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1.  Methods for the Design of Vasomotor Symptom Trials: The MsFLASH Network 
Menopause (New York, N.Y.)  2014;21(1):10.1097/GME.0b013e31829337a4.
This report describes the "Menopausal Strategies: Finding Lasting Answers to Symptoms and Health” (MsFLASH) network and methodological issues addressed in designing and implementing vasomotor symptom trials.
Established in response to a National Institute of Health request for applications, the network was charged with conducting rapid throughput randomized trials of novel and understudied available interventions postulated to alleviate vasomotor and other menopausal symptoms. Included are descriptions of and rationale for criteria used for interventions and study selection, common eligibility and exclusion criteria, common primary and secondary outcome measures, consideration of placebo response, establishment of a biorepository, trial duration, screening and recruitment, statistical methods, and quality control. All trial designs are presented including: 1) a randomized, double-blind, placebo-controlled clinical trial designed to evaluate effectiveness of the selective serotonin reuptake inhibitor escitalopram in reducing vasomotor symptom frequency and severity; 2) a 2×3 factorial design trial to test three different interventions (yoga, exercise, and omega-3 supplementation) for improvement of vasomotor symptom frequency and bother; and 3) a three-arm comparative efficacy trial of the serotonin-norepinephrine reuptake inhibitor venlafaxine and low-dose oral estradiol versus placebo for reducing vasomotor symptom frequency compared to placebo. The network’s structure and governance are also discussed.
The methods used and lessons learned in the MsFLASH trials are shared to encourage and support the conduct of similar trials and encourage collaborations with other researchers.
PMCID: PMC3796184  PMID: 23760428
2.  Antidepressant Use in Pregnancy and the Risk of Cardiac Defects 
The New England journal of medicine  2014;370(25):2397-2407.
There is controversy regarding whether the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants in pregnancy is associated with increased risks for congenital cardiac defects. In particular, concerns exist about a possible association between paroxetine and right ventricular outflow tract obstruction (RVOTO), and between sertraline and ventricular septal defects (VSD).
We performed a cohort study nested in the 2000–2007 nationwide Medicaid Analytic eXtract. The study included 949,504 pregnant women enrolled in Medicaid from three months before conception through one month post delivery, and their live-born infants. We compared the risk of major cardiac defects in women with antidepressant medication use during the first trimester versus no use, restricting the cohort to women with depression and using propensity score adjustment to control for depression severity and other potential confounders.
64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6,403 infants not exposed to antidepressants were born with a cardiac defect (72.3 per 10,000), compared with 580 infants exposed (90.1 per 10,000). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. For SSRIs, relative risks for any cardiac defect were 1.25 (95%CI, 1.13–1.38) unadjusted, 1.12 (1.00–1.26) depression-restricted, and 1.06 (0.93–1.22) depression-restricted and fully-adjusted. We found no significant associations between the use of paroxetine and RVOTO (1.07, 0.59–1.93), or the use of sertraline and VSD (1.04, 0.76–1.41).
Results of this large population-based cohort study suggest no substantial increased risk of cardiac malformations attributable to SSRIs.
PMCID: PMC4062924  PMID: 24941178
3.  Randomized Controlled Trial of Low-Dose Estradiol and the SNRI Venlafaxine for Vasomotor Symptoms 
JAMA internal medicine  2014;174(7):1058-1066.
Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine is used widely as a non-hormonal treatment. While clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial.
To determine the efficacy and tolerability of low-dose oral 17-beta-estradiol and low-dose venlafaxine XR in alleviating vasomotor symptoms.
Design and Participants
339 peri- and postmenopausal women with ≥2 bothersome vasomotor symptoms per day (mean 8.1, SD 5.3/day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites November 2011—October 2012.
Participants were randomized to double-blinded treatment with low-dose oral 17-beta-estradiol 0.5-mg/day (n=97), low-dose venlafaxine XR 75-mg/day (n=96), or placebo (n=146) for 8 weeks.
