Jesus B. Fernandez

Cerebrospinal fluid dopamine in HIV-1 infection

BackgroundIncreasing evidence suggests significant involvement of the basal ganglia in patients with HIV-1 infection. ObjectiveTo study the effect of HIV-1 infection on cerebrospinal fluid (CSF) dopamine levels. DesignCSF dopamine levels were measured by high-performance liquid chromatography. SettingA university-based outpatient clinic in south Florida involved in clinical AIDS research. SubjectsTwenty-two subjects were enrolled in a prospective, longitudinal study of the neurological complications of AIDS. Five subjects were HIV-seronegative, but at risk for HIV-1 infection, 11 were HIV-1-seropositive without neurological disease and six had HIV-1-related neurological disease. ResultsThe CSF dopamine mean values were significantly lower in the HIV-1-seropositive group with (P< 0.0001) or without (P < 0.0001) neurological disease than in the HIV-seronegative group. There was a very strong correlation between CD4 lymphocyte counts and CSF dopamine levels (P=0.004) in the neurologically symptomatic group (P= 0.0008), but not in the other two groups. ConclusionHIV-1 infection appears to have an effect on the central nervous system dopaminergic systems, as reflected in levels of CSF dopamine.

Cognitive-behavioral stress management buffers decreases in dehydroepiandrosterone sulfate (DHEA-S) and increases in the cortisol:DHEA-S ratio and reduces mood disturbance and perceived stress among HIV-seropositive men

This study examined the effects of a 10-week cognitive-behavioral stress management (CBSM) intervention on dehydroepiandrosterone sulfate (DHEA-S) levels and the ratio of cortisol to DHEA-S (cortisol/DHEA-S), potential surrogate adrenal markers of HIV disease progression, in relation to alterations in mood and distress. HIV-seropositive men were randomized to either a group-based CBSM intervention (n = 43) or to a wait-list control group (n = 24), with both hormonal and distress measures assessed just prior to and immediately following the 10-week period. Results showed that CBSM buffers decreases in DHEA-S and increases in the cortisol/DHEA-S ratio. Further examination also revealed that changes in the cortisol/DHEA-S ratio were significantly and positively related to changes in total mood disturbance and perceived stress over time. These findings demonstrate that a short-term CBSM intervention can buffer against decrements in DHEA-S and increments in the cortisol/DHEA-S ratio among symptomatic, HIV-positive men, and that alterations in the cortisol/DHEA-S ratio move in concert with changes in mood and distress observed during CBSM.

Human immunodeficiency virus type 1 in the central nervous system leads to decreased dopamine in different regions of postmortem human brains

Human immunodeficiency virus type 1 (HIV-1) invades the central nervous system (CNS) shortly after infection and becomes localized in varying concentrations in different brain regions, the most vulnerable is the basal ganglia (BG). It is hypothesized that HIV-1-mediated neuropathogenesis involves degeneration of dopaminergic neurons in the substantia nigra and the loss of dopaminergic terminals in the BG, leading to deficits in the central dopaminergic activity, resulting in progressive impairment of neurocognitive and motor functions. In the era of highly active antiretroviral therapy (HAART), although the incidence of HIV-associated dementia (HAD) has decreased, the neurocognitive and neuropsychological deficits continue to persist after HAART. In this study, We investigated the impact of HIV-1 on dopaminergic activity with respect to concentrations of dopamine (DA) and homovanillic acid (HVA) in different regions of postmortem human brains of HIV-1negative and HIV-1+ individuals and their relationship to neurocognitive impairment. We found that in HIV-1+ as well as HIV-negative cases, dopamine and HVA concentrationsin ranged widely in different brain regions. In HIV-negative brain regions, the highest concentration of DA was found in putamen, caudate, substantia nigra, and the basal ganglia. In HIV-1+ cases, there was a significant decrease in DA levels in caudate nucleus, putamen, globus pallidus, and substantia nigra compared to that in HIV-negative cases. In HIV-1+ cases, a strong correlation was found between DA levels in substantia nigra and other brain regions. Concentration of HVA in HIV-negative cases was also highest in the regions containing high dopamine levels. However, no significant decrease in regional HVA levels was found in HIV-1+ cases. HIV-1 RNA load (nondetectable [ND] to log10 6.9 copies/g tissue) also ranged widely in the same brain regions of HIV-1+ cases. Interestingly, the brain regions having the highest HIV-1 RNA had the maximum decrease in DA levels. Age, gender, ethnicity, and postmortem interval were not correlated with decrease in DA levels. Profile of DA, HVA, and HIV-1 RNA levels in the brain regions of HIV-1+ individuals treated with HAART was similar to those not treated with HAART. A majority of HIV-1+ individuals had variable degrees of neurocognitive impairments, but no specific relationship was found between the regional DA content and severity of neurocognitive deficits. These findings suggest widespread deficits in dopamine in different brain regions of HIV-1-infected cases, and that these deficits may be the results of HIV-1-induced neurodegeneration in the subcortical regions of human brain.

