Low-Dose Elagolix for the Treatment of Heavy Menstrual Bleeding in Patients With Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the safety and efficacy of elagolix 150 mg once-daily monotherapy in patients with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: A phase 4, randomized, double-blind, placebo-controlled, 6-month treatment study was conducted in premenopausal patients aged 18-51 years with heavy menstrual bleeding (defined as menstrual blood loss greater than 80 mL during one menstrual cycle) associated with uterine leiomyomas. Patients were randomized 2:1 to receive elagolix 150 mg once daily or placebo. The primary endpoint was reduction in menstrual blood loss volume to less than 80 mL at the final month and at least a 50% reduction in menstrual blood loss volume from baseline to the final month. RESULTS: Of 82 randomized patients, 54 received elagolix 150 mg and 28 received placebo. With elagolix, 49.4% (95% CI 35.1-63.8%) of patients met the primary endpoint, compared with 23.3% (95% CI 7.2-39.5%) of patients who received placebo ( P =.035). Statistically significant differences between elagolix and placebo in mean reduction of menstrual blood loss from baseline were seen as early as month 1 ( P <.05 for months 1-3 and 5). Significantly more patients receiving elagolix experienced suppression of bleeding compared with placebo ( P =.036). Greater improvements were observed in the elagolix group (vs placebo) in the proportion of patients with amenorrhea, in hemoglobin concentrations, and in health-related quality of life. No serious or severe adverse events were reported for elagolix, compared with 7.1% of participants in the placebo group having serious adverse events (coronavirus disease 2019 [COVID-19] n=1, enlarged uvula n=1). Three patients (5.6%) discontinued elagolix due to adverse events. CONCLUSION: Elagolix 150 mg once-daily monotherapy significantly improved heavy menstrual bleeding associated with uterine leiomyomas compared with placebo in premenopausal patients. Treatment with elagolix 150 mg once daily was generally well-tolerated in this study, with no new safety signals. FUNDING SOURCE: AbbVie Inc. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03886220.

Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria.

The first total synthesis of a C5-curcumin-2-hexadecynoic acid (C5-Curc-2-HDA, 6) conjugate was successfully performed. Through a three-step synthetic route, conjugate 6 was obtained in 13% overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that 6 was active against eight MRSA strains at MICs that range between 31.3 and 62.5 µg/mL. It was found that the presence of 2-hexadecynoic acid (2-HDA, 4) in conjugate 6 increased 4-8-fold its antibacterial activity against MRSA strains supporting our hypothesis that the chemical connection of 4 to C5-curcumin (2) increases the antibacterial activity of 2 against Gram-positive bacteria. Combinational index (CIn) values that range between 1.6 and 2.3 were obtained when eight MRSA strains were treated with an equimolar mixture of 2 and 4. These results demonstrated that an antagonistic effect is taking place. Finally, it was investigated whether conjugate 6 can affect the replication process of S. aureus, since this compound inhibited the supercoiling activity of the S. aureus DNA gyrase at minimum inhibitory concentrations (MIC) of 250 µg/mL (IC50=100.2±13.9 µg/mL). Moreover, it was observed that the presence of 4 in conjugate 6 improves the anti-topoisomerase activity of 2 towards S. aureus DNA gyrase, which is in agreement with results obtained from antibacterial susceptibility tests involving MRSA strains.

The (5Z)-5-Pentacosenoic and 5-Pentacosynoic Acids Inhibit the HIV-1 Reverse Transcriptase.

The natural fatty acids (5Z)-5-pentacosenoic and (9Z)-9-pentacosenoic acids were synthesized for the first time in eight steps starting from either 4-bromo-1-butanol or 8-bromo-1-butanol and in 20-58% overall yields, while the novel fatty acids 5-pentacosynoic and 9-pentacosynoic acids were also synthesized in six steps and in 34-43% overall yields. The ∆(5) acids displayed the best IC50's (24-38 µM) against the HIV-1 reverse transcriptase (RT) enzyme, comparable to nervonic acid (IC50 = 12 µM). The ∆(9) acids were not as effective towards HIV-RT with the (9Z)-9-pentacosenoic acid displaying an IC50 = 54 µM and the 9-pentacosynoic acid not inhibiting the enzyme at all. Fatty acid chain length and position of the unsaturation was important for the observed inhibition. None of the synthesized fatty acids were toxic (IC50 > 500 µM) towards peripheral blood mononuclear cells. Molecular modeling studies indicated the structural determinants underlying the biological activity of the most potent compounds. These results provide new insights into the structural requirements that must be present in fatty acids so as to enhance their inhibitory potential towards HIV-RT.