Main Outcomes
Primary outcome was the mean daily frequency of vasomotor symptoms after 8 weeks of treatment. Secondary outcomes were vasomotor symptom severity, bother and interference. Intent-to-treat analyses compared change in vasomotor symptom frequency between each active intervention and placebo and between the two active treatments.
Compared to baseline, mean vasomotor symptom frequency at week 8 decreased by 53% with estradiol, 48% with venlafaxine, and 29% with placebo. Estradiol reduced the frequency of symptoms by 2.3 (95% CI 1.3–3.4) more per day than placebo (p<0.001), and venlafaxine by 1.8 (95% CI 0.8–2.7) more per day than placebo (p=0.005). Results were consistent for VMS severity, bother and interference. Low-dose estradiol reduced symptom frequency by 0.6 more per day than venlafaxine (95% CI, 1.8 more per day to 0.6 fewer per day than venlafaxine; p=0.09). Treatment satisfaction was highest (69%) on estradiol (p<0.001 versus placebo), lowest (39%) on placebo, and intermediate (52%) for venlafaxine (p=0.06 versus placebo). Both interventions were well tolerated.
Low-dose oral estradiol and venlafaxine are both effective treatments for vasomotor symptoms in midlife women. While efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small in magnitude and of uncertain clinical relevance. identifier
PMCID: PMC4179877  PMID: 24861828
4.  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.
PMCID: PMC3649637  PMID: 23589585
bias; depression; prospective studies
5.  Design and Methods of a Multi-Site, Multi-Behavioral Treatment Trial for Menopausal Symptoms: The MsFLASH Experience 
Contemporary clinical trials  2013;35(1):25-34.
Behavioral strategies are recommended for menopausal symptoms, but little evidence exists regarding efficacy.
Describe design and methodology of a randomized controlled 3 by 2 factorial trial of yoga, exercise and omega-3 fatty acids.
Women from three geographic areas with a weekly average of ≥14 hot flashes/night sweats, who met exclusion/inclusion criteria, were randomized to 12 weeks of: 1) yoga classes and daily home practice; 2) supervised, facility-based aerobic exercise training; or 3) usual activity. Women in each arm were further randomized to either omega-3 supplement or placebo. Standardized training, on-going monitoring, and site visits were adopted to ensure consistency across sites and fidelity to the intervention. Participant adherence to the intervention protocol was monitored continuously, and retention was actively encouraged by staff. Information on adverse events was systematically collected.
Of 7,377 women who responded to mass mailings, 355 (4.8%) were randomized; mean age was 54.7 (sd=3.7), 26.2% were African American, 81.7% were post-menopausal, and mean baseline frequency of daily hot flashes/night sweats was 7.6 (sd=3.8). Adherence of ≥ 80% was 59% for yoga, 77% for exercise training, and 80% for study pills. Final week 12 data were collected from 95.2%
Conducting a multi-site, multi-behavioral randomized trial for menopausal symptoms is challenging but feasible. Benefits included cost-effective study design, centralized recruitment, and methodologic standardization.
PMCID: PMC3670607  PMID: 23462342
vasomotor symptoms; randomized controlled trial; yoga; exercise; omega-3 fatty acids; factorial design
Menopause (New York, N.Y.)  2013;20(3):261-268.
Vasomotor symptoms (VMS) recur after discontinuation of hormonal therapy. Selective serotonin reuptake-inhibitors (SSRI) are used increasingly to treat VMS, but whether VMS recur after cessation of SSRI is unknown. We hypothesized that relapse of VMS back to baseline levels after SSRI cessation would be common and predicted by menopausal and psychological characteristics.
Recurrence of VMS (frequency, severity, and bother) was measured using daily diaries for 3 weeks after cessation of escitalopram, which was administered in an 8-week randomized placebo-controlled trial in peri/postmenopausal women with hot flashes and night sweats. Blinding of staff and participants was maintained throughout. Relapse was defined as mean daily VMS frequency, severity, or bother ≤20% lower than pre-treatment levels.
Of 76, 57, and 51 women included in the analysis for VMS frequency, severity, and bother, respectively, 34.2%, 38.6%, and 37.3% had relapse of VMS frequency, severity, and bother. In adjusted models, VMS frequency relapse was predicted by higher levels of pre-treatment insomnia symptoms (p=0.02) and a weaker response to escitalopram (p=0.03).
