A retrospective case study of successful translational research: Cardiovascular disease risk assessment, experiences in community engagement.

In underserved communities across New York City, uninsured adults encounter a greater risk of cardiovascular disease (CVD) and diabetes. The Heart-to-Heart Community Outreach Program (H2H) addresses these disparities by screening for CVD risk factors, identifying healthcare access barriers, and fostering community engagement in translational research at the Weill Cornell Medicine Clinical and Translational Science Award (CTSA) hub. Screening events are hosted in partnership with faith-based institutions. Participants provide a medical history, complete a survey, and receive counseling by clinicians with referrals for follow-up care. This study aims to quantify H2H screening participant health status; identify socioeconomic, health access, and health-related barriers disproportionately promoting the onset of CVD and diabetes; and develop long-term community partnerships to enable underserved communities to influence activities across the translational research spectrum at our CTSA hub. The population served is disproportionately non-white, and uninsured, with many low-income and underserved individuals. The program was developed in partnership with our Community Advisory Board to empower this cohort to make beneficial lifestyle changes. Leveraging partnerships with faith-based institutions and community centers in at-risk New York City neighborhoods, H2H addresses the increasing burden of diabetes and CVD risk factors in vulnerable individuals while promoting community involvement in CTSA activities, serving as a model for similar initiatives.

A Retrospective Case Study of Successful Translational Research: Cardiovascular Disease Risk Assessment, Experiences in Community Engagement.

In underserved communities in New York City, uninsured adults encounter a greater risk of cardiovascular disease and diabetes. The Heart-to-Heart Community Outreach Program (H2H) is addressing these disparities by providing screenings for diabetes and other cardiovascular disease risk factors, fostering community engagement in translational research at our CTSC. Screening events are hosted in partnership with community faith-based institutions. Participants provide medical history, complete a survey, and receive individualized counseling by clinicians with referrals for follow-up care. The population served is disproportionately non-white, uninsured, with low-income, and underserved. The program empowers participants to make beneficial lifestyle changes using myriad strategies to reach those most in need. This required strong foundational program leadership, effective inter-institutional collaboration, and maintaining of community trust. Leveraging partnerships with faith-based institutions and community centers in at-risk NYC neighborhoods, H2H addresses the increasing burden of diabetes and cardiovascular disease risk factors in vulnerable individuals and provides a model for similar initiatives.

Effective Low-Cost Ophthalmological Screening With a Novel iPhone Fundus Camera at Community Centers.

Ophthalmologic care is inaccessible to many people due to a variety of factors, including the availability of providers, cost of equipment for ophthalmologic care, and transportation to clinics and appointments. Because many causes of blindness are both highly prevalent and preventable once identified, it is essential to address gaps in care for underserved populations. We developed a novel 3D-printed mobile retinal camera. In this study, we organized recurring student-run screening events around New York City that took place in community centers and churches, at which we utilized our device to take retinal images. Our screening events reached a diverse population of New Yorkers, disproportionately those with lower household income, many of whom had not had recent eye exams. To validate the device for use in telehealth ophthalmologic visits, we transmitted the images to a remote ophthalmologist for evaluation and compared the result with an on-site attending physician's dilated eye exam. The subjective assessment indicated that 97% of images captured with the mobile retinal camera were acceptable for telehealth analysis. Remote image assessment by achieved 92% sensitivity and 83% specificity in detecting optic disc cupping, compared to the gold-standard on-site dilated eye exam. In addition, the device was portable, affordable, and able to be used by those with relatively little ophthalmologic training. We have demonstrated the utility of this affordable mobile retinal camera for telehealth ophthalmologic evaluation during community screening events that reached an underserved population to detect disease and connect with long-term care.

Social and Clinical Determinants of COVID-19 Outcomes: Modeling Real-World Data from a Pandemic Epicenter.