Synthesis of novel C5-curcuminoid-fatty acid conjugates and mechanistic investigation of their anticancer activity.

The first synthesis of C5-curcumin-fatty acid (C5-Curc-FA) conjugates was successfully performed. Through a two-step synthetic route, 10 analogs were synthesized for a structure-activity relationship (SAR) study. It was found that C5-Curc-FA conjugates containing either decanoic acid or palmitic acid moieties were cytotoxic against colorectal adenocarcinoma cell (CCL-229) at IC50s ranging from 22.5 to 56.1µg/mL, being 5c the most active C5-Curc-FA conjugate. Our results strongly suggests that a decanoic acid moiety at the meta position in C5-Curc-FA conjugates is important for their anticancer activity effect. Possible mechanisms for the anticancer activity of C5-Curc-FA conjugates were also investigated including apoptosis induction, mitochondrial damage and caspases activation. It was shown that 5c inhibited the luminescence activity of NFκB, a key signaling molecule involved in cell apoptosis and cell proliferation, at IC50=18.2µg/mL. In addition, it was demonstrated that 5c displayed significant apoptotic effect at GI50=46.0µg/mL in colorectal adenocarcinoma cell line (ATCC CCL-222), which can be explained by the significant mitochondrial membrane permeabilization and caspases 3 and 7 activation effect of 5c. Finally, it was investigated that C5-Curc-FA conjugates can affect the replication process of cancer cells, since compounds 5c, 5e, and 6c inhibited the relaxing activity of the human DNA topoisomerase I at minimum inhibitory concentrations (MICs) that range from 50 to 250µg/mL. Our results strongly support the hypothesis that the inhibition of both NFκB and DNA topoisomerase I by C5-Curc-FA conjugates is associated with their anticancer activity.

Paraoxon and Pyridostigmine Interfere with Neural Stem Cell Differentiation.

Acetylcholinesterase (AChE) inhibition has been described as the main mechanism of organophosphate (OP)-evoked toxicity. OPs represent a human health threat, because chronic exposure to low doses can damage the developing brain, and acute exposure can produce long-lasting damage to adult brains, despite post-exposure medical countermeasures. Although the main mechanism of OP toxicity is AChE inhibition, several lines of evidence suggest that OPs also act by other mechanisms. We hypothesized that rat neural progenitor cells extracted on embryonic day 14.5 would be affected by constant inhibition of AChE from chronic exposure to OP or pyridostigmine (a reversible AChE blocker) during differentiation. In this work, the OP paraoxon decreased cell viability in concentrations >50 µM, as measured with the MTT assay; however, this effect was not dose-dependent. Reduced viability could not be attributed to blockade of AChE activity, since treatment with 200 µM pyridostigmine did not affect cell viability, even after 6 days. Although changes in protein expression patterns were noted in both treatments, the distribution of differentiated phenotypes, such as the percentages of neurons and glial cells, was not altered, as determined by flow cytometry. Since paraoxon and pyridostigmine each decreased neurite outgrowth (but did not prevent differentiation), we infer that developmental patterns may have been affected.

Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca²âº]i, oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity.

Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca²âº]i, ROS, H2O2, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca²âº]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1ß, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca²âº]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca²âº]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS.

Antibacterial activity of 2-alkynoic fatty acids against multidrug-resistant bacteria.

The first study aimed at determining the structural characteristics needed to prepare antibacterial 2-alkynoic fatty acids (2-AFAs) was accomplished by synthesizing several 2-AFAs and other analogs in 18-76% overall yields. Among all the compounds tested, the 2-hexadecynoic acid (2-HDA) displayed the best overall antibacterial activity against Gram-positive Staphylococcus aureus (MIC=15.6 µg/mL), Staphylococcus saprophyticus (MIC=15.5 µg/mL), and Bacillus cereus (MIC=31.3 µg/mL), as well as against the Gram-negative Klebsiella pneumoniae (7.8 µg/mL) and Pseudomonas aeruginosa (MIC=125 µg/mL). In addition, 2-HDA displayed significant antibacterial activity against methicillin-resistant S. aureus (MRSA) ATCC 43300 (MIC=15.6 µg/mL) and clinical isolates of MRSA (MIC=3.9 µg/mL). No direct relationship was found between the antibacterial activity of 2-AFAs and their critical micelle concentration (CMC) suggesting that the antibacterial properties of these fatty acids are not mediated by micelle formation. It was demonstrated that the presence of a triple bond at C-2 and the carboxylic acid moiety in 2-AFAs are important for their antibacterial activity. 2-HDA has the potential to be further evaluated for use in antibacterial formulations.

