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Director's Report to the National Advisory Council on Drug Abuse - February, 2010

Research Findings - Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV)

Pharmacokinetic Interactions Between Buprenorphine/Naloxone and Tipranavir/Ritonavir In HIV-Negative Subjects Chronically Receiving Buprenorphine/Naloxone

HIV-infected patients with opioid dependence often require opioid replacement therapy. Pharmacokinetic interactions between HIV therapy and opioid dependence treatment medications can occur. HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone (BUP/NLX) therapy sequentially underwent baseline and steady-state pharmacokinetic evaluation of open-label, twice daily tipranavir 500 mg co-administered with ritonavir 200 mg (TPV/r). Twelve subjects were enrolled and 10 completed the study. Prior to starting TPV/r, the geometric mean BUP AUC(0-24h) and C(max) were 43.9 ng h/mL and 5.61 ng/mL, respectively. After achieving steady-state with TPV/r (> or = 7 days), these values were similar at 43.7 ng h/mL and 4.84 ng/mL, respectively. Similar analyses for norBUP, the primary metabolite of BUP, demonstrated a reduction in geometric mean for AUC(0-24h) [68.7-14.7 ng h/mL; ratio=0.21 (90% CI 0.19-0.25)] and C(max) [4.75-0.94 ng/mL; ratio=0.20 (90% CI 0.17-0.23)]. The last measurable NLX concentration (C(last)) in the concentration-time profile, never measured in previous BUP/NLX interaction studies with antiretroviral medications, was decreased by 20%. Despite these pharmacokinetic effects on BUP metabolites and NLX, no clinical opioid withdrawal symptoms were noted. TPV steady-state AUC(0-12h) and C(max) decreased 19% and 25%, respectively, and C(min) was relatively unchanged when compared to historical control subjects receiving TPV/r alone. No dosage modification of BUP/NLX is required when co-administered with TPV/r. Though mechanistically unclear, it is likely that decreased plasma RTV levels while on BUP/NLX contributed substantially to the decrease in TPV levels. BUP/NLX and TPV/r should therefore be used cautiously to avoid decreased efficacy of TPV in patients taking these agents concomitantly. Bruce RD, Altice FL, Moody DE, et al. Drug Alcohol Depend. 2009 Dec 1;105(3):234-9. Epub 2009 Sep 1.

Medication Assisted Treatment In the Treatment of Drug Abuse and Dependence In HIV/AIDS Infected Drug Users

Drug use and HIV/AIDS are global public health issues. The World Health Organization (WHO) estimates that up to 30% of HIV infections are related to drug use and associated behaviors. The intersection of the twin epidemics of HIV and drug/alcohol use, results in difficult medical management issues for the health care providers and researchers who work in the expanding global HIV prevention and treatment fields. Access to care and treatment, medication adherence to multiple therapeutic regimens, and concomitant drug -drug interactions of prescribed treatments are difficult barriers for drug users to overcome without directed interventions. Injection drug users are frequently disenfranchised from medical care and suffer sigma and discrimination creating additional barriers to care and treatment for their drug abuse and dependence as well as HIV infection. In an increasing number of studies, medication assisted treatment of drug abuse and dependence has been shown to be an important HIV prevention intervention. Controlling the global transmission of HIV will require further investment in evidence-based interventions and programs to enhance access to care and treatment of individuals who abuse illicit drugs and alcohol. In this review, the investigators present the cumulative evidence of the importance of medication assisted treatment in the prevention, care, and treatment of HIV infected individuals who also abuse drugs and alcohol. Kresina TF, Bruce RD, McCance-Katz EF. Curr HIV Res. 2009 Jul 7(4):354-364.

