Measuring fecal testosterone in females and fecal estrogens in males: comparison of RIA and LC/MS/MS methods for wild baboons (Papio cynocephalus).

The development of non-invasive methods, particularly fecal determination, has made possible the assessment of hormone concentrations in wild animal populations. However, measuring fecal metabolites needs careful validation for each species and for each sex. We investigated whether radioimmunoassays (RIAs) previously used to measure fecal testosterone (fT) in male baboons and fecal estrogens (fE) in female baboons were well suited to measure these hormones in the opposite sex. We compared fE and fT concentrations determined by RIA to those measured by liquid chromatography combined with triple quadropole mass spectrometry (LC/MS/MS), a highly specific method. Additionally, we conducted a biological validation to assure that the measurements of fecal concentrations reflected physiological levels of the hormone of interest. Several tests produced expected results that led us to conclude that our RIAs can reliably measure fT and fE in both sexes, and that within-sex comparisons of these measures are valid: (i) fTRIA were significantly correlated to fTLC/MS/MS for both sexes; (ii) fTRIA were higher in adult than in immature males; (iii) fTRIA were higher in pregnant than non-pregnant females; (iv) fERIA were correlated with 17ß-estradiol (fE2) and with estrone (fE1) determined by LC/MS/MS in pregnant females; (v) fERIA were significantly correlated with fE2 in non-pregnant females and nearly significantly correlated in males; (vi) fERIA were higher in adult males than in immature males. fERIA were higher in females than in males, as predicted, but unexpectedly, fTRIA were higher in females than in males, suggesting a difference in steroid metabolism in the two sexes; consequently, we conclude that while within-sex comparisons are valid, fTRIA should not be used for intersexual comparisons. Our results should open the field to important additional studies, as to date the roles of testosterone in females and estrogens in males have been little investigated.

Smoking cessation and outcome after ischemic stroke or TIA.

OBJECTIVE: To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. METHODS: We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. RESULTS: At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48-0.90). CONCLUSION: Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.

White matter fractional anisotropy over two time points in early onset schizophrenia and adolescent cannabis use disorder: A naturalistic diffusion tensor imaging study.

Recurrent exposure to cannabis in adolescence increases the risk for later development of psychosis, but there are sparse data regarding the impact of cannabis use on brain structure during adolescence. This pilot study investigated the effect of cannabis use disorder (CUD) upon white matter fractional anisotropy (WM FA) values in non-psychotic treatment-seeking adolescents relative to adolescents with early onset schizophrenia-spectrum disorders (EOSS) and to healthy control (HC) participants. Diffusion tensor imaging (DTI) and tractography methods were used to examine fractional anisotropy (FA) of the cingulum bundle, superior longitudinal fasciculus (SLF), corticospinal tract (CST), inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF) and uncinate fasciculus in adolescents with EOSS (n=34), CUD (n=19) and HC (n=29). Participants received DTI and substance use assessments at baseline and at 18-month follow-up. Using multivariate analysis of variance, a significant main effect of diagnostic group was observed. Post-hoc testing revealed that adolescents with CUD showed an altered change in FA values in the left ILF and in the left IFOF (trend level) compared with HC adolescents. Greater consumption of cannabis during the inter-scan interval predicted a greater decrease in left ILF FA in CUD. These preliminary longitudinal data suggest that heavy cannabis use during adolescence, or some factor associated with cannabis use, is associated with an altered change in WM FA values in a fiber bundle that has been implicated in the pathophysiology of EOSS (i.e., the left ILF). Additional studies are needed to clarify the clinical significance of these findings.

Altered cortical maturation in adolescent cannabis users with and without schizophrenia.