Of women whose VMS improved on escitalopram, approximately one-third relapsed swiftly after discontinuation of the medication. Those with pre-treatment insomnia and those with a weaker response to escitalopram may be at greatest risk for VMS relapse after treatment discontinuation. Women should be educated about the likelihood of VMS symptom relapse when they discontinue SSRI’s after receiving benefit from short-term treatment.
PMCID: PMC3561495  PMID: 23435022
hot flash; vasomotor symptoms; SSRI; escitalopram; randomized trial; recurrence; relapse
7.  Effects of Escitalopram on Menopause-specific Quality of Life and Pain in Healthy Menopausal Women with Hot Flashes: A Randomized Controlled Trial 
Maturitas  2012;73(4):361-368.
To evaluate the effects of escitalopram 10-20 mg/day on menopause-related quality of life and pain in healthy menopausal women with hot flashes.
Study Design
A double-blind, placebo-controlled randomized trial of escitalopram 10-20 mg/day vs. identical placebo was conducted among 205 women ages 40-62 years with an average of > 4 daily hot flashes recruited at 4 clinical sites from July 2009 - June 2010.
Main Outcome Measures
The primary trial outcomes, reported previously, were the frequency and severity of vasomotor symptoms at 8 weeks. Here, we report on the pre-specified secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and the Pain Intensity and Interference Scale (PEG).
Outcome data were collected on 97% of randomized women and 87% of women took at least 70% of their study medication. Treatment with escitalopram resulted in significantly greater improvement in total MENQOL scores (mean difference at 8 weeks of −0.41; 95% confidence interval (CI) −0.71 to −0.11; p<0.001), as well as Vasomotor, Psychosocial, and Physical domain scores with the largest difference seen in the Vasomotor domain (mean difference −0.75; 95% CI −1.28 to −0.22; p=0.02). There was no significant treatment group difference for the Sexual Function domain. Escitalopram treatment resulted in statistically significant improvements in PEG scores compared to placebo (mean treatment group difference at 8 weeks of −0.33; 95% CI - 0.81 to 0.15; p=0.045).
Treatment with escitalopram 10-20 mg/day in healthy women with vasomotor symptoms significantly improved menopause-related quality of life and pain.
PMCID: PMC3645479  PMID: 23031421
antidepressants; escitalopram; menopausal quality of life; randomized controlled trial; vasomotor symptoms
8.  A Prospective, Naturalistic, Blinded Study of Early Neurobehavioral Outcomes for Infants Following Prenatal Antidepressant Exposure 
The Journal of clinical psychiatry  2011;72(7):1002-1007.
This study examined the potential effects of antidepressant exposure in pregnancy on early infant neurobehavioral outcomes.
In this prospective, naturalistic study, neurobehavioral assessments using the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) were completed by blinded raters between March 2001 and August 2005 on 64 infants who were born to mothers in 1 of 3 categories: (1) women with a history of DSM-IV-diagnosed major depressive disorder (MDD) who were treated with antidepressants during pregnancy, (2) women with a history of DSM-IV-diagnosed MDD who discontinued or chose not to be treated with antidepressants during pregnancy, and (3) a nonpsychiatric control group. Summary scores for the BNBAS were obtained within the first week of life and at 6 to 8 weeks of age.
No significant differences were observed between groups at either the first week after delivery or at 6 to 8 weeks of age on any of the summary scores for the 7 major clusters of the BNBAS.
Antidepressant exposure during pregnancy does not appear to have major adverse effects on indices of early infant neurobehavioral development during the first 2 months of life as assessed by the BNBAS. While this finding is encouraging, further studies with larger samples and longer follow-up are needed.
PMCID: PMC3785073  PMID: 21672498
9.  Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: a preliminary open trial 
Menopause (New York, N.Y.)  2011;18(3):279-284.
We sought to obtain preliminary data regarding the efficacy of omega-3 fatty acids for major depressive disorder associated with the menopausal transition. Secondary outcomes were assessed for vasomotor symptoms (or hot flashes).