Long-Term Combination Antiretroviral Therapy Is Associated With the Risk of Coronary Plaques In African Americans With HIV Infection

The aim of the study was to assess whether long-term antiretroviral therapy (ART) is associated with the risk of coronary plaques in HIV-infected cardiovascularly asymptomatic African Americans. Between August 2003 and December 2007, 176 HIV-infected cardiovascularly asymptomatic African Americans were consecutively enrolled in an observational study investigating the effects of ART on subclinical atherosclerosis in Baltimore, Maryland. Computed tomography coronary angiography was performed to detect coronary plaques. The overall prevalence rate of coronary plaques was 30%. After adjusting for gender, total cholesterol, and cocaine use, logistic regression analysis revealed that exposure to ART for more than 18 months (adjusted odds ratio [OR]: 2.20, 95% confidence interval [CI]: 1.01, 4.79) was independently associated with the presence of coronary plaques. A higher HIV viral load was univariately associated with the presence of noncalcified plaques. Use of ART (>18 months) was independently associated with the presence of noncalcified plaques (adjusted OR: 7.61, 95% CI: 1.67, 34.7), whereas cocaine use (>15 years) was independently associated with the presence of calcified plaques (adjusted OR: 2.51, 95% CI: 1.11, 5.67). This study suggests that long-term exposure to ART may be associated with coronary plaques. Because long-term use of ART and HIV replication may be associated with the presence of noncalcified plaques, some of which may be more vulnerable to rupture, an intensive lifestyle intervention to reduce traditional risk factors for coronary artery disease (CAD) is ultimately vital to those who are on ART. This study also suggests that cocaine cessation is the single most effective strategy to prevent CAD in HIV-infected cocaine users. Lai S, Bartlett J, Lai H, Moore R, Cofrancesco J Jr, Pannu H, Tong W, Meng W, Sun H, Fishman EK. AIDS Patient Care STDS. 2009 Oct 23(10):815-824.

HIV Infection and Abnormal Regional Ventricular Function

The goal of this study was to examine the effect of HIV infection on regional left ventricular dysfunction in cardiovascularly asymptomatic individuals. Nineteen HIV-negative and 27 HIV-positive cardiovascularly asymptomatic study participants in Baltimore, Maryland were selected and underwent tagged cardiac magnetic resonance imaging. Regional left ventricular myocardial mid-wall peak systolic circumferential strain (Ecc) and early diastolic strain rate (SRE) of the left ventricle were assessed with the use of the harmonic phase analysis. The average Ecc and SRE measurements were compared between HIV-negative and HIV-positive individuals. Compared with the HIV-negatives, the HIV-positives had lower average Ecc and SRE measurements in 90% of the 16 standard left ventricular segments. Of the 14 segments with decreased Ecc strain, 3 were statistically significant and of 14 with decreased strain rate (SRE), 6 were statistically significant. HIV infection may be associated with subclinical regional left ventricular systolic and diastolic dysfunction in individuals free of overt cardiovascular disease. Lai H, Redheuil A, Tong W, Bluemke DA, Lima JA, Ren S, Lai S. Int J Cardiovasc Imaging. 2009 Sep 11. [Epub ahead of print]

Differential Regulation of Indoleamine-2,3-Dioxygenase (IDO) By HIV Type 1 Clade B and C at Protein

