressive episode and symptoms of insomnia received open-label fluoxetine for 9 weeks and also received blinded, randomized eszopiclone 3 mg or placebo at bedtime after the first week of fluoxetine. Insomnia symptoms were assessed with the Insomnia Severity Index (ISI), and suicidal ideation was assessed with The Scale for Suicide Ideation (SSI). Depression symptoms were assessed with the depressed mood item and the anhedonia item from the Hamilton Rating Scale for Depression-24 (HRSD24), as well as a sum score for all non-sleep and non-suicide items from the HRSD (HRSD20). Measurements were taken at baseline and weeks 1, 2, 4, 6, and 8. SSI was examined by generalized linear mixed models for repeated measures as the outcome of interest for all 60 participants with ISI and various mood symptoms as independent variables, with adjustment for age, gender, treatment assignment, and baseline SSI. Results: Higher levels of insomnia corresponded to significantly greater intensity of suicidal thinking (p < 0.01). The depressed mood item of the HRSD, and the sum of the HRSD20, both corresponded to greater suicidal thinking (p < 0.001). The anhedonia item did not correspond with suicidal thinking. When both ISI and the depressed mood item, or ISI and the anhedonia item, were included together in the same model, the ISI remained an independent predictor of suicidal thinking. Conclusions: The results support the concept that insomnia may be a useful indicator for suicidal ideation and now extend this idea into clinical trials. Insomnia remains an independent indicator of suicidal ideation, even taking into account the core symptoms of depression such as depressed mood and anhedonia. The complaint of insomnia during a depression clinical trial might indicate that more direct questioning about suicide is warranted.
Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine
Insomnia-pharmacology clinical trials routinely exclude primary sleep disorders, such as obstruct... more Insomnia-pharmacology clinical trials routinely exclude primary sleep disorders, such as obstructive sleep apnea (OSA) and periodic limb movement disorder (PLMD), with a single night of polysomnography (PSG). Given the expense of PSG, we examined whether a thorough clinical screening, combined with actigraphy, would successfully identify OSA and PLMD as part of baseline screening for a clinical trial of insomnia treatment in depressed patients. Of the 73 patients with a complete baseline dataset, 12 screened positive for OSA/PLMD (AHI > 15, or PLMAI > 15), while 61 "passed" the PSG screen. The OSA/PLMD+ patients were older (51.4 +/- 10.2 y) and took more naps (2.6 per week) than the OSA/PLMD- patients (41.3 +/- 12.8 y; and 1.1 naps per week). The combination of age and nap frequency produced a "good" receiver operating characteristic (ROC) model for predicting OSA/PLMD+, with the area under the curve of 0.82. There were no other demographic, sleep diary, or...
Sleep Medicine, 2011
Objectives: Our prior work has shown that there is improvement in self-reported sleep in persons ... more Objectives: Our prior work has shown that there is improvement in self-reported sleep in persons receiving placebo in hypnotic clinical trials. We examined the components of the ''placebo response'' in a hypnotic clinical trial. Methods: This was an exploratory analysis of a randomized, double-blind clinical trial of eszopiclone versus placebo in the treatment of persons with depression and insomnia who were also receiving fluoxetine at a clinic of a teaching hospital. Sixty adults with both depression and insomnia symptoms, who were free of significant primary sleep disorders, received open-label fluoxetine for 9 weeks. Patients were further randomized 1:1 to receive either masked eszopiclone 3 mg or placebo at bedtime after the first week of fluoxetine. We examined the respective contributions of three factors associated with the ''placebo effect'': (1) regression to the mean, (2) expectancy, and (3) social desirability. Results: There was evidence for regression to the mean for the continuous measurement of the Insomnia Severity Index (ISI) and the Hamilton Depression Rating Scale. There was evidence for expectancy in selfreported Wake After Sleep Onset, continuous measurement of ISI, and dichotomous remission/nonremitter measurement of ISI. There was evidence of social desirability affecting self-reported Total Sleep Time.
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, Jan 15, 2010
Insomnia is associated with poor health related quality of life (HRQOL) in depressed patients. Pr... more Insomnia is associated with poor health related quality of life (HRQOL) in depressed patients. Prior clinical trials of hypnotic treatment of insomnia in depressed patients have shown improvement in HRQOL, but in these studies HRQOL was relegated to a secondary outcome, and objective measures of sleep were not undertaken. Double-blind, randomized, placebo-controlled clinical trial. Outpatient clinic and sleep laboratory. 60 depressed, insomniac outpatients. One week of open-label fluoxetine (FLX), followed by 8 more weeks of FLX combined with either eszopiclone (ESZ) 3 mg or placebo at bedtime. The primary HRQOL measure was the daily living and role functioning subscale (DLRF) of the Basis-32. Other measures included the Q-LES-Q, self-reported sleep, PSG, actigraphy, depression severity (HRSD). At the end of randomized treatment, patients receiving ESZ had lower (better) DLRF scores (0.81 +/- 0.64) than those receiving placebo (1.2 +/- 0.72), p = 0.01. The effect size for DLRF was 0...