After a single-blind placebo lead-in, participants received 8 weeks of treatment with open-label omega-3 fatty acid capsules (eicosapentaenoic acid and docosahexaenoic acid, 2 g/d). The Montgomery-Asberg Depression Rating Scale (MADRS) was the primary outcome measure. Hot flashes were monitored prospectively using daily diaries and the Hot Flash Related Daily Interference Scale. Blood samples for plasma pretreatment and post treatment essential fatty acid assays were obtained. Because of the small sample size, data were analyzed using nonparametric techniques.
Of 20 participants treated with omega-3 fatty acids, 19 (95%) completed the study. None discontinued because of adverse effects. The pretreatment and final mean MADRS scores were 24.2 and 10.7, respectively, reflecting a significant decrease in MADRS scores (P G 0.0001). The response rate was 70% (MADRS score decrease of Q50%), and the remission rate was 45% (final MADRS score of e7). Responders had significantly lower pretreatment docosahexaenoic acid levels than nonresponders did (P = 0.03). Hot flashes were present in 15 (75%) participants. Among those with hot flashes at baseline, the number of hot flashes per day improved significantly from baseline (P = 0.02) and Hot Flash Related Daily Interference Scale scores decreased significantly (P = 0.006).
These data support further study of omega-3 fatty acids for major depressive disorder and hot flashes in women during the menopausal transition.
PMCID: PMC3195360  PMID: 21037490
Depression; Major depressive disorder; Omega-3 fatty acids; Menopause; Eicosapentaenoic acid; Docosahexaenoic acid
10.  Analysis of Arf GTP-binding Protein Function in Cells 
This unit describes techniques and approaches that can be used to study the functions of the ADP-ribosylation factor (Arf) GTP-binding proteins in cells. There are 6 mammalian Arfs and many more Arf-like proteins (Arls) and these proteins are conserved in eukaryotes from yeast to man. Like all GTPases, Arfs cycle between GDP-bound, inactive and GTP-bound active conformations, facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) that catalyze GTP binding and hydrolysis respectively. Here we describe approaches that can be taken to examine the localization and function of Arf and Arl proteins in cells (Protocol 1). We also provide a simple protocol for measuring activation (GTP-binding) of specific Arf proteins in cells using a pull-down assay (Protocol 2). We then discuss approaches that can be taken to assess function of GEFs and GAPs in cells (Protocol 3).
PMCID: PMC2969170  PMID: 20853342
Arf; GTP-binding proteins; guanine nucleotide exchange factors; GTPase activating proteins
11.  Efficacy of Escitalopram for Hot Flashes in Healthy Menopausal Women: A Randomized Controlled Trial 
Concerns for the risks of hormone therapy have resulted in its decline and a demand for non-hormonal treatments with demonstrated efficacy for hot flashes.
Determine the efficacy and tolerability of 10–20 mg/day escitalopram, a selective serotonin reuptake inhibitor, in alleviating the frequency, severity and bother of menopausal hot flashes.
Design, Setting and Patients
Randomized, double-blind, placebo-controlled, parallel arm trial for 8 weeks in a sample stratified by race (African American n=95; white n=102) and conducted at 4 MsFlash network sites between July 2009 and June 2010. Of 205 women randomized, 194 (95%) completed week 8 (intervention endpoint), and 183 completed post-treatment follow-up.
Main Outcome Measures
Primary outcomes were the frequency and severity of hot flashes assessed by prospective daily diaries. Secondary outcomes were hot flash "bother" recorded on daily diaries and clinical improvement (hot flash frequency >=50% decrease from baseline).
Hot flash frequency was 9.78/day (SD 5.60) at baseline. At week 8, reduction in hot flash frequency was greater in the escitalopram group versus placebo (−4.60, SD 4.28 and −3.20, SD 4.76, respectively, P=0.004). Fifty-five percent of the escitalopram group (versus 36% of the placebo group) reported >=50% decreases in hot flash frequency (P=0.009). Differences in decreases in the severity and bother of hot flashes were significant (P=0.003 and P=0.013, respectively), paralleling the decreases in hot flash frequency. Three weeks after treatment ended, hot flash frequency increased in the escitalopram group to the level of the placebo group, which remained stable in the follow-up interval (P=0.020). Overall discontinuation due to side effects was 4% (7 drug, 2 placebo).