IMPORTANCE: As the United States continues to accumulate COVID-19 cases and deaths, and disparities persist, defining the impact of risk factors for poor outcomes across patient groups is imperative. OBJECTIVE: Our objective is to use real-world healthcare data to quantify the impact of demographic, clinical, and social determinants associated with adverse COVID-19 outcomes, to identify high-risk scenarios and dynamics of risk among racial and ethnic groups. DESIGN: A retrospective cohort of COVID-19 patients diagnosed between March 1 and August 20, 2020. Fully adjusted logistical regression models for hospitalization, severe disease and mortality outcomes across 1-the entire cohort and 2- within self-reported race/ethnicity groups. SETTING: Three sites of the NewYork-Presbyterian health care system serving all boroughs of New York City. Data was obtained through automated data abstraction from electronic medical records. PARTICIPANTS: During the study timeframe, 110,498 individuals were tested for SARS-CoV-2 in the NewYork-Presbyterian health care system; 11,930 patients were confirmed for COVID-19 by RT-PCR or covid-19 clinical diagnosis. MAIN OUTCOMES AND MEASURES: The predictors of interest were patient race/ethnicity, and covariates included demographics, comorbidities, and census tract neighborhood socio-economic status. The outcomes of interest were COVID-19 hospitalization, severe disease, and death. RESULTS: Of confirmed COVID-19 patients, 4,895 were hospitalized, 1,070 developed severe disease and 1,654 suffered COVID-19 related death. Clinical factors had stronger impacts than social determinants and several showed race-group specificities, which varied among outcomes. The most significant factors in our all-patients models included: age over 80 (OR=5.78, p= 2.29x10-24) and hypertension (OR=1.89, p=1.26x10-10) having the highest impact on hospitalization, while Type 2 Diabetes was associated with all three outcomes (hospitalization: OR=1.48, p=1.39x10-04; severe disease: OR=1.46, p=4.47x10-09; mortality: OR=1.27, p=0.001). In race-specific models, COPD increased risk of hospitalization only in Non-Hispanics (NH)-Whites (OR=2.70, p=0.009). Obesity (BMI 30+) showed race-specific risk with severe disease NH-Whites (OR=1.48, p=0.038) and NH-Blacks (OR=1.77, p=0.025). For mortality, Cancer was the only risk factor in Hispanics (OR=1.97, p=0.043), and heart failure was only a risk in NH-Asians (OR=2.62, p=0.001). CONCLUSIONS AND RELEVANCE: Comorbidities were more influential on COVID-19 outcomes than social determinants, suggesting clinical factors are more predictive of adverse trajectory than social factors.

Dual action of NSC606985 on cell growth and apoptosis mediated through PKCδ in prostatic cancer cells.

Chemotherapy is a vital therapeutic strategy for castration-resistant prostate cancer (CRPC). We have previously shown that NSC606985 (NSC), a camptothecin (CPT) analog, induced cell apoptosis via interacting with topoisomerase I (Topo I) in prostate cancer cells. In the present study, the effect and mechanism of CPT analogs in LAPC4 cells were investigated. LAPC-4 cells were treated with NSC, CPT, and topotecan. Cell proliferation, apoptosis, and protein kinase Cδ (PKCδ) subcellular activation were measured at different doses and time-points, with or without PKCδ inhibition or knockdown of PKCδ expression. NSC at doses ranging from 10 to 100 nM induced a dose-dependent increase in viable cell number and DNA biosynthesis with mild cell apoptosis, whereas, at doses ranging from 500 nM to 5 mM, NSC produced a dose-dependent decrease in cell proliferation and DNA biosynthesis with a significant induction of cell apoptosis. Both NSC-induced cell proliferation and apoptosis were blocked by knockdown of PKCδ with a specific RNAi, or by the co-administration of rottlerin, a PKCδ inhibitor. Moreover, NSC produced a dose-dependent subcellular activation of PKCδ. The dose-dependent dual action of NSC is mediated at least in part through the differential subcellular activation of PKCδ in LAPC4 cells. The demonstration of a differential cell response to camptothecin analogs would facilitate the identification of biomarker(s) to CPT sensitivity and promote the personalization of CPT chemotherapy in CRPC.

Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells.