Previous studies have demonstrated that infection with HIV-1 clades might differentially contribute to the neuropathogenesis of HIV-1-associated dementia (HAD). HIV-1 transactivator regulatory protein (Tat) plays a major role in the process of disruption of neuronal function. It is not well understood how these HIV-1 subtypes exert different neuropathogenic effects. Activation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway, leads to increased tryptophan catabolism and the generation of neurotoxins such as kynurenine (KYN). It is known that KYN plays a crucial role in the neuropathogenesis of HAD. It was hypothesized that HIV-1 clade B and C Tat proteins might exert differential effects on human primary astrocytes by the upregulation of the IDO gene and protein expression as well as its activity and production of the neurotoxin KYN. RNA extracted from human primary astrocytes treated with either HIV-1 clade B and C Tat proteins was reverse transcribed and analyzed by quantitative real-time PCR to determine IDO gene expression. In addition, the enzymatic activity of IDO and the concentration of KYN were measured in cell lysates and culture supernatants. These results indicate that HIV-1 clade B Tat protein significantly upregulated the IDO gene and protein expression, IDO enzyme activity, as well as KYN concentration compared to HIV-1 clade C Tat protein. Thus, these studies for the first time demonstrate that HIV-1 clade B Tat protein in human primary astrocytes appears to increase the level of neuropathogenic agents, such as IDO and KYN, as compared to HIV-1 clade C Tat protein. These results provide further evidence that the prevalence of HAD may be correlated with the difference in clades of HIV-1. Samikkannu T, Saiyed ZM, Rao KV, Babu DK, Rodriguez JW, Papuashvili MN, Nair MP. AIDS Res Hum Retroviruses. 2009 Mar 25(3):329-335.

Differential Effects of HIV Type 1 Clade B and Clade C Tat Protein on Expression of Proinflammatory and Antiinflammatory Cytokines By Primary Monocytes

The existence of multiple subtypes of HIV-1 worldwide has created new challenges to control HIV-1 infection and associated neuropathogenesis. Previous studies indicate a difference in neuropathogenic manifestations of HIV-1-associated neuroAIDS between clade B- and clade C-infected subjects with clade B being more neuropathogenic than clade C. However, the exact mechanism underlying the differences in the neuropathogenesis by both the subtypes remains elusive. Development of neuroAIDS is associated with a complex interplay between proinflammatory and antiinflammatory cytokines and chemokines. In the current study, the investigators hypothesize that HIV-1 clade B and C Tat protein exert differential effects on human primary monocytes leading to differences in gene and protein expression of cytokines implicated in neuroAIDS. Primary human monocytes were treated with clade B and clade C Tat protein and quantitative real time PCR was performed to determine gene expression of proinflammatory cytokines (IL-6 and TNF-alpha) and antiinflammatory cytokines (IL-4 and IL-10). Further, cytokine secretion was measured in culture supernatants by ELISA, whereas intracellular cytokine expression was detected by flow cytometry. Results indicate that monocytes treated with Tat B showed significant upregulation of proinflammatory cytokines, IL-6 and TNF-alpha, as compared to Tat C-treated cultures. However, expression of antiinflammatory molecules and IL-4 and IL-10 was found to be higher in Tat C-treated compared to Tat B-treated cultures. Thus, this result shows for the first time that Tat B and Tat C differentially modulate expression of neuropathogenic molecules that may be correlated with the differences in neuroAIDS manifestation induced by clade-specific infections. Gandhi N, Saiyed Z, Thangavel S, Rodriguez J, Rao KV, Nair MP. AIDS Res Hum Retroviruses. 2009 Jul 25(7):691-699.

Kupffer Cells are Depleted With HIV Immunodeficiency and Partially Recovered With Antiretroviral Immune Reconstitution

HIV-related enhancement of gut microbial translocation is associated with progression of hepatic fibrosis. Although hepatic macrophages (Kupffer cells) clear most microbial translocation products and can be infected by HIV, their fate in HIV progression has not been carefully investigated. Kupffer cell density (KCD) was studied in 76 HIV-hepatitis C virus coinfected patients investigated at various stages of liver disease and CD4(+) lymphocyte depletion (and restoration). KCD averaged 23 cells per high-powered field (range 4.4-52.2) and was highest in portal and periportal regions as compared with centrilobular regions (P < 0.001). No differences were detected in KCD by age, liver fibrosis stage, or hepatic inflammatory score. Compared with individuals without apparent HIV-related immunosuppression, however, KCD was substantially lower in persons with lower peripheral blood CD4(+) lymphocyte counts (P = 0.027) and lowest among those with deepest CD4(+) lymphocyte nadir (P = 0.006). After the initial liver biopsy, eight patients began antiretroviral therapy and had immune restoration (> or = 2-fold increase in peripheral CD4(+) lymphocyte count) and a second histologic evaluation with a median of 36.8 months later (range 28.1-58.4 months); KCD increased in all (P = 0.007). Given the central role of Kupffer cells in controlling microbial translocation, these data suggest Kupffer cell loss needs to be considered in the pathogenesis of liver fibrosis in HIV-hepatitis C virus coinfected persons. The abundance of portal and periportal Kupffer cells is suggestive of their contribution to fibrosis in periportal regions in chronic viral hepatitis. Balagopal A, Ray SC, De Oca RM, et al. AIDS. 2009 Nov 27;23(18):2397-2404.