Escitalopram 10–20 mg/day provides non-hormonal off-label treatment for menopausal hot flashes that is effective and well-tolerated in healthy women.
PMCID: PMC3129746  PMID: 21245182
12.  A serotonin transporter gene polymorphism predicts peripartum depressive symptoms in an at risk psychiatric cohort 
Journal of psychiatric research  2009;44(10):640-646.
Peripartum major depressive disorder (MDD) is a prevalent psychiatric disorder with potential detrimental consequences for both mother and child. Despite its enormous health care relevance, data regarding genetic predictors of peripartum depression are sparse. The aim of this study was to investigate associations of the serotonin-transporter linked polymorphic region (5-HTTLPR) genotype with peripartum MDD in an at-risk population.
274 women with a prior history of MDD were genotyped for 5-HTTLPR and serially evaluated in late pregnancy (gestational weeks 31-40), early postpartum (week 1-8) and late postpartum (week 9-24) for diagnosis of a current major depressive episode (MDE) and depressive symptom severity.
5-HTTLPR S-allele carrier status predicted the occurrence of a MDE in the early postpartum period only (OR = 5.13, p = 0.017). This association persisted despite continued antidepressant treatment.
The 5-HTTLPR genotype may be a clinically relevant predictor of early postpartum depression in an at-risk population.
PMCID: PMC2891911  PMID: 20045118
peripartum depression; pregnancy; serotonin transporter; 5-HTTLPR; polymorphism; at risk population
13.  Depression Vulnerability Predicts Cigarette Smoking among College Students: Gender and Negative Reinforcement Expectancies as Contributing Factors 
Addictive behaviors  2010;35(6):607-611.
This study examined the association between vulnerability to depression and smoking behavior in college students in 1214 college students (54% female), and evaluated gender and expectancies of negative affect reduction as moderators or mediators of this relationship. Depression vulnerability predicted smoking in females, but not males. The relationship between depression vulnerability and smoking status was mediated by expectancies of negative affect reduction in females only. Female college students who are vulnerable to depression may smoke because they expect smoking to relieve negative affect. Smoking interventions for college females may increase in effectiveness by targeting depression and emphasizing mood regulation.
PMCID: PMC2838988  PMID: 20181432
Cigarette Smoking; College Students; Depression; Gender; Negative Affect Reduction; Smoking Expectancies
14.  Pharmacological Treatment of Postpartum Women with New Onset Major Depressive Disorder: A Randomized Controlled Trial with Paroxetine 
Approximately 6–8% of postpartum women suffer from major depressive disorder (MDD) but only a few controlled trials have investigated the efficacy of pharmacological treatments. The current study determined the relative efficacy of paroxetine compared to placebo in the treatment of acute postpartum MDD.
This was an 8-week, multi-center, parallel, placebo-controlled trial of paroxetine for treatment of postpartum depression. Subjects were eligible if they had an onset of MDD after, but within 3 months of delivery and had a minimum score of 16 on the 17-item Hamilton Rating Scale for Depression (HRS-D17) at intake. Seventy women were randomly assigned to either immediate-release paroxetine or matching placebo and 31 completed the trial. Subjects were reassessed with the HRS-D17, the Inventory of Depressive Symptomatology-Self Report (IDS-SR) form and the Clinical Global Impression (CGI) Scales.
Both groups improved over time and did not differ significantly on HRS-D17 or the IDS-SR at follow-up. However, greater improvement in overall clinical severity was found for the paroxetine (CGI-S =1.8 ±1.4) compared with the control group (CGI-S=3.1 ± 1.4; p=0.05). The paroxetine group also had a significantly higher rate of remission, compared to the placebo group (37% vs 15%; OR=3.5; 95% CI = 1.1–11.5). The rate of adverse effects did not differ significantly between groups.