Castration-resistant prostate cancer (CRPC) is a major cause of prostate cancer (Pca) death. Chemotherapy is able to improve the survival of CRPC patients. We previously found that NSC606985 (NSC), a highly water-soluble camptothecin analog, induced cell death in Pca cells via interaction with topoisomerase 1 and activation of the mitochondrial apoptotic pathway. To further elucidate the role of NSC, we studied the effect of NSC on ER-stress and its association with NSC-induced cell death in Pca cells. NSC produced a time- and dose-dependent induction of GRP78, CHOP and XBP1s mRNA, and CHOP protein expression in Pca cells including DU145, indicating an activation of ER-stress. However, unlike conventional ER-stress in which GRP78 protein is increased, NSC produced a time- and dose-dependent U-shape change in GRP78 protein in DU145 cells. The NSC-induced decrease in GRP78 protein was blocked by protease inhibitors, N-acetyl-L-leucyl-L-leucylnorleucinal (ALLN), a lysosomal protease inhibitor, and epoxomicin (EPO), a ubiquitin-protease inhibitor. ALLN, but not EPO, also partially inhibited NSC-induced cell death. However, both 4-PBA and TUDCA, two chemical chaperons that effectively reduced tunicamycin-induced ER-stress, failed to attenuate NSC-induced GRP78, CHOP and XBP1s mRNA expression and cell death. Moreover, knockdown of NSC induction of CHOP expression using a specific siRNA had no effect on NSC-induced cytochrome c release and NSC-induced cell death. These results suggest that NSC produced an atypical ER-stress that is dissociated from NSC-induced activation of the mitochondrial apoptotic pathway and NSC-induced cell death in DU145 prostate cancer cells.

The effect of 5α-reductase-2 deficiency on human fertility.

A most interesting and intriguing male disorder of sexual differentiation is due to 5α-reductase-2 isoenzyme deficiency. These male infants are born with ambiguous external genitalia due to a deficiency in their ability to catalyze the conversion of T to dihydrotestosterone. Dihydrotestosterone is a potent androgen responsible for differentiation of the urogenital sinus and genital tubercle into the external genitalia, urethra, and prostate. Affected males are born with a clitoral-like phallus, bifid scrotum, hypospadias, blind shallow vaginal pouch from incomplete closure of the urogenital sinus, and a rudimentary prostate. At puberty, the surge in mainly T production prompts virilization, causing most boys to choose gender reassignment to male. Fertility is a challenge for affected men for several reasons. Uncorrected cryptorchidism is associated with low sperm production, and there is evidence of defective transformation of spermatogonia into spermatocytes. The underdeveloped prostate and consequent low semen volumes affect sperm transport. In addition, semen may not liquefy due to a lack of prostate-specific antigen. In the present review, we discuss the 5α-reductase-2 deficiency syndrome and its impact on human fertility.

Models of interinstitutional partnerships between research intensive universities and minority serving institutions (MSI) across the Clinical Translational Science Award (CTSA) consortium.

Health disparities are an immense challenge to American society. Clinical and Translational Science Awards (CTSAs) housed within the National Center for Advancing Translational Science (NCATS) are designed to accelerate the translation of experimental findings into clinically meaningful practices and bring new therapies to the doorsteps of all patients. Research Centers at Minority Institutions (RCMI) program at the National Institute on Minority Health and Health Disparities (NIMHD) are designed to build capacity for biomedical research and training at minority serving institutions. The CTSA created a mechanism fostering formal collaborations between research intensive universities and minority serving institutions (MSI) supported by the RCMI program. These consortium-level collaborations activate unique translational research approaches to reduce health disparities with credence to each academic institutions history and unique characteristics. Five formal partnerships between research intensive universities and MSI have formed as a result of the CTSA and RCMI programs. These partnerships present a multifocal approach; shifting cultural change and consciousness toward addressing health disparities, and training the next generation of minority scientists. This collaborative model is based on the respective strengths and contributions of the partnering institutions, allowing bidirectional interchange and leveraging NIH and institutional investments providing measurable benchmarks toward the elimination of health disparities.

Suppression of DHT-induced paracrine stimulation of endothelial cell growth by estrogens via prostate cancer cells.

