Biomarkers of Recent Cannabis Use in Blood, Oral Fluid and Breath.

Proving driving under the influence of cannabis (DUIC) is difficult. Establishing a biomarker of recent use to supplement behavioral observations may be a useful alternative strategy. We determined whether cannabinoid concentrations in blood, oral fluid (OF) or breath could identify use within the past 3 h-likely the period of the greatest impairment. In a randomized trial, 191 frequent (≥4/week) and occasional (<4/week) cannabis users smoked one cannabis (placebo [0.02%], or 5.9% or 13.4% Δ9-tetrahydrocannabinol [THC]) cigarette ad libitum. Blood, OF and breath samples were collected prior to and up to 6 h after smoking. Samples were analyzed for 10 cannabinoids in OF, 8 in blood and THC in breath. Frequent users had more residual THC in blood and were more likely to be categorized as 'recently used' prior to smoking; this did not occur in OF. Per se limits ranging from undetectable to 5 ng/mL THC in blood offered limited usefulness as biomarkers of recent use. Cannabinol (CBN, cutoff = 1 ng/mL) in blood offered 100% specificity but only 31.4% sensitivity, resulting in 100% positive predictive value (PPV) and 94.0% negative predictive value (NPV) at 4.3% prevalence; however, CBN may vary by cannabis chemovar. A 10 ng/mL THC cutoff in OF exhibited the overall highest performance to detect its use within 3 h (99.7% specificity, 82.4% sensitivity, 92.5% PPV and 99.2% NPV) but was still detectable in 23.2% of participants ∼4.4 h post-smoking, limiting specificity at later time points. OF THC may be a helpful indicator of recent cannabis intake, but this does not equate to impairment. Behavioral assessment of impairment is still required to determine DUIC. This study only involved cannabis inhalation, and additional research evaluating alternative routes of ingestion (i.e., oral) is needed.

Plasma CXCL10 correlates with HAND in HIV-infected women.

HIV-associated neurocognitive disorder (HAND) is characterized by chronic immune activation. We aimed to identify biomarkers associated with HAND and to investigate their association with cognitive function and sex, in a homogenous cohort of HIV-infected (HIV+) young adults, parenterally infected during early childhood. One hundred forty-four HIV+ Romanian participants (51% women) without major confounders underwent standardized neurocognitive and medical evaluation in a cross-sectional study. IFN-γ, IL-1ß, IL-6, CCL2, CXCL8, CXCL10, and TNF-α were measured in plasma in all participants and in cerebrospinal fluid (CSF) in a subgroup of 56 study participants. Biomarkers were compared with neurocognitive outcomes, and the influence of sex and HIV disease biomarkers was assessed. In this cohort of young adults (median age of 24 years), the rate of neurocognitive impairment (NCI) was 36.1%. Median current CD4+ count was 479 cells/mm3 and 36.8% had detectable plasma viral load. Women had better HIV-associated overall status. In plasma, controlling for sex, higher levels of IL-6 and TNF-α were associated with NCI (p < 0.05). Plasma CXCL10 showed a significant interaction with sex (p = 0.02); higher values were associated with NCI in women only (p = 0.02). Individuals with undetectable viral load had significantly lower plasma CXCL10 (p < 0.001) and CCL2 (p = 0.02) levels, and CSF CXCL10 (p = 0.01), IL-6 (p = 0.04), and TNF-α (p = 0.04) levels. NCI in young men and women living with HIV was associated with higher IL-6 and TNF-α in plasma, but not in the CSF. CXCL10 was identified as a biomarker of NCI specifically in women with chronic HIV infection.

Everyday Multitasking Abilities in Older HIV+ Adults: Neurobehavioral Correlates and the Mediating Role of Metacognition.

OBJECTIVE: The prevalence of older adults living with HIV is rising, as is their risk for everyday functioning problems associated with neurocognitive dysfunction. Multitasking, the ability to maintain and carry out subgoals in support of a larger goal, is a multidimensional skill ubiquitous during most real-life tasks and associated with prefrontal networks that are vulnerable in HIV. Understanding factors associated with multitasking will improve characterization of HIV-associated neurocognitive disorders. Metacognition is also associated with frontal systems, is impaired among individuals with HIV, and may contribute to multitasking. METHOD: Ninety-nine older (≥50 years) adults with HIV completed: the Everyday Multitasking Test (MT), a performance-based measure during which participants concurrently attempt four everyday tasks (e.g., medication management) within a time limit; a comprehensive neuropsychological battery; measures of metacognition regarding their MT performance (e.g., metacognitive knowledge and online awareness). RESULTS: Better global neuropsychological performance (i.e., average T-score across all domains) was associated with better Everyday MT total scores (rho = 0.34; p < .001), as was global metacognition (rho = 0.37, p < .01). Bootstrapping mediation analysis revealed global metacognition was a significant partial mediator between neurocognition and Everyday MT (b = 0.09, 95% confidence interval [CI] = 0.01, 0.25). Specifically, metacognitive knowledge (but not online awareness) drove this mediation (b = 0.13, 95% CI = 0.03, 0.27). CONCLUSIONS: Consistent with findings among younger persons with HIV, neuropsychological performance is strongly associated with a complex, laboratory-based test of everyday multitasking, and metacognition of task performance was a pathway through which successful multitasking occurred. Interventions aimed at modifying metacognition to improve daily functioning may be warranted among older adults with HIV.