LHRH antagonist Cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia.

Recent findings suggest that BPH has an inflammatory component. Clinical trials have documented that therapy with LHRH antagonist Cetrorelix causes a marked and prolonged improvement in LUTS in men with symptomatic BPH. We investigated the mechanism of action and effect of Cetrorelix in a rat model of BPH.

A modified HPLC technique for simultaneous measurement of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in cerebrospinal fluid, platelet and plasma

A sensitive, reliable and simplified HPLC assay for simultaneous measurement of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in human cerebrospinal fluid (CSF), platelets and plasma is described. Perchloric acid is used for one step precipitation of proteins and extraction of 5-HT and 5-HIAA. Precision of the assay has been increased by calibration of the instrument using serotonin-free plasma spiked with known amount of standards and N-w-methyl-5-hydroxytryptamine as internal standard. Integration of the peaks and calculations are achieved by a preprogrammed data module using ratio method. As little as 20 pg/ml of serotonin in the deproteinated sample can be detected using this procedure. In a group of surgical patients, plasma 5-HT concentration is (Mean +/- S D) 3.4 +/- 2.7 ng/ml and that of platelet 748.3 +/- 448.3 ng/10(9) platelets. In CSF, 5-HT is found to be 3.3 +/- 3.4 ng/ml and 5-HIAA is 15.1 +/- 7.3 ng/ml. A good correlation (r = 0.648, p less than .0001) is observed between 5-HT and 5-HIAA in CSF.

Cognitive-behavioral stress management increases free testosterone and decreases psychological distress in HIV-seropositive men

The effects of a 10-week group-based cognitive-behavioral stress management (CBSM) intervention on psychological distress and plasma free testosterone in symptomatic, HIV-seropositive men were examined. Participants were randomized to either CBSM (n = 42) or a wait-list control group (n = 23). Men in the CBSM intervention showed significant increases in testosterone, whereas control participants showed significant decreases. Those participating in CBSM had significant distress reductions, whereas controls showed no such change. Alterations in free testosterone were inversely related to changes in distress states over time, independent of any changes in cortisol. These findings demonstrate that a short-term CBSM intervention increases free testosterone levels among symptomatic, HIV-seropositive men, and alterations in free testosterone are associated with changes in psychological distress observed during CBSM.

Adrenocortical Response to Ovine Corticotropin-Releasing Hormone in Young Men: Cortisol Measurement in Matched Samples of Saliva and Plasma

Background: Assessment of hypothalamic-pituitary-adrenal (HPA) axis function in stress-related health problems in humans is frequently carried out as a dynamic test by measuring the profile of increment in adrenocortical hormone (ACTH) and/or cortisol level in plasma in response to corticotropin-releasing hormone (CRH) administration. However, obtaining multiple blood samples for this type of test is not only an invasive procedure but also problematic to use in individuals with constricted or damaged veins which collapse during the blood draw such as the injecting drug users (IDUs) and HIV-1-infected individuals. Salivary cortisol measurement presents a non-invasive alternate approach to evaluate HPA axis activity in different situations. In order to validate the efficacy of salivary cortisol measurement for a dynamic test in IDUs and HIV-1-infected individuals, the present study was carried out to evaluate the cortisol profile in matched samples of plasma and saliva in healthy young men in response to ovine CRH (oCRH) administration. Methods: Cortisol levels were measured in matched samples of plasma and saliva of healthy young men at baseline and over a 90-min period after administration of a single low dose of oCRH (1 µg/kg). Results: Salivary cortisol levels were found to follow the profile similar to that of plasma, increasing significantly at each time point after oCRH administration from their respective baseline values (all Sign tests, p < 0.05). The peak level of cortisol occurred at 30 min in both fluids. Although salivary cortisol concentration was a fraction of the total plasma cortisol levels at all time points, there was a significant correlation in the values between the two fluids at baseline (r = 0.87, p < 0.02) as well as at 90 min (r = 0.70, p < 0.03). Conclusion: The findings support the earlier studies and substantiate the efficacy of using salivary free cortisol measurement for assessment of dynamic function of pituitary-adrenal axis in healthy young men and its application in individuals such as IDUs and HIV-infected individuals who may have difficulty in donating multiple blood samples.