Study results were limited by lower than expected enrollment and higher than anticipated attrition. Nonetheless, paroxetine treatment was associated with a significantly higher rate of remission among women with postpartum onset of MDD.
PMCID: PMC3073141  PMID: 18363420
postpartum depression; depressive episode; paroxetine; postnatal
15.  Psychosocial predictors of the onset of anxiety disorders in women: Results from a prospective 3-year longitudinal study 
Journal of anxiety disorders  2009;23(8):1165-1169.
In a prospective, longitudinal, population-based study of 643 women participating in the Harvard Study of Moods and Cycles we examined whether psychosocial variables predicted a new or recurrent onset of an anxiety disorder. Presence of anxiety disorders was assessed every six months over three years via structured clinical interviews. Among individuals who had a new episode of anxiety, we confirmed previous findings that history of anxiety, increased anxiety sensitivity (the fear of anxiety related sensations), and increased neuroticism were significant predictors. We also found trend level support for assertiveness as a predictor of anxiety onset. However, of these variables, only history of anxiety and anxiety sensitivity provided unique prediction. We did not find evidence for negative life events as a predictor of onset of anxiety either alone or in interaction with other variables in a diathesis-stress model. These findings from a prospective longitudinal study are discussed in relation to the potential role of such predictors in primary or relapse prevention efforts.
PMCID: PMC2760601  PMID: 19699609
16.  The association of depressive, anxiety, and stress symptoms and postpartum relapse to smoking: A longitudinal study 
Nicotine & Tobacco Research  2009;11(6):707-714.
The aim of this prospective repeated measures, mixed-methods observational study was to assess whether depressive, anxiety, and stress symptoms are associated with postpartum relapse to smoking.
A total of 65 women who smoked prior to pregnancy and had not smoked during the last month of pregnancy were recruited at delivery and followed for 24 weeks. Surveys administered at baseline and at 2, 6, 12, and 24 weeks postpartum assessed smoking status and symptoms of depression (Beck Depression Inventory [BDI]), anxiety (Beck Anxiety Inventory [BAI]), and stress (Perceived Stress Scale [PSS]). In-depth interviews were conducted with women who reported smoking.
Although 92% of the participants reported a strong desire to stay quit, 47% resumed smoking by 24 weeks postpartum. Baseline factors associated with smoking at 24 weeks were having had a prior delivery, not being happy about the pregnancy, undergoing counseling for depression or anxiety during pregnancy, and ever having struggled with depression (p < .05). In a repeated measures regression model, the slope of BDI scores from baseline to the 12-week follow-up differed between nonsmokers and smokers (−0.12 vs. +0.11 units/week, p = .03). The slope of PSS scores also differed between nonsmokers and smokers (−0.05 vs. +0.08 units/week, p = .04). In qualitative interviews, most women who relapsed attributed their relapse and continued smoking to negative emotions.
Among women who quit smoking during pregnancy, a worsening of depressive and stress symptoms over 12 weeks postpartum was associated with an increased risk of smoking by 24 weeks.
PMCID: PMC2722237  PMID: 19436040
17.  Clathrin-Independent Endocytosis: A unique Platform for Cell Signaling and PM Remodeling 
Cellular signalling  2008;21(1):1-6.
There is increasing interest in endocytosis that occurs independently of clathrin coats and the fates of membrane proteins internalized by this mechanism. The appearance of clathrin-independent endocytic and membrane recycling pathways seems to vary with different cell types and cargo molecules. In this review we focus on studies that have been performed using Hela and COS cells as model systems for understanding this membrane trafficking system. These endosomal membranes contain signaling molecules including H-Ras, Rac1, Arf6 and Rab proteins, and a lipid environment rich in cholesterol and PIP2 providing a unique platform for cell signaling. Furthermore, activation of some of these signaling molecules (H-Ras, Rac and Arf6) can switch the constitutive form of clathrin-independent endocytosis into a stimulated one, associated with PM ruffling and macropinocytosis.