During late adolescence, progressive cortical thinning occurs in heteromodal association cortex (HASC) that is thought to subserve cognitive development. However, the impact of cannabis use disorder (CUD) upon cortical gray matter development in both healthy adolescents and adolescents with early-onset schizophrenia (EOS) is unclear. T1-weighted magnetic resonance images were acquired from 79 adolescents at baseline and after an 18-month follow-up: 17 with EOS, 17 with CUD, 11 with EOS+CUD, and 34 healthy controls (HC). Mean age at baseline was 16.4years (CUD+) and 17.0years (CUD-). Using FreeSurfer, measures of cortical thickness for ROIs within HASC were obtained. A 2 (EOS versus no EOS)×2 (CUD versus no CUD) multivariate analysis of covariance was applied to change scores from baseline to follow-up to test for main effects of EOS and CUD and an interaction effect. After adjusting for covariates, a significant main effect of CUD was observed. Adolescents with CUD showed an attenuated loss of cortical thickness in the left and right supramarginal, left and right inferior parietal, right pars triangularis, left pars opercularis, left superior frontal, and left superior temporal regions compared to non-using subjects. Stepwise linear regression analysis indicated that greater cumulative cannabis exposure predicted greater cortical thickness in both the left (p=.008) and right (p=.04) superior frontal gyri at study endpoint after adjusting for baseline cortical thickness for the entire sample. These preliminary longitudinal data demonstrate an atypical pattern of cortical development in HASC in adolescents with CUD relative to non-using subjects, across diagnostic groups. Additional studies are needed to replicate these data and to clarify the clinical significance of these findings.

Executive attention impairment in adolescents with schizophrenia who have used cannabis.

OBJECTIVE: Repeated exposure to cannabis in nonpsychotic adolescents is associated with impairments in executive control of attention, similar to those observed in young adults with first-episode schizophrenia. To assess the impact of recurrent exposure to cannabis on cognitive function, this study characterized attention performance in both nonpsychotic adolescents and adolescents with early-onset schizophrenia (EOS). METHOD: The Attention Network Test, a standard procedure that estimates the functional state of neural networks controlling the efficiency of three different attentional behaviors (alerting, orienting, and executive attention), was administered to four groups of participants: (1) adolescents with EOS and comorbid cannabis use disorder (EOS+CUD; n=18), (2) "Pure" schizophrenia (EOS; n=34), (3) "Pure" cannabis use disorder (CUD; n=29), and (4) Healthy controls (HC; n=53). Task performance was examined with a 2×2 design (EOS+ versus EOS- and CUD+ versus CUD-) using multivariate analysis of covariance. Correlative analyses were conducted between executive attention performance and measures of surface area in the right anterior cingulate cortex. RESULTS: A significant EOS×CUD interaction was observed. In the executive attention network, adolescents with EOS+CUD showed reduced efficiency relative to adolescents with pure EOS, whereas no group differences were found between adolescents with pure CUD and HC. Less efficient executive attention was significantly associated with smaller surface area in the right caudal anterior cingulate cortex in EOS+CUD. CONCLUSIONS: These preliminary data suggest that the presence of CUD has a moderating effect on attentional performance in adolescents with schizophrenia compared to nonpsychotic adolescents. These deficits could have a role in difficulties with self-regulation and predisposition to substance misuse in this patient group. The anatomic substrate of this cognitive deficit may be related to surface area in the right caudal anterior cingulate cortex.

White matter abnormalities and cognitive impairment in early-onset schizophrenia-spectrum disorders.

OBJECTIVE: To characterize white matter abnormalities in adolescents with early-onset schizophrenia (EOS) relative to 3 comparison groups (adolescents at clinical high risk for developing schizophrenia [CHR], adolescents with cannabis use disorder [CUD], and healthy controls [HC]), and to identify neurocognitive correlates of white matter abnormalities in EOS. METHOD: We used diffusion tensor imaging and tractography methods to examine fractional anisotropy (FA) of the cingulum bundle, superior longitudinal fasciculus, corticospinal tract (CST), inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus in adolescents with EOS (n = 55), CHR (n = 21), CUD (n = 31), and HC (n = 55). FA in tracts that were significantly altered in EOS was correlated with neurocognitive performance. RESULTS: EOS and CHR groups had significantly lower FA than HC in 4 tracts, namely, bilateral CST, left ILF, and left IFOF. CUD had lower FA than HC in left IFOF. Lower FA in left IFOF and left ILF predicted worse neurocognitive performance in EOS. CONCLUSIONS: This study identified white matter abnormalities of the left ILF and left IFOF as possible biomarkers of vulnerability for developing schizophrenia. Lower FA in these tracts may disrupt functioning of ventral visual and language streams, producing domain-specific neurocognitive deficits that interfere with higher-order cognitive abilities.