Faculty Bibliography

Recent studies have indicated a gene-by-environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques (Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one 's' allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A 'juvenile' CSF sample was obtained at approximately 3 years of age. CSF CRF concentrations were elevated specifically in the VFD 's/s' and 's/l' allele group in comparison to each of the remaining three groups, indicating a gene-by-environment (GxE) interaction

PURPOSE/OBJECTIVE:The obesity epidemic raises concerns about the impact of excessive and insufficient weight gain during pregnancy. METHODS:We examined the association between gestational weight gain (GWG) and preterm birth, term small- and large-for-gestational-age (SGA and LGA), term birthweight, and term primary Cesarean delivery, considering prepregnancy body mass index (BMI) and ethnicity in a cohort of 33,872 New York City residents who gave birth between 1995 and 2003 and delivered in hospitals elsewhere in New York State. RESULTS:Preterm birth (<37 weeks' gestation) showed a modest U-shaped relationship, with projected GWG of <10 kg and 20+ kg associated with odds ratios of 1.4 and 1.3, respectively, relative to 10 to 14 kg. The pattern was stronger for preterm birth <32 weeks' and for underweight women with low GWG and overweight/obese women with high GWG. Term SGA decreased and term LGA and birthweight increased monotonically with increasing GWG. Primary Cesarean delivery followed the same pattern as LGA, but less strongly. CONCLUSIONS:Although the study is limited by potential selection bias and measurement error, our findings support the contention that GWG may be a modifiable predictor of pregnancy outcome that warrants further investigation, particularly randomized trials, to assess whether the relation is causal.

BACKGROUND: The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous opioidergic regulation increases sensitivity to CO2, separation distress and panic attacks. In panic disorder (PD) patients, both spontaneous clinical panics and lactate-induced panics markedly increase tidal volume (TV), whereas normals have a lesser effect, possibly due to their intact endogenous opioid system. We hypothesized that impairing the opioidergic system by naloxone could make normal controls parallel PD patients' response when lactate challenged. Whether actual separations and losses during childhood (childhood parental loss, CPL) affected naloxone-induced respiratory contrasts was explored. Subjective panic-like symptoms were analyzed although pilot work indicated that the subjective aspect of anxious panic was not well modeled by this specific protocol. METHOD: Randomized cross-over sequences of intravenous naloxone (2 mg/kg) followed by lactate (10 mg/kg), or saline followed by lactate, were given to 25 volunteers. Respiratory physiology was objectively recorded by the LifeShirt. Subjective symptomatology was also recorded. RESULTS: Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL. CONCLUSIONS: Opioidergic dysregulation may underlie respiratory pathophysiology and suffocation sensitivity in PD. Comparing specific anti-panic medications with ineffective anti-panic agents (e.g. propranolol) can test the specificity of the naloxone+lactate model. A screen for putative anti-panic agents and a new pharmacotherapeutic approach are suggested. Heuristically, the experimental unveiling of the endogenous opioid system impairing effects of CPL and separation in normal adults opens a new experimental, investigatory area

The renal vasopressin V(2) receptor (V(2)R) plays a critical role in physiological and pathophysiological processes associated with arginine vasopressin (AVP)-induced antidiuresis. Because clinical data suggests that females may be more prone to hyponatremia from AVP-mediated antidiuresis, we investigated whether there are sex differences in the expression and function of the renal V(2)R. In normal Sprague-Dawley rat kidneys, V(2)R mRNA and protein expression was 2.6- and 1.7-fold higher, respectively, in females compared with males. To investigate the potential physiological implications of this sex difference, we studied changes in urine osmolality induced by the AVP V(2)R agonist desmopressin. In response to different doses of desmopressin, there was a graded increase in urine osmolality and decrease in urine volume during a 24-h infusion. Females showed greater mean increases in urine osmolality and greater mean decreases in urine volume at 0.5 and 5.0 ng/h infusion rates. We also studied renal escape from antidiuresis produced by water loading in rats infused with desmopressin (5.0 ng/h). After 5 days of water loading, urine osmolality of both female and male rats escaped to the same degree physiologically, but V(2)R mRNA and protein in female kidneys was reduced to a greater degree (-63% and -73%, respectively) than in males (-32% and -48%, respectively). By the end of the 5-day escape period, renal V(2)R mRNA and protein expression were reduced to the same relative levels in males and females, thereby abolishing the sex differences in V(2)R expression seen in the basal state. Our results demonstrate that female rats express significantly more V(2)R mRNA and protein in kidneys than males, and that this results physiologically in a greater sensitivity to V(2)R agonist administration. The potential pathophysiological implications of these results are that females may be more susceptible to the development of dilutional hyponatremia because of a greater sensitivity to endogenously secreted AVP.