Genetic Variation In IL28B and Spontaneous Clearance of Hepatitis C Virus

Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, the investigators genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). The C/C genotype was shown to strongly enhance resolution of HCV infection among individuals of both European and African ancestry. To the author's knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection. Thomas DL, Thio CL, Martin MP, et al. Nature. 2009 Oct 8;461(7265):798-801.

Spontaneous Control of Primary Hepatitis C Virus Infection and Immunity Against Persistent Reinfection

Patients with ongoing hepatitis C virus (HCV) exposure following control of an initial HCV infection to determine whether primary control conferred protection against future persistent infections were followed. Twenty-two active injection drug users (IDU) who had cleared a primary hepatitis C viremia for at least 60 days were monitored monthly. Reinfection was defined as the detection of a new HCV infection. Protection was assessed based on the magnitude and duration of viremia following reinfection and generation of T-cell and neutralizing antibody (nAb) responses. Reinfection occurred in 11 IDU (50%) who previously spontaneously controlled primary HCV infection. Although viral clearance occurs in approximately 25% of patients with primary infections, spontaneous viral clearance was observed in 83% of reinfected patients. The duration and maximum level of viremia during subsequent episodes of reinfection were significantly decreased compared with those of the primary infection in the same subjects. In contrast to chronic infection, reinfection was associated with a significant increase in the breadth of T-cell responses. During acute infection, nAbs against heterologous viral pseudoparticles were detected in 60% of reinfected subjects; cross-reactive nAbs are rarely detected in patients who progress to chronic infection. HCV reinfection is associated with a reduction in the magnitude and duration of viremia (compared with the initial infection), broadened cellular immune responses, and generation of cross-reactive humoral responses. These findings are consistent with development of adaptive immunity that is not sterilizing but protects against chronic disease. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. Osburn WO, Fisher BE, Dowd KA, et al. Gastroenterology. 2009 Sep 24. [Epub ahead of print]

Factors Associated With Serum Retinol, Alpha-Tocopherol, Carotenoids, and Selenium In Hispanics With Problems of HIV, Chronic Hepatitis C, and Drug Use

The effects of hepatitis and drug use on nutritional problems in HIV infection have rarely been examined despite the importance of drug use in the global HIV pandemic. The effects of HIV, hepatitis C, and drug use on serum micronutrients in 300 US Hispanic adults were examined. Chronic hepatitis C infection was associated with lower serum retinol (-8.2 microg/dl, P < 0.0001), alpha-tocopherol (-0.10 ln microg/dl, P = 0.024), and carotenoids (-19.8 microg/dl, P < 0.0001). HIV infection was associated with lower selenium (-6.1 microg/l, P = 0.028). Elevated triglycerides in HIV infection were associated with higher serum retinol and alpha-tocopherol. Drug use was not independently associated with micronutrient alterations. It was concluded that hepatitis C is an important determinant of low serum micronutrients, and should be considered in any nutritional assessment of HIV infected populations. As the safety of micronutrient supplementation is not established, policy for appropriate HIV clinical care should distinguish between populations with and without hepatitis coinfection. Forrester JE, Wang XD, Knox TA, et al. J Public Health Policy. 2009 Sep 30(3):285-992.