Latent toxoplasmosis is associated with neurocognitive impairment in young adults with and without chronic HIV infection.

We evaluated the impact of latent toxoplasmosis (LT) on neurocognitive (NC) and neurobehavioural functioning in young adults with and without chronic HIV infection, using a standardised NC test battery, self-reported Beck Depression Inventory, Frontal System Behavior Scale, MINI-International Neuropsychiatric Interview and risk-assessment battery. 194 young adults (median age 24years, 48.2% males) with chronic HIV infection (HIV+) since childhood and 51 HIV seronegative (HIV-) participants were included. HIV+ individuals had good current immunological status (median CD4: 479 cells/µl) despite a low CD4 nadir (median: 93 cells/µl). LT (positive anti-Toxoplasma IgG antibodies) was present in one third of participants. The impairment rates in the HIV- with and without Toxo were not significantly different (p=0.17). However, we observed an increasing trend (p<0.001) in impairment rates with HIV and LT status: HIV-/LT- (6.1%); HIV-/LT+ (22%), HIV+/LT- (31%), HIV+/LT+ (49%). In a multivariable analysis using the entire study group there were main effects on cognition for HIV and also for LT. Within the HIV+ group LT was associated with worse performance globally (p=0.006), in memory (p=0.009), speed of information processing (p=0.01), verbal (p=0.02) and learning (p=0.02) domains. LT was not associated with depressive symptoms, frontal systems dysfunction or risk behaviors in any of the groups. HIV participants with lower Toxoplasma antibody concentration had worse NC performance, with higher GDS values (p=0.03) and worse learning (p=0.002), memory (p=0.006), speed of information processing (p=0.01) T scores. Latent Toxoplasmosis may contribute to NC impairment in young adults, including those with and without chronic HIV infection.

The impact of ethnicity/race on the association between the Veterans Aging Cohort Study (VACS) Index and neurocognitive function among HIV-infected persons.

The Veterans Aging Cohort Study (VACS) Index was developed as a risk index for health outcomes in HIV, and it has been consistently associated with mortality. It shows a significant, yet relatively weak, association with neurocognitive impairment, and little is known about its utility among ethnic/racial minority groups. We examined whether the association between the VACS Index and neurocognition differed by ethnic/racial group. Participants included 674 HIV-infected individuals (369 non-Hispanic whites, 111 non-Hispanic blacks, and 194 Hispanics). Neurocognitive function was assessed via a comprehensive battery. Scaled scores for each neurocognitive test were averaged to calculate domain and global neurocognitive scores. Models adjusting for demographics and HIV disease characteristics not included in the VACS Index showed that higher VACS Index scores (indicating poorer health) were significantly associated with worse global neurocognition among non-Hispanic whites. This association was comparable in non-Hispanic blacks, but nonsignificant among Hispanics (with similar results for English and Spanish speaking). We obtained comparable findings in analyses adjusting for other covariates (psychiatric and medical comorbidities and lifestyle factors). Analyses of individual neurocognitive domains showed similar results in learning and delayed recall. For other domains, there was an effect of the VACS Index and no significant interactions with race/ethnicity. Different components of the VACS Index were associated with global neurocognition by race/ethnicity. In conclusion, the association between the VACS Index and neurocognitive function differs by ethnic/racial group. Identifying key indicators of HIV-associated neurocognitive impairment by ethnic/racial group might play an important role in furthering our understanding of the biomarkers of neuroAIDS.

Predictors of Attrition in a Cohort Study of HIV Infection and Methamphetamine Dependence.

Longitudinal cohort studies of HIV and substance use disorders play an important role in understanding these conditions, but high rates of attrition can threaten their integrity and generalizability. This study aimed to identify factors associated with attrition in a 5-year observational cohort study of 469 individuals with and without HIV infection and methamphetamine (MA) dependence. Rates of attrition in our four study groups were approximately 24% in HIV-MA-, 15% in HIV+MA-, 56% in HIV-MA+, and 47% in HIV+MA+ individuals. Predictors of attrition in the overall cohort included history of MA, alcohol, and other substance dependence, learning impairment, reduced cognitive reserve, and independence in activities of daily living (all ps < .05), but varied somewhat by clinical group. Of particular note, enrollment in a neuroimaging substudy was associated with significantly boosted rates of retention in the MA groups. Results from this investigation highlight the complexity of the clinical factors that influence retention in cohort studies of HIV-infected MA users and might guide the development and implementation of targeted retention efforts.