PMCID: PMC2754696  PMID: 18647649
Arf6; clathrin-independent; endocytosis; macropinocytosis; phosphoinositides; signaling; src; ras
18.  Smoking Prevalence and Awareness Among Undergraduate and Health Care Students 
Approximately 10,000 undergraduates from 12 Texas colleges and universities and 350 health care students completed a Web-based survey assessing the prevalence and awareness of cigarette smoking. There were few differences between health care and undergraduate students on trying smoking or quitting smoking. Health care students reported lower rates of current smoking than undergraduate students, even though both groups demonstrated similar knowledge of tobacco-related health risks. Gender differences are discussed. Findings suggest that tobacco awareness programs should continue to target young adults as an at-risk population, and that health care training programs should place a greater emphasis on tobacco cessation.
PMCID: PMC2757300  PMID: 18463994
19.  Saliva estriol levels in women with and without prenatal antidepressant treatment 
Biological psychiatry  2008;64(6):533-537.
Prenatal antidepressant use has been associated with shorter pregnancy duration and an increased risk for preterm birth. This study measured saliva levels of estriol, a hormone which increases exponentially in the few weeks before spontaneous labor, in pregnant women with and without antidepressant treatment.
Saliva estriol levels were obtained across the day at three time points during pregnancy in 77 subjects with either a history of DSM-IV major depressive disorder (MDD) who were treated with antidepressants in pregnancy (Group 1), a history of DSM-IV major depressive disorder who were not treated or had limited exposure to antidepressants during pregnancy (Group 2), and a normal control group (Group 3).
Mean estriol levels in the second half of pregnancy were significantly higher for Group 1 (h/o MDD, on meds) than Group 2 (h/o MDD, off meds) or Group 3 (control).
Prenatal antidepressant use was associated with significantly higher saliva estriol levels in the second half of pregnancy. Whether estriol reflects a causal mechanism by which women on antidepressants have shorter pregnancy duration remains to be further studied.
PMCID: PMC2562039  PMID: 18495086
20.  Active Arf6 Recruits ARNO/Cytohesin GEFs to the PM by Binding Their PH Domains 
Molecular Biology of the Cell  2007;18(6):2244-2253.
ARNO is a soluble guanine nucleotide exchange factor (GEF) for the Arf family of GTPases. Although in biochemical assays ARNO prefers Arf1 over Arf6 as a substrate, its localization in cells at the plasma membrane (PM) suggests an interaction with Arf6. In this study, we found that ARNO activated Arf1 in HeLa and COS-7 cells resulting in the recruitment of Arf1 on to dynamic PM ruffles. By contrast, Arf6 was activated less by ARNO than EFA6, a canonical Arf6 GEF. Remarkably, Arf6 in its GTP-bound form recruited ARNO to the PM and the two proteins could be immunoprecipitated. ARNO binding to Arf6 was not mediated through the catalytic Sec7 domain, but via the pleckstrin homology (PH) domain. Active Arf6 also bound the PH domain of Grp1, another ARNO family member. This interaction was direct and required both inositol phospholipids and GTP. We propose a model of sequential Arf activation at the PM whereby Arf6-GTP recruits ARNO family GEFs for further activation of other Arf isoforms.
PMCID: PMC1877112  PMID: 17409355
21.  College campus smoking policies and programs and students' smoking behaviors 
BMC Public Health  2005;5:74.
Although tobacco use in the United States has declined over the past 20 years, cigarette use among college students remains high. Additional research is thus needed to determine how university tobacco control policies and preventive education programs affect college students' smoking behaviors.
Approximately 13,000 undergraduate students at 12 universities or colleges in the state of Texas completed a web-based survey. College smoking policies were obtained from a survey of college administrators and from college websites. Logistic regression analyses were conducted to estimate the effects of individual smoking policies and programs on the odds of cigarette smoking.
Of the individual programs, only having a preventive education program on campus was associated with lower odds of smoking. The existence of smoking cessation programs and designated smoking areas were associated with higher odds of smoking. Policies governing the sale and distribution of cigarettes were insignificantly associated with smoking.
Rather than focusing on policies restricting cigarette sales and use, college administrators should consider implementing or expanding tobacco prevention and education programs to further reduce student smoking rates.
PMCID: PMC1177969  PMID: 16001977

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