Faculty Bibliography

Our study is the first investigation of the effects of advanced paternal age (APA) on the developmental trajectory of social behavior in rodent offspring. Given the strong epidemiological association between APA and sexually dimorphic neurodevelopmental disorders that are characterized by abnormalities in social behavior (autism, schizophrenia), we assessed sociability in male and female inbred mice (C57BL/6J) across postnatal development (N = 104) in relation to paternal age. We found differences in early social behavior in both male and female offspring of older breeders, with differences in this social domain persisting into adulthood in males only. We showed that these social deficits were not present in the fathers of these offspring, confirming a de novo origin of an altered social trajectory in the offspring generation. Our results, highly novel in rodent research, support the epidemiological observations in humans and provide evidence for a causal link between APA, age-related changes in the paternal sperm DNA and neurodevelopmental disorders in their offspring.

The current study uses the actor-partner interdependence model to examine the predictors of relationship satisfaction for mothers and fathers of children with autism spectrum disorder. Sixty-seven couples completed measures of optimism, benefit finding, coping strategies, social support, and relationship satisfaction. Results indicated that parent's positive strengths predicted better personal relationship satisfaction. Moreover, parents' benefit finding, use of emotional support, and perceived social support from their partner also predicted their partner's relationship satisfaction. The results of this study highlight the importance of focusing on positive factors that can enhance relationship quality. Implications for the development of parent-focused interventions are discussed.

BACKGROUND:The superior temporal gyrus (STG) is one of the key regions implicated in psychosis, given that abnormalities in this region are associated with an increased risk of conversion from an at-risk mental state to psychosis. However, inconsistent results regarding the functional connectivity strength of the STG have been reported, and the regional heterogeneous characteristics of the STG should be considered. METHODS:To investigate the distinctive functional connection of each subregion in the STG, we parcellated the STG of each hemisphere into three regions: the planum temporale, Heschl's gyrus, and planum polare. Resting-state functional magnetic resonance imaging was obtained from 22 first-episode psychosis (FEP) patients, 41 individuals at ultra-high-risk for psychosis (UHR), and 47 demographically matched healthy controls. RESULTS:Significant group differences (in seed-based connectivity) were demonstrated in the left planum temporale and from both the right and left Heschl's gyrus seeds. From the left planum temporale seed, the FEP and UHR groups exhibited increased connectivity to the bilateral dorsolateral prefrontal cortex. In contrast, the FEP and UHR groups demonstrated decreased connectivity from the bilateral Heschl's gyrus seeds to the dorsal anterior cingulate cortex. The enhanced connectivity between the left planum temporale and right dorsolateral prefrontal cortex was positively correlated with positive symptom severity in individuals at UHR (r = .34, p = .03). CONCLUSIONS:These findings corroborate the fronto-temporal connectivity disruption hypothesis in schizophrenia by providing evidence supporting the altered fronto-temporal intrinsic functional connection at earlier stages of psychosis. Our data indicate that subregion-specific aberrant fronto-temporal interactions exist in the STG at the early stage of psychosis, thus suggesting that these aberrancies are the neural underpinning of proneness to psychosis.

Acinetobacter baumannii has quickly become one of the most insidious and prevalent nosocomial infections. Recently, the reverse-amide class of 2-aminoimidazole compounds (RA-2AI) was found both to prevent A. baumannii biofilm formation and also to disperse preexisting formations, putatively through interactions with cytosolic response regulators. Here we focus on how this class of antibiofilm agent traverses cellular membranes. Following the discovery of dosage-dependent growth rate changes, the cellular effects of RA-2AI were investigated using a combination of molecular assays and microscopic techniques. It was found that RA-2AI exposure has measureable effects on the bacterial membranes, resulting in a period of increased permeability and visible structural aberrations. Based on these results, we propose a model that describes how the structure of RA-2AI allows it to insert itself into and disrupt the fluidity of the membrane, creating an opportunity for increased molecular permeability.

OBJECTIVE:Enhanced HIV prevention interventions, such as preexposure prophylaxis for high-risk individuals, require substantial investments. We sought to estimate the medical cost saved by averting 1 HIV infection in the United States. METHODS:We estimated lifetime medical costs in persons with and without HIV to determine the cost saved by preventing 1 HIV infection. We used a computer simulation model of HIV disease and treatment (CEPAC) to project CD4 cell count, antiretroviral treatment status, and mortality after HIV infection. Annual medical cost estimates for HIV-infected persons, adjusted for age, sex, race/ethnicity, and transmission risk group, were from the HIV Research Network (range, $1854-$4545/mo) and for HIV-uninfected persons were from the Medical Expenditure Panel Survey (range, $73-$628/mo). Results are reported as lifetime medical costs from the US health system perspective discounted at 3% (2012 USD). RESULTS:The estimated discounted lifetime cost for persons who become HIV infected at age 35 is $326,500 (60% for antiretroviral medications, 15% for other medications, 25% nondrug costs). For individuals who remain uninfected but at high risk for infection, the discounted lifetime cost estimate is $96,700. The medical cost saved by avoiding 1 HIV infection is $229,800. The cost saved would reach $338,400 if all HIV-infected individuals presented early and remained in care. Cost savings are higher taking into account secondary infections avoided and lower if HIV infections are temporarily delayed rather than permanently avoided. CONCLUSIONS:The economic value of HIV prevention in the United States is substantial given the high cost of HIV disease treatment.

Despite a growing number of reports, there is still limited knowledge of the clinical features that precede the onset of bipolar disorder (BD). To explore this, we investigated baseline data from a prospectively evaluated longitudinal cohort of subjects aged 12-30 years to compare: first, lifetime rates of clinical features between a) subjects at increased genetic risk for developing BD ('AR'), b) participants from families without mental illness ('controls'), and c) those with established BD; and, second, prior clinical features that predict the later onset of affective disorders in these same three groups. This is the first study to report such comparisons between these three groups (though certainly not the first to compare AR and control samples). 118 AR participants with a parent or sibling with BD (including 102 with a BD parent), 110 controls, and 44 BD subjects were assessed using semi-structured interviews. AR subjects had significantly increased lifetime risks for depressive, anxiety and behavioural disorders compared to controls. Unlike prior reports, preceding anxiety and behavioural disorders were not found to increase risk for later onset of affective disorders in the AR sample, perhaps due to limited sample size. However, preceding behavioural disorders did predict later onset of affective disorders in the BD sample. The findings that i) AR subjects had higher rates of depressive, anxiety and behavioural disorders compared to controls, and ii) prior behavioural disorders increased the risk to later development of affective disorders in the BD group, suggest the possibility of therapeutic targeting for these disorders in those at high genetic risk for BD.