Infection and Immunity, 1999
We previously showed that heat-killed Borrelia burgdorferi spirochetes and lipidated outer surfac... more We previously showed that heat-killed Borrelia burgdorferi spirochetes and lipidated outer surface protein A (L-OspA) stimulated the in vitro production of interleukin-10 (IL-10) in peripheral blood mononuclear cells (PBMC) from uninfected humans and rhesus monkeys (G. Giambartolomei et al., Infect. Immun. 66:2691-2697, 1998). Here we demonstrate that uninfected human peripheral blood monocytes, but not B or T cells, are the cells that transcribe the IL-10 cytokine gene in response to heat-killed B. burgdorferi. B. burgdorferi similarly induced an upregulation of the IL-1 and IL-6 cytokine genes in monocytes and the production of IL-10 and IL-6 in culture supernatants of the human monocytic cell line THP-1. Purified L-OspA (but not unlipidated OspA [U-OspA] or U-OspC) also stimulated the production of both cytokines in THP-1 cells in a dosedependent fashion, suggesting that acylation of the OspA protein molecule is required for the production of both anti-and pro-inflammatory cytokines in naive monocytes. A lipohexapeptide that contained the tripalmitoyl-modified cysteine motif (Pam 3 Cys-Hex) of B. burgdorferi lipoproteins but with an arbitrary peptide sequence had the same effect. Monoclonal antibodies (MAbs) MY4 and 60bca, both of which bind to CD14 and are known to block lipopolysaccharide (LPS)-mediated cytokine production, were able to block L-OspAmediated IL-10 and IL-6 cytokine production. In contrast, MAb 26ic, which also binds to CD14 but does not block LPS function, failed to inhibit L-OspA-mediated cytokine production. These data suggest that activation of monocytes and production of both anti-and pro-inflammatory cytokines induced by lipoproteins proceeds via the CD14 receptor. LPS binding protein was not required for OspA-induced cytokine production. Our results demonstrate that pro-and anti-inflammatory cytokines induced by B. burgdorferi lipoproteins in PBMC are produced by monocytes and that lipoprotein and LPS signaling pathways share at least the initial signaling event that involves the CD14 receptor.
The Journal of Infectious Diseases, 2001
The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poo... more The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poorly understood. To investigate whether Wolbachia, symbiotic bacteria living within filarial nematodes, may be involved in disease progression, Wolbachia-specific immune responses were assayed in a group of Brugia malayi-infected rhesus monkeys. Serum IgG antibodies specific for a major Wolbachia surface protein (WSP) were detected in 2 of 12 infected monkeys. It is interesting that both of these monkeys developed lymphedema after becoming amicrofilaremic. WSP-specific antibody responses were temporally associated with increases in antifilarial IgG1 antibodies as well as lymphedema development. These findings suggest that Wolbachia may be important in understanding disease caused by filarial worms.
Infection and Immunity, 2002
We have recently demonstrated that interleukin-10 (IL-10), produced by THP-1 monocytes in respons... more We have recently demonstrated that interleukin-10 (IL-10), produced by THP-1 monocytes in response to Borrelia burgdorferi lipoproteins, dampens the production of concomitantly elicited inflammatory cytokines. Thus, IL-10 could potentially down-regulate inflammatory and microbicidal effector mechanisms of the innate immune response to a B. burgdorferi infection, facilitating the establishment of the spirochete. To understand the mechanism(s) implicated in the regulation of the synthesis and release of IL-10 during early infection, we investigated the autocrine effects of IL-6, IL-12, tumor necrosis factor alpha (TNF-␣), and IL-10 itself, as well as the exocrine effect of IFN-␥ on the production of macrophage-derived IL-10 with lipoprotein as a stimulant. In addition, in view of the differences in the receptor and signal transduction pathways of lipopolysaccharide (LPS) and bacterial lipoproteins, we also investigated the effects described above with LPS as a stimulant. The THP-1 human monocytic cell line and purified recombinant lipidated OspA (L-OspA) were used as the model target cell and stimulant, respectively. TNF-␣ increased the production of IL-10, as elicited by lipoproteins. The production of IL-10 by THP-1 cells stimulated with L-OspA was autoregulated by a negative feedback mechanism involving the IL-10 receptor (IL-10R). Exogenous IFN-␥ significantly inhibited the production of IL-10. Both autocrine (IL-10) and exocrine (IFN-␥) inhibition of IL-10 production resulted in an increase in the production of the proinflammatory cytokines IL-6 and IL-12. The same results were obtained when the stimulant was LPS. The results further illustrate that IL-10 may play a pivotal role in Lyme disease pathogenesis. Moreover, the regulation of its production with lipoprotein as a stimulant is indistinguishable from that observed when LPS acts as a stimulant.