BACKGROUND: Androgen modulation of angiogenesis in prostate cancer may be not directly mediated by androgen receptor (AR) as AR is not detected in the prostatic endothelial cells. METHODS: We examined the paracrine stimulation of cell proliferation by prostate tumor cells and its modulation by androgen and estrogens in a murine endothelial cell line (MEC) that does not express AR. RESULTS: Tumor cell conditioned media (TCM) collected from LAPC-4 or LNCaP prostatic tumor cells produced a time- and concentration-dependent induction of cell growth in MECs, which was parallel to the VEGF concentration in the TCM. This TCM-induced cell growth in MECs was enhanced by the treatment of prostatic tumor cells with dihydrotestosterone (DHT). Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist. Co-administration of 17α-estradiol or 17ß-estradiol with DHT in prostatic tumor cells completely inhibited the DHT-enhancement effect while treatment with DHT, 17α-estradiol or 17ß-estradiol did not produce any significant direct effect in MECs. Moreover, administration of 17α-estradiol or 17ß-estradiol in xenograft animals with LAPC-4 or LNCaP prostate tumor significantly decreased the microvessel number in the tumor tissues. CONCLUSIONS: Our study indicated that prostate tumor cells regulate endothelial cell growth through a paracrine mechanism, which is mainly mediated by VEGF; and DHT is able to modulate endothelial cell growth via tumor cells, which is inhibited by 17α-estradiol and 17ß-estradiol. Thus, both17α-estradiol and 17ß-estradiol are potential agents for anti-angiogenesis therapy in androgen-responsive prostate cancer.

Differential effects of estrogen receptor ligands on regulation of dihydrotestosterone-induced cell proliferation in endothelial and prostate cancer cells.

Androgen deprivation therapy of prostate cancer with estrogens shows significant cardiovascular side-effects. To develop effective prostate cancer therapeutic agent(s) with minimal cardiovascular side-effects, we compared the effects of various estrogen receptor (ER) ligands on the modulation of dihydrotestosterone (DHT) actions in LAPC-4 and LNCaP prostate cancer cells and human aortic endothelial cells (HAECs). DHT stimulated the proliferation of HAEC, LAPC-4 and LNCaP cells and induced PSA mRNA expression in LAPC-4 cells. These DHT actions were differentially modulated by ER ligands in a cell-dependent manner. In LAPC-4 cells, knockdown of ERß expression partially eliminated the ßE2 inhibition of DHT-induced LAPC-4 cell proliferation, and a parallel change was observed between ER ligand modulation of DHT-induced cell proliferation and cyclin A expression. The obtained data suggest that it is feasible to develop effective agent(s) for prostate cancer therapy with minimal cardiovascular side-effects and 17α-estradiol and genistein are such potential agents.

The first successful paternity through in vitro fertilization-intracytoplasmic sperm injection with a man homozygous for the 5α-reductase-2 gene mutation.

OBJECTIVE: To report a case of successful paternity from a male homozygous for 5α-reductase-2 deficiency. DESIGN: Case report. SETTING: Academic center, division of reproductive endocrinology. PATIENT(S): A 45-year-old Dominican man and his 32-year-old wife. INTERVENTION(S): In vitro fertilization and intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Pregnancy. RESULT(S): Viable twin gestation. CONCLUSION(S): Men homozygous for 5α-reductase-2 deficiency can achieve biologic paternity through in vitro fertilization with intracytoplasmic sperm injection despite severely abnormal semen parameters.

Androgen stimulates endothelial cell proliferation via an androgen receptor/VEGF/cyclin A-mediated mechanism.