Partial uncoupling of luteinizing hormone and prolactin pulse coincidence in hyperandrogenemic women.

A partly synchronized pulsatile secretion of luteinizing hormone (LH) and prolactin has previously been suggested as an indication of the coupling of the respective pulse generators under certain conditions. In women with hyperandrogenemic chronic anovulation, episodic LH secretion is disturbed. It was, therefore, the aim of the present study to evaluate possible changes in episodic prolactin secretion pattern and in LH/prolactin co-pulsatility, and to relate the results to the accelerated LH pulse frequencies often seen in patients with hyperandrogenemic chronic anovulation. Blood samples of 32 patients with hyperandrogenemia were taken at 10-min intervals between 10.00 and 20.00. Nine regularly cycling women with normal hormone levels served as controls. In the women with hyperandrogenemia, despite an average 41% rise of LH pulse frequency, prolactin pulse frequency decreased slightly by 14% as compared to controls; no correlation between the two parameters was found (r = 0.162). The number of coincident LH and prolactin pulses increased continuously with accelerating LH frequency. The best fitting function was a hyperbola which was limited by the maximal observed prolactin frequency. As a consequence, the fraction of LH pulses that were co-secreted with prolactin episodes decreased with higher LH pulse frequencies, while the fraction of prolactin pulses concomitant with LH pulses increased. Our data provide evidence that in women with hyperandrogenemic chronic anovulation a pathological LH pulse frequency is no longer coupled with pulsatile prolactin secretion, suggesting an isolated alteration of the central neuronal control mechanism for LH secretion.

[Dexamethasone does not normalize disordered LH pulsatility in hyperandrogenemic ovarian insufficiency]. / Dexamethason normalisiert nicht die gestörte LH-Pulsatilität bei der hyperandrogenämischen Ovarialinsuffizienz.

Application of dexamethasone (DEX) is well accepted for treatment of hyperandrogenemic ovarian failure (HOI). In some cases of clomiphene resistance, additional DEX can induce ovulatory cycles. In this study, we evaluated the influence of adrenal androgen reduction on the gonadotroph during longterm therapy with 0.5 mg DEX daily in a larger group of patients (n = 25) in order to investigate subgroups of HOI. Women with elevated DHEA-sulfate levels only (DS-group); with elevated testosterone and/or androstenedione levels only (TA); with polycystic ovaries in ultrasound (PCO), with highest LH levels (LH); with secondary amenorrhea (SA); with oligomenorrhea (OL) and with elevated body mass index (BMI) were included. Blood samples were taken at 10 min intervals for 12 h sampling periods (8am-8pm) and analyzed by RIA. In amenorrhoeic patients, investigations took place at monthly intervals; in cycling women preferentially on day 5 of the cycle. LH and FSH profiles were evaluated by 3 different computerized peak identification programs ("pulsar", "ultra" and "modified Santen and Bardin"). DEX resulted in significant decreases in T, A, DS and progesterone serum levels in all subgroups. No significant alterations were found in estradiol levels and only small variations in few subgroups with estrone. Mean LH concentrations exhibited small decreases (p less than 0.05) in DS-, LH- and OL subgroups and no changes in the others. With the exception of a decrease in "pulsar" pulse frequency in the OL subgroup, no changes in pulse frequency or amplitude were found in any other group during DEX therapy. Mean FSH concentrations and pulsatility did not vary either.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of clobetasone in rabbit eye tissues after topical application.

This study describes the bioavailability of Clobetasone, which is topically applied as an anti-inflammatory drug. Right eyes of Chinchilla rabbits received Clobetasone eye drops 3 times daily over a period of consecutive 14 days. 30 min up to 96 h after the last application animals were killed at different times and the eyes removed immediately. Nine different eye tissue samples were prepared for Clobetasone estimation by radioimmunoassay (RIA) using 3H-labeled Clobetasone and an antibody directed against Clobetasone. Results indicate that Clobetasone penetrates relatively fast into the different eye tissues. The concentrations are different in the various tissues and show a relationship to the distance from cornea to vitreous. Concentrations decline in the following order: cornea greater than conjunctiva, sclera, iris (200 ng/g) greater than lens, vitreous, aqueous humour (5-15 ng/g). In all samples investigated Clobetasone levels decrease with time. No accumulation of the drug has been measured at any time. Clobetasone levels in the left, untreated eye, indicate that the compound has a small systemic resorption.