Infection and Immunity, 2000
We determined previously that lipoproteins of Borrelia burgdorferi stimulate inflammatory and ant... more We determined previously that lipoproteins of Borrelia burgdorferi stimulate inflammatory and anti-inflammatory cytokines (interleukin-10 [IL-10]) in monocytes. IL-10 could have an effect on innate and acquired immune responses to B. burgdorferi and influence the magnitude of the infectious inoculum and disease outcome. To understand the mechanism(s) of IL-10 action during early infection, when innate immunity expressed chiefly by skin macrophages is key, we investigated the effect of exogenous and endogenous IL-10 on the production of the macrophage-derived cytokines IL-6, IL-1, IL-12, and tumor necrosis factor alpha (TNF-␣). We used the THP-1 human monocytic cell line and recombinant lipidated OspA (L-OspA) as the model target cell and stimulant, respectively. To determine the kinetics of cytokine production by THP-1 cells, we stimulated them with L-OspA and also with heat-killed B. burgdorferi cells (HBb) and lipopolysaccharide (LPS). Exogenous IL-10 dampened production of inflammatory cytokines, as elicited by lipoproteins. The inhibition of endogenous IL-10 function by anti-IL-10 antibody reduced the production of IL-12 and IL-6 but not that of IL-1 and TNF-␣. An inspection of the kinetics of cytokine production clarified this finding. TNF-␣ was produced prior to, and IL- was produced at the same time as, IL-10, whereas IL-6 and IL-12 were produced later. HBb, LPS, and L-OspA yielded similar kinetics of cytokine production. This result reinforces the notion that lipoproteins are the functional molecules in HBb and perhaps in vivo. It indicates also that signaling pathways utilized by LPS and lipoproteins may be extensively shared. The results are consistent with a major role played by IL-10 in controlling the initial phase of infection with this spirochete.
Experimental Parasitology, 1998
monkeys. The rhesus could be an extremely useful model for understanding the evolution of patholo... more monkeys. The rhesus could be an extremely useful model for understanding the evolution of pathology and pathogenesis of the dis-and Campeau, R. J. 1998. Histopathological, lymphoscintigraphical, and immunological changes in the inguinal lymph nodes of rhesus ease. ᭧ 1998 Academic Press Index Descriptors and Abbreviations: Rhesus monkey; Macaca mu-monkeys during the early course of infection with Brugia malayi. Experimental Parasitology. 89, 143-152. The relationship of the early latta; Brugia malayi; nematode; filariasis; lymphatic; blastogenesis; lymphoscintigraphy; flow cytometry; pathology; lymphocytes. lymphatic pathophysiological alterations with those of tissue inflammatory and cellular responses in the inguinal lymph nodes of Brugia malayi-infected rhesus monkeys was examined. Each of five animals was inoculated subcutaneously in the right calf with 200 third stage larvae (L 3 ) and 5 weeks later, before the onset of patency [10 to 12 weeks postinoculation (PI)], their right inguinal nodes began to show 143
Experimental Parasitology, 1998
European Journal of Immunology, 2003
Brain invasion by Borrelia burgdorferi, the agent of Lyme disease, results in an inflammatory and... more Brain invasion by Borrelia burgdorferi, the agent of Lyme disease, results in an inflammatory and neurodegenerative disorder called neuroborreliosis. In humans, neuroborreliosis has been correlated with enhanced concentration of glial fibrillary acidic protein in the cerebrospinal fluid, a sign of astrogliosis. Rhesus monkeys infected by us with B. burgdorferi showed evidence of astrogliosis, namely astrocyte proliferation and apoptosis. We formulated the hypothesis that astrogliosis could be caused by spirochetal lipoproteins. We established primary cultures of rhesus monkey astrocytes and stimulated the cells with recombinant lipidated outer surface protein A (L-OspA), a model B. burgdorferi lipoprotein, and tripalmitoyl-S-glyceryl-Cys-Ser-Lys 4 -OH (Pam 3 Cys), a synthetic lipopeptide that mimics the structure of the lipoprotein lipid moiety. L-OspA elicited not only astrocyte proliferation but also apoptosis, two features observed during astrogliosis. Astrocytes produced both IL-6 and TNF- § in response to L-OspA and Pam 3 Cys. Proliferation induced by L-OspA was diminished in the presence of an excess of anti-IL-6 antibody, and apoptosis induced by this lipoprotein was completely suppressed with anti-TNF- § antibody. Hence, IL-6 contributes to, and TNF- § determines, astrocyte proliferation and apoptosis, respectively, as elicited by lipoproteins. Our results provide proof of the principle that spirochetal lipoproteins could be key virulence factors in Lyme neuroborreliosis, and that astrogliosis might contribute to neuroborreliosis pathogenesis. Abbreviations: Pam 3 Cys: Tripalmitoyl-S-glyceryl-Cys-Ser-Lys 4 -OH L-OspA: Lipidated outer surface protein A CNS: Central nervous system CSF: Cerebrospinal fluid BrdU: Bromodeoxyuridine TUNEL: Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling PI: Propidium iodide GFAP: Glial fibrillary acidic protein Eur.
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Papers by Barbara Lasater