Growing evidences support that androgen displays beneficial effects on cardiovascular functions although the mechanism of androgen actions remains to be elucidated. Modulation of endothelial cell growth and function is a potential mechanism of androgen actions. We demonstrated in the present study that androgens [dihydrotestosterone (DHT) and testosterone], but not 17ß-estradiol, produced a time- and dose-dependent induction of cell proliferation in primary human aortic endothelial cells (HAECs) as evident by increases in viable cell number and DNA biosynthesis. Real-time qRT-PCR analysis showed that DHT induced androgen receptor (AR), cyclin A, cyclin D1, and vascular endothelial growth factor (VEGF) gene expression in a dose- and time-dependent manner. The addition of casodex, a specific AR antagonist, or transfection of a specific AR siRNA blocked DHT-induced cell proliferation and target gene expression, indicating that the DHT effects are mediated via AR. Moreover, coadministration of SU5416 to block VEGF receptors, or transfection of a specific VEGF-A siRNA to knockdown VEGF expression, produced a dose-dependent blockade of DHT induction of cell proliferation and cyclin A gene expression. Interestingly, roscovitine, a selective cyclin-dependent kinase inhibitor, also blocked the DHT stimulation of cell proliferation with a selective inhibition of DHT-induced VEGF-A expression. These results indicate that androgens acting on AR stimulate cell proliferation through upregulation of VEGF-A, cyclin A, and cyclin D1 in HAECs, which may be beneficial to cardiovascular functions since endothelial cell proliferation could assist the repair of endothelial injury/damage in cardiovascular system.

Inhibition of aberrant androgen receptor induction of prostate specific antigen gene expression, cell proliferation and tumor growth by 17α-estradiol in prostate cancer.

PURPOSE: Androgen independent prostate cancer growth and metastasis are a major cause of prostate cancer death. Aberrant androgen receptor activation due to androgen receptor mutation is an important mechanism of androgen independence. We determined the effectiveness and mechanism of 17α-estradiol (Sigma®) in blocking aberrant androgen receptor activation due to androgen receptor mutation. MATERIALS AND METHODS: We used LNCaP and MDA Pca-2b prostatic tumor cells (ATCC®) containing a mutated androgen receptor and WT estrogen receptor ß to test 17α-estradiol inhibition of aberrant androgen receptor activation of prostate specific antigen gene expression and cell growth. Cotransfection analysis was used to further elucidate the mechanism of 17α-estradiol action. Xenograft animals with an LNCaP prostate tumor were prepared to study the in vivo effect of 17α-estradiol on tumor growth inhibition. RESULTS: In LNCaP cells 17α-estradiol produced a dose dependent inhibition of cyproterone acetate (Sigma) or dihydrotestosterone induced prostate specific antigen gene expression. In MDA Pca-2b cells 17α-estradiol inhibited cortisol (Sigma) induced prostate specific antigen expression and blocked dihydrotestosterone and cortisol induced cell proliferation in LNCaP and MDA Pca-2b cells, respectively. Cotransfection analysis showed that 17α-estradiol inhibition of aberrant androgen receptor activation of prostate specific antigen gene expression was medicated via estrogen receptors. In xenograft mice with LNCaP prostate cancer 17α-estradiol but not 17ß-estradiol (Sigma) significantly inhibited tumor growth, although each estrogen tended to decrease tumor growth. CONCLUSIONS: Results suggest that 17α-estradiol with less classic estrogenic activity is a potential therapeutic agent for androgen independent prostate cancer due to androgen receptor mutation.

5alpha-reductase isozymes and androgen actions in the prostate.

Androgens acting via the androgen receptor play critical roles in prostate development, growth, and pathogenesis. There are two potent androgens, testosterone and dihydrotestosterone (DHT), in humans and mammals. DHT is converted from testosterone by 5alpha-reductase isozymes. Two 5alpha-reductase isozymes have been identified. Although both isozymes are expressed, 5alpha-reductase-2 is the predominant isozyme in the human prostate. Mutations in 5alpha-reductase-2 gene cause the 5alpha-reductase-2 deficiency syndrome. Affected 46, XY individuals have a small, nonpalpable, and rudimentary prostate in adulthood. Neither benign prostate hyperplasia (BPH) nor prostate cancer has been reported in these patients. The prostate is small in animals with 5alpha-reductase-2 gene knockout or treated with specific 5alpha-reductase inhibitors. 5alpha-reductase isozymes are molecular targets for the prevention and treatment of BPH and prostate cancer. Moreover, androgen actions on prostate gene expression and cell growth are directly modulated by estrogen receptor ligands via protein-protein interactions. The studies of 5alpha-reductases and androgen actions highlight the importance of 5alpha-reductase isozymes in male sexual differentiation and prostate physiology and pathophysiology.

NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells.