Hepatitis B and Long-Term HIV Outcomes In Coinfected HAART Recipients

Chronic hepatitis B (CH-B) is common among HIV-infected individuals and increases liver-related mortality in the absence of HAART. The impact of CH-B on long-term HAART outcomes has not been fully characterized. To address this question, HAART initiators enrolled in the Multicenter AIDS Cohort Study were retrospectively analyzed. Patients were classified by hepatitis B category based on serology at the time of HAART initiation. The association of CH-B with mortality, AIDS-defining illnesses, CD4 cell rise, and HIV suppression was assessed using regression analysis. Of 816 men followed for a median of 7 years on HAART, 350 were never hepatitis B virus (HBV) infected, 357 had past infection, 45 had CH-B, and 64 were only core-antibody positive. Despite HAART, AIDS-related mortality was the most common cause of death [8.3/1000 person-years (PYs)]. It was highest in those with CH-B (17/1000 PYs, 95% confidence interval 7.3, 42) and lowest among never HBV infected (2.9/1000 PYs, 95% confidence interval 1.4, 6.4). In a multivariable model, patients with CH-B had a 2.7-fold higher incidence of AIDS-related mortality compared with those never infected (P = 0.08). Non-AIDS-related mortality was also highest among those with CH-B (22/1000 PYs), primarily due to liver disease (compared to never infected, adjusted hazard ratio 4.1, P = 0.04). There was no significant difference in AIDS-defining events, HIV RNA suppression, and CD4 cell increase. In HIV-infected patients receiving long-term HAART, HBV status did not influence HIV suppression or CD4 cell increase. However, mortality was highest among those with CH-B and was mostly due to liver disease despite HBV-active HAART. Hoffmann CJ, Seaberg EC, Young S, et al. AIDS. 2009 Sep 10;23(14): 1881-1889.

Health-Related Quality of Life In Methadone Maintenance Patients With Untreated Hepatitis C Virus Infection

To assess health-related quality of life (HRQOL) in methadone maintenance treatment (MMT) patients with untreated chronic HCV infection and to determine the clinical factors that predict HRQOL. HRQOL was measured in 100 MMT patients entering an HCV treatment trial. Subjects were mostly male (61%) and white (81%) with a mean age of 43 (+/-10). 57% had a current non-substance use psychiatric disorder. 55% had a current (past 12 months) substance use disorder, including 44% with current opioid or cocaine abuse/dependence. HRQOL in our sample was compared to published reports for the general population as well as for non-MMT HCV patients. To assess predictors of SF-36 HRQOL, hierarchical multiple regression techniques were used to assess model improvement with four blocks of baseline predictors: Demographics, Medical Severity, Addiction Severity, and Depression Severity. HRQOL scores were significantly lower than scores for the general population and were also lower than scores reported for untreated HCV patients not in MMT. Regression analysis demonstrated a consistent pattern whereby Depression Severity increased predictive accuracy for HRQOL measures over simpler models. Beck Depression Inventory scores significantly predicted quality of life across both the mental and physical composite scores and all eight sub-scales of the SF-36. Untreated HCV patients in MMT had lower HRQOL than HCV patients not in MMT. Depression Severity was associated with significantly lower quality of life measures, suggesting that psychiatric evaluation and intervention prior to the start of HCV treatment may improve overall quality of life and could influence HCV treatment outcomes in MMT patients. Batki SL, Canfield KM, Smyth E, Ploutz-Snyder R. Drug Alcohol Depend. 2009 May 1;101(3):176-182.