A Simplified HPLC-ECD Technique for Measurement of Urinary Free Catecholamines

Abstract A simplified HPLC assay is described for quantification of free urinary catecholamines. The procedure involves exraction of catecholamines, (norepinephrine, epinephrine and dopamine) from urine, using columns filled with Biorex-70. The catecholamines from the extract were separated on a high performance liquid chromatographic system using reverse phase C18, 5 u column and determined by electrochemical detection. Integration and calculations are achieved by a data module using area ratio method with dihydroxybenzylamine as internal standard. Recovery of more than 90% was achieved for each catecholamine. A linear relationship between a wide range of concentrations and ratio of the area of amines to that of internal standard was observed. The method is simple and rapid and therefore can be used to analyze a large number of samples in one day and should prove useful in studies involving the role of catecholamines in different psychiatric disorders.

Peripheral Serotonin Levels in Women: Role of Aging and Ethnicity

Serotonin has been implicated to play an important role in regulating emotions and behavior, and it is well accepted that the platelet serotonergic system mirrors the presynaptic central serotonergic system. Since prevalence of psychiatric problems increases with age and women are known to be more vulnerable than men, the present investigation was carried out to study the relationship between serotonin activity and age in women. Levels of serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in platelets and plasma in women (n = 49) aged 40– 84 years (30 women aged 40–60 years and 19 women aged 61–84 years). There was a significant age difference between the two groups (mean: 47.6 ± 5.91 years in the younger and 73.0 ± 6.83 years in the older women, respectively, p < 0.00001). Platelet 5-HT as well as 5-HIAA levels were significantly higher in older women as compared to those in the younger women (89.41 ± 21.95 ng/108 platelets in younger vs. 112.9 ± 36.07 in older women, p < 0.02, and 1.20 ± 1.10 in younger vs. 2.19 ± 1.88 ng/108 platelets in older women, p < 0.05, respectively). Pearson correlation coefficients determined in the combined group (n = 49) showed a significant positive correlation between platelet 5-HT and age (r = 0.31, p < 0.03). Plasma 5-HT levels on the other hand were lower in older women compared to those in the younger women (4.50 ± 3.20 in younger vs. 1.04 ± 1.28 ng/ml plasma in older women, p < 0.0001) and a significant negative correlation was observed between plasma 5-HT and age (r = –0.44, p < 0.002). Plasma 5-HIAA concentration did not differ between the two groups. Platelet 5-HT levels in the younger group were independent of ethnicity. Since high serotonin activity has also been associated with psychiatric problems, our results of increased concentration of platelet 5-HT as well as 5-HIAA with age may have implications in predisposing aging women to behavioral/psychiatric problems.

Cerebrospinal Fluid 5-Hydroxytryptamine and 5-Hydroxyindoleacetic Acid in HIV-1 Infection

Reduced level of serotonin (5-hydroxytryptamine, 5-HT) in humans has been associated with a number of mental health and behavioral problems including depression, aggression, violence, sexual dysfunctions, sleep and eating disorders. Even though among HIV-1-infected individuals, prevalence of mental health and behavioral problems are common, their relationship with central nervous system serotonin functions is not clearly understood. This investigation was carried out to study the status of CSF 5-HT in HIV-1+ subjects (n = 21), in the early stage of infection, and HIV-1– control subjects (n = 24). Samples of CSF were obtained by lumbar puncture and were analyzed for 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), using high-performance liquid chromatography equipped with electrochemical detector. Levels of CSF 5-HT were significantly lower in the HIV-1+ group compared to the HIV-1– group. There was no significant difference in the CSF 5-HIAA levels between the two groups. In both groups, however, there was a significant correlation between CSF 5-HT and 5-HIAA. In the HIV-1 + group, although CSF 5-HT level was significantly negatively correlated with serostatus, there was no correlation between either CSF 5-HT or 5-HIAA levels and CD4 cell number or any behavioral measures evaluated in this study, including Beck’s Depression Inventory and state/trait anxiety scores. These data suggest that HIV-1 infection affects the CNS 5-HT status with no significant association with measures of depression and anxiety, at least in the early stage of infection.