PURPOSE: Prostate cancer is a major cause of cancer mortality in American males. Once prostate cancer has metastasized, there is currently no curative therapy available. The development of effective agents is therefore a continuing effort to combat this disease. In the present study, the effects and potential mechanisms of NSC606985 (NSC), a water-soluble camptothecin analog, in prostate cancer cells were investigated. METHODS: Prostatic tumor cells, DU-145, LNCaP and PC-3, were used for the study. Cell proliferation, cell cycle, cell apoptosis and caspase 3/7 activity were determined in the presence or absence of NSC. The levels of Bax and Bak, and the release of cytochrome c from mitochondria were analyzed by Western blot. RESULTS: Treatment with NSC at nanomolar concentrations produced a time- and dose-dependent decrease in viable cell numbers of multiple prostate cancer cells. In DU-145 cells, NSC produced a time-and dose-dependent induction of cell apoptosis and cell cycle arrest as evidenced by cell morphological changes, increases in S-phase and sub-G1 cell fractions, an elevation of caspase 3/7 activity, DNA fragmentation and apoptotic cells. NSC increased the levels of apoptotic proteins, Bax and Bak, and induced a release of cytochrome c from mitochondria to cytosol in DU-145 cells. Co-administration of Z-VAD-FMK, a pan-caspase inhibitor, blocked NSC-induced caspase 3/7 activity and cell apoptosis without affecting NSC-induced cell cycle arrest. In contrast, co-administration of a PKCdelta inhibitor, rottlerin, had no significant effect on NSC induction of caspase activity, and slightly potentiated NSC-induced cell death. Furthermore, like camptothecin, a mutation of topoisomerase 1 that prevents the binding of camptothecin to the enzyme completely abolished the NSC effect in DU-145 cells. CONCLUSION: The data obtained suggest that NSC is able to decrease cell growth, induce cell apoptosis and cause growth arrest in prostatic tumor cells, which may involve an interaction with topoisomerase 1 and an activation of mitochondrial apoptotic pathway.

17alpha-estradiol inhibits LAPC-4 prostatic tumor cell proliferation in cell cultures and tumor growth in xenograft animals.

BACKGROUND: Blockade of androgen activity is a major effective therapy for advanced prostate cancer. Estrogen analogs have been used for prostate cancer therapy for years presumably by inhibiting testosterone biosyntheses, but with considerable adverse events due to their classic estrogenic activity. With the discovery of the estrogen receptor (ER) beta and its presence in prostate tumor cells, evaluation of estrogen analogs with less classic estrogenic activity in prostate cancer therapy is emerging. METHODS: The effects of 17alpha-estradiol (alphaE2), a stereo-isomer of 17beta-estradiol (betaE2), on dihydrotestosterone (DHT)-induced cell growth and gene expressions were examined in androgen-dependent LAPC-4 prostatic tumor cells and in LAPC-4 xenograft animals, and compared to those of betaE2. RESULTS: Both alphaE2 and betaE2 attenuated DHT induction of PSA gene expression, cell proliferation, and cell growth in cultured LAPC-4 cells. The inhibition of cell proliferation was associated with a blockade of DHT-induced cyclin A and cyclin D1 expression by alphaE2 and betaE2. In LAPC-4 xenograft mice, alphaE2 significantly inhibited tumor growth without altering the plasma testosterone level, while betaE2 failed to inhibit tumor growth even though it significantly inhibited PSA gene expression. CONCLUSION: alphaE2 is an effective agent for inhibition of DHT-induced PSA, cyclin A, cyclin D1 gene expression, and cell proliferation in LAPC-4 cells, and tumor growth in LAPC-4 xenograft mice.

Gender differences in object location memory: a meta-analysis.