Antiviral Activity of Geneticin Against Dengue Virus

The aminoglycoside, geneticin (G418), was recently shown to have antiviral activity against bovine viral diarrhea virus (BVDV). Since BVDV, dengue virus (DENV) and yellow fever virus (YFV) all belong to the Flaviviridae family, it seemed possible that a common step in their life cycle might be affected by this aminoglycoside. Here it is shown that geneticin prevented the cytopathic effect (CPE) resulting from DENV-2 infection of BHK cells, in a dose-dependent manner with an 50% effective concentration (EC(50)) value of 3+/-0.4microg/ml. Geneticin had no detectable effect on CPE caused by YFV in BHK cells. Geneticin also inhibited DENV-2 viral yield with an EC(50) value of 2+/-0.1microg/ml and an EC(90) value of 20+/-2microg/ml. With a CC(50) value of 165+/-5microg/ml, the selectivity index of anti-DENV activity of geneticin in BHK cells was established to be 66. Furthermore, 25microg/ml of geneticin nearly completely blocked plaque formation induced by DENV-2, but not YFV. In addition, geneticin, inhibited DENV-2 viral RNA replication and viral translation. Gentamicin, kanamycin, and the guanidinylated geneticin showed no anti-DENV activity. Neomycin and paromomycin demonstrated weak antiviral activity at high concentrations. Finally, aminoglycoside-3'-phosphotransferase activity of neomycin-resistant gene abolished antiviral activity of geneticin. Zhang XG, Mason PW, Dubovi EJ, et al. Antiviral Res. 2009 Jul 83(1):21-27.

Morningness/Eveningness and Menstrual Symptoms in Adolescent Females

Two types of sleep preference have been supported in the literature. Morning types awaken early and are refreshed upon waking, whereas Evening types rise later and have more erratic sleep schedules. Sleep affects menstrual functioning in adult women. However, there is scant research on the association between sleep preference and menstrual functioning in adolescents. Thus, the present study examined the asso-ciation between sleep preference and menstrual functioning in 210 adolescent girls (11-17 years old). Data represent baseline measures from a longitudinal study examining the association of psychological functioning and smoking with reproductive and bone health. Measures included the Menstrual Symptom Questionnaire (MSQ), regularity and duration of menstrual cycles, and the Morningness/ Eveningness scale (measuring sleep preference).MSQ factor scores were used in analyses: abdominal pain, negative affect/somatic complaints, back pain, and anxiety/fatigue. The results from hierarchical linear regression analyses showed significant associations between Evening preference and more symptoms of abdominal pain (P<.01), negative affect/somatic complaints (P<.01), anxiety/fatig ue (P<.01), and shorter menses (P<.05). Adolescent girls with Evening preference experience more menstrual symptoms than those with Morning preference. Future research should include sleep preference in studies of health and behavior particularly in adolescence when there is a normative shift toward Evening preference. Negriff S, Dorn LD. J Psychosom Res. 2009;67(2):169-172.

Toxic Effect of Methamphetamine on the Retina of CD1 Mice

The goal of this study was to investigate whether systemic administration of methamphetamine (METH) induces retinal damage in CD1 mice. Eighteen male CD1 mice were randomly assigned to three groups, six mice per group: Group 1 receiving a single dose of 40 mg/kg METH, Group 2 receiving four doses of 10 mg/kg METH, and Group 3 (control) receiving 40 mg/kg 0.9% NaCl solution. METH and NaCl were administered by intraperitoneal injection. Immunostaining of glial fibrillary acidic protein (GFAP), S-100 for astrocytes and Muller cells, CD11b for microglia, and tyrosine hydroxylase (TH) and TUNEL labeling for apoptotic cell death were performed on the retinal sections on day 1 and day 7 post-exposure. GFAP and S-100 immunoreactivity was observed in Group 1 mice. CD11b+ cells in Group 1 mice showed more intensely stained shorter and thicker cellular processes than Groups 2 and 3, indicating activated microglia in the mice exposed to large-dose METH. No significant difference in TH level was seen among the three groups. TUNEL labeling did not reveal positive cells in the retinas of any of the 18 CD1 mice. A single large dose of METH induces an increase in short-term protein expression of GFAP and S-100 and in microglial activation. The results suggest that METH has a neurotoxic effect on CD1 mouse retina. Lai H, Zeng H, Zhang C, et al.Curr Eye Res. 2009 Sep 34(9):785-790.