BACKGROUND: Social dysfunction is a hallmark symptom of schizophrenia which commonly precedes the onset of psychosis. It is unclear if social symptoms in clinical high-risk patients reflect depressive symptoms or are a manifestation of negative symptoms. METHOD: We compared social function scores on the Social Adjustment Scale-Self Report between 56 young people (aged 13-27 years) at clinical high risk for psychosis and 22 healthy controls. The cases were also assessed for depressive and 'prodromal' symptoms (subthreshold positive, negative, disorganized and general symptoms). RESULTS: Poor social function was related to both depressive and negative symptoms, as well as to disorganized and general symptoms. The symptoms were highly intercorrelated but linear regression analysis demonstrated that poor social function was primarily explained by negative symptoms within this cohort, particularly in ethnic minority patients. CONCLUSIONS: Although this study demonstrated a relationship between social dysfunction and depressive symptoms in clinical high-risk cases, this association was primarily explained by the relationship of each of these to negative symptoms. In individuals at heightened risk for psychosis, affective changes may be related to a progressive decrease in social interaction and loss of reinforcement of social behaviors. These findings have relevance for potential treatment strategies for social dysfunction in schizophrenia and its risk states and predict that antidepressant drugs, cognitive behavioral therapy and/or social skills training may be effective

OBJECTIVE: To examine the association between memory for previously encoded emotional faces and depression symptoms assessed over 4 years in adolescent girls. Investigating the interface between memory deficits and depression in adolescent girls may provide clues about depression pathophysiology. METHOD: Participants were 213 girls recruited from a longitudinal, community-based study; the majority were African American. Scores on depressive screening measures at age 8 were used to increase the base rate of depression. Depression symptoms and diagnoses were assessed annually for 4 years. In year 4, when the girls were 12 to 13 years old, a face emotion encoding task was administered during which ratings were generated in response to sad, fearful, angry, and happy faces. A surprise memory task followed whereby participants identified which of two faces, displaying neutral expressions, they had seen previously. RESULTS: Girls with higher depression symptom levels from ages 9 to 12 years evidenced lower accuracy in identifying previously encoded emotional faces. Controlling for IQ, higher depression symptom level was associated with a memory deficit specific to previously encoded sad and happy faces. These effects were not moderated by race. CONCLUSIONS: Individual differences in face memory deficits relate to individual differences in emerging, early adolescent depression, and may be vulnerability markers for depression.

OBJECTIVE: To determine how to use the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) to classify patients according to disease severity (mild, moderate, and severe) and to identify which patients respond to therapy. DESIGN: Cohort. SETTING: The connective-tissue disease clinic at the Hospital of the University of Pennsylvania, Philadelphia. PATIENTS: Seventy-five patients with clinical or histopathologic evidence of cutaneous lupus erythematosus or systemic lupus erythematosus were included in the study. MAIN OUTCOME MEASURES: The CLASI, Skindex-29, and the physician's subjective assessment of severity and improvement were completed at every visit. RESULTS: Disease severity was assessed with 45 patient visits. Mild, moderate, and severe disease corresponded with CLASI activity score ranges of 0 to 9, 10 to 20, and 21 to 70, respectively. Improvement in disease activity was assessed in 74 patients. A clinical improvement was associated with a mean 3-point or 18% decrease in the CLASI activity score. However, receiver operating characteristic analysis demonstrated an increased percentage of patients correctly classified when a 4-point (sensitivity, 39%; specificity, 93%; correctly classified, 76%) or 20% (sensitivity, 46%; specificity, 78%; correctly classified, 67%) decrease in the CLASI activity score was used instead to identify improvement. CONCLUSION: The CLASI can be used to classify patients into groups according to disease severity and to identify clinically significant improvements in disease activity.

BACKGROUND: The impact of respiratory dynamics on odor response has been poorly studied at the olfactory bulb level. However, it has been shown that sniffing in the behaving rodent is highly dynamic and varies both in frequency and flow rate. Bulbar odor response could vary with these sniffing parameter variations. Consequently, it is necessary to understand how nasal airflow can modify and shape odor response at the olfactory bulb level. METHODOLOGY AND PRINCIPAL FINDINGS: To assess this question, we used a double cannulation and simulated nasal airflow protocol on anesthetized rats to uncouple nasal airflow from animal respiration. Both mitral/tufted cell extracellular unit activity and local field potentials (LFPs) were recorded. We found that airflow changes in the normal range were sufficient to substantially reorganize the response of the olfactory bulb. In particular, cellular odor-evoked activities, LFP oscillations and spike phase-locking to LFPs were strongly modified by nasal flow rate. CONCLUSION: Our results indicate the importance of reconsidering the notion of odor coding as odor response at the bulbar level is ceaselessly modified by respiratory dynamics.