The goal of the present study was to quantify the magnitude of gender differences in object location memory tasks. A total of 123 effect sizes (d) drawn from 36 studies were included in a meta-analysis using a hierarchical approach. Object identity memory (37 effect sizes) and object location memory (86 effect sizes) tasks were analyzed separately. Object identity memory task showed significant gender differences that were homogeneous and in favor of women. For the object location memory tasks, effect sizes had to be partitioned by age (younger than 13, between 13 and 18, older than 18), object type (common, uncommon, gender neutral, geometric, masculine, feminine), scoring method (accuracy, time, distance), and type of measure (recall, recognition) to achieve homogeneity. Significant gender differences in favor of females were obtained in all clusters above the age of 13, with the exception of feminine, uncommon, and gender-neutral objects. Masculine objects and measures of distance produced significant effects in favor of males. Implications of these results for future work and for theoretical interpretations are discussed.

Sex specificity of ventral anterior cingulate cortex suppression during a cognitive task.

Ventral anterior cingulate cortex (vACC) is a highly interconnected brain region considered to reflect the sometimes competing demands of cognition and emotion. A reciprocal relationship between vACC and dorsal ACC (dACC) may play a role in maintaining this balance between cognitive and emotional processing. Using functional MRI in association with a cognitively-demanding visuospatial task (mental rotation), we found that only women demonstrated vACC suppression and inverse functional connectivity with dACC. Sex differences in vACC functioning--previously described under conditions of negative emotion--are extended here to cognition. Consideration of participant sex is essential to understanding the role of vACC in cognitive and emotional processing.

The relation between computerized and paper-and-pencil mental rotation tasks: a validation study.

The present study aimed at validating a computerized mental rotation task developed for use in functional Magnetic Resonance Imaging (fMRI) studies. Eighty-three females and 74 males completed the computerized task, two pencil-and-paper tests of mental rotation, and reported their high school grades in mathematics, English, and history. The computerized task involved the presentation of pairs of three-dimensional stimuli that differed in orientation by 0, 40, 80, 120, or 160 degrees. Results showed significant gender differences in favor of males in the three main tasks, although gender interacted with angle of rotation in the computerized task. Evidence for concurrent validity was obtained in the form of significant correlations between performance on tasks relevant to mental rotation (paper and pencil tests and mathematics grades), whereas discriminant validity was demonstrated by a lack of correlation with tasks deemed irrelevant to mental rotation (English and history grades). These findings support the use of our computerized mental rotation task as a valid measure of mental rotation abilities in fMRI studies.

Bone mineral density in the complete androgen insensitivity and 5alpha-reductase-2 deficiency syndromes.

CONTEXT: Subjects with complete androgen insensitivity (CAI) and 5alpha-reductase-2 deficiency (5alphaRD-2) are natural human models to study the direct effect of androgens on bone mineral density (BMD). OBJECTIVE: The objective of this study was to test the hypothesis that androgens have a direct effect on BMD in men. DESIGN: This was a prospective, observational study (1989-1999) using dual energy x-ray absorptiometry. SETTING: The study was set in an outpatient specialty referral center. PATIENTS OR OTHER PARTICIPANTS: All known subjects with these conditions (12 CAI and 16 5alphaRD-2) from diverse sociodemographic backgrounds were recruited for the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: Mean Z score and weight-matched Z score at lumbar spine and femoral neck for CAI and 5alphaRD-2 subjects were determined. RESULTS: Twelve CAI subjects had mean Z score at L2-L4 of -2.84 (+/-0.97, P < 0.001) and a mean weight-matched Z score of -2.52 (+/-0.94, P < 0.001). The mean Z score at the femoral neck was -1.33 (+/-0.91, P < 0.001) and the mean weight-matched Z score was -1.10 (+/-0.82, P = 0.001). Sixteen 5alphaRD-2 subjects had a mean Z score at L2-L4 of -0.84 (+/-1.29, P = 0.02) and a mean weight-matched Z score for 15 of 16 patients of -0.44 (+/-1.08, P = 0.14). The mean Z score at the femoral neck was 0.14 (+/-1.02, P = 0.58) and the mean weight-matched Z score for 15 of 16 patients was 0.49 (+/-0.94, P = 0.06). Therefore, in CAI subjects, BMD was significantly decreased in the spine and hip. 5alphaRD-2 subjects had normal BMD values. CONCLUSIONS: 1) Androgens are of direct importance in the development and/or maintenance of BMD; and 2) testosterone and/or low levels of dihydrotestosterone appear to be sufficient for BMD development and/or maintenance.