Determination of Relative Timing of Pubertal Maturation through Ordinal Logistic Modeling: Evaluation of Growth and Timing Parameters

The purpose of this study is (1) To propose a new method using statistical modeling to determine relative timing of pubertal maturation; (2) to validate the new method by evaluating its relationship with pubertal growth and timing parameters, including age at menarche, age onset of areolar maturation, age of peak height velocity, age at attainment of adult height, adult height, peak height velocity, body mass index, and percent body fat; and (3) to contrast the new method with relative timing of menarche on these pubertal parameters. The timing of puberty has a well-known impact on anthropometric and psychosocial outcomes. Multiple methods have been used to determine pubertal timing, but all with limitations. A uniformly applicable method is needed for different study designs and study populations. Using the National Heart Lung and Blood Institute Growth and Health Study data, an ordinal logistic modeling was used to assess relative timing of pubertal maturation. The proposed method demonstrated good reliability and strong associations with all pubertal timing parameters, also body mass index and percent body fat. Timing was not significantly associated with adult height and peak height velocity. The proposed method is highly feasible, easy to implement, and valid. The study demonstrated important differences between the relationships of relative timing of secondary sexual characteristics and the timing of menarche on pubertal parameters and also demonstrates that individuals with early or late timing at one point of time are likely to maintain the same relative timing throughout puberty. Huang B, Biro FM, Dorn LD. J Adolesc Health. 2009 Oct 5(4):383-388.

Upregulation of Serotonin Transporter By Alcohol In Human Dendritic Cells: Possible Implication In Neuroimmune Deregulation

Alcohol is the most widely abused substance and its chronic consumption causes neurobehavioral disorders. It has been shown that alcohol affects the function of immune cells. Dendritic cells (DC) serve as the first line of defense against infections and are known to accumulate neurotransmitters such as 5-hydroxytryptamine (5-HT). The enzyme monoamine oxidase-A (MAO-A) degrades 5-HT that is associated with clinical depression and other neurological disorders. 5-HT is selectively transported into neurons through the serotonin transporter (SERT), which is a member of the sodium- and chloride-dependent neurotr ansmitter transporter (SLC6) family. SERT also serves as a receptor for psychostimulant recreational drugs. It has been demonstrated that several drugs of abuse such as amphetamine and cocaine inhibit the SERT expression; however, the role of alcohol is yet to be elucidated. The author's hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium. Dendritic cells were treated with different concentrations (0.05% to 0.2%v/v) of alcohol for 24-72 hours and processed for SERT and MAO-A expression using Q-PCR and Western blots analysis. In addition, SERT function in DC treated with alcohol both in the presence and absence of imipramine, a SERT inhibitor was measured using 4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide uptake assay. 5-HT levels in culture supernatant and intracellular 5-hydroxy indole acetic acid (5-HIAA) and cyclic AMP were also quantitated using ELISA. Dendritic cells treated with 0.1% alcohol for 24 hours showed significant upregulation of SERT and MAO-A expression compared with untreated DC. It was observed that 0.1% alcohol enhanced the function of SERT and decreased extracellular 5-HT levels compared with untreated DC cultures, and this was associated with the elevation of intracellular 5-HIAA and cyclic AMP levels. This study suggests that alcohol upregulates SERT and MAO-A by elevating cyclic AMP, which may lead to decreased concentration of 5-HT in the extracellular medium. As 5-HT is a major neurotransmitter and an inflammatory mediator, its alcohol-mediated depletion may cause both neurological and immunological deregulation. Babu DK, Diaz A, Samikkannu T, et al. Alcohol Clin Exp Res. 2009 Oct 33(10):1731-1738. Epub 2009 Jul 1.


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