Combinatorial cytotoxic effects of Curcuma longa and Zingiber officinale on the PC-3M prostate cancer cell line.

BACKGROUND: Many plant-derived products exhibit potent chemopreventive activity against animal tumor models as well as rodent and human cancer cell lines. They have low side effects and toxicity and presumably modulate the factors that are critical for cell proliferation, differentiation, senescence and apoptosis. The present study investigates the effects of some medicinal plant extracts from generally recognized as safe plants that may be useful in the prevention and treatment of cancer. METHODS: Clonogenic assays using logarithmically-growing cells were performed to test the effect. The cytotoxic effects of Curcuma longa and Zingiber officinale were studied using sulforhodamine B assay, tetrazolium dye assay, colony morphology and microscopic analysis. RESULTS: Out of the 13 lyophilized plant-derived extracts evaluated for growth-inhibitory effects on the PC-3M prostate cancer cell line, two extracts derived from C. longa and Z. officinale showed significant inhibitory effects on colony-forming ability. The individual and augmentative effects of these two extracts were tested for their narrow range effective lower concentration on PC-3M in clonogenic assays. At relatively lower concentrations, C. longa showed significant inhibition of colony formation in clonogenic assays; whereas at same concentrations Z. officinale showed only moderate inhibitory effects. However, when both the agents were tested together at the same concentrations, the combined effects were much more significant than their individual ones. On normal prostate epithelial cells both C. longa and Z. officinale had similar effects but at a lower magnitude. These observations were confirmed by several cytotoxicity assays involving the morphological appearance of the colonies, microscopic observations, per cent inhibition in comparison to control by sulforhodamine B and tetrazolium dye assay. CONCLUSIONS: From these observations, it was concluded that the combined effects of C. longa and Z. officinale are much greater than their individual effects, suggesting the role of multiple components and their synergistic mode of actions to elicit stronger beneficial effects.

Implications of ER stress, the unfolded protein response, and pro- and anti-apoptotic protein fingerprints in human monocyte-derived dendritic cells treated with alcohol.

BACKGROUND: Dendritic cells (DCs) are responsible for the activation of T cells and B cells. There is accumulating evidence that psychoactive substances such as alcohol can affect immune responses. We hypothesize that this occurs by modulating changes in proteins triggering a process known as unfolded protein response (UPR). This process protects cells from the toxic effects of misfolded proteins responsible for causing endoplasmic reticulum (ER) stress. Although much is known about ER stress, little is understood about the consequences of ethanol use on DC's protein expression. METHODS: In this study, we investigated alterations in the proteins of human monocyte-derived dendritic cells (MDDC) treated with 0.1% of alcohol by two-dimensional (2D) gel electrophoresis followed by liquid chromatography-tandem mass spectrometry, protein identification, and confirmation at the gene expression level by qRT-PCR. RESULTS: Proteomes of related samples demonstrated 32 differentially expressed proteins that had a 2-fold or greater change in expression (18 spots were up-regulated and 14 were down-regulated), compared to the control cultures (untreated cells). Alcohol significantly changed the expression of several components of the UPR stress-induced pathways that include chaperones, ER stress, antioxidant enzymes, proteases, alcohol dehydrogenase, cytoskeletal and apoptosis-regulating proteins. qRT-PCR analyses highlighted the enhanced expression of UPR and antioxidant genes that increased (18 hours) with alcohol treatment. CONCLUSION: Results of these analyses provide insights into alcohol mechanisms of regulating DC and suggest that alcohol induced specifically the UPR in DC. We speculate that activation of a UPR by alcohol may protect the DC from oxidant injury but may lead to the development of alcohol-related diseases.

Upregulation of serotonin transporter by alcohol in human dendritic cells: possible implication in neuroimmune deregulation.

BACKGROUND: 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 neurotransmitter 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. We hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium. METHODS: 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. RESULTS: Dendritic cells treated with 0.1% alcohol for 24 hours showed significant upregulation of SERT and MAO-A expression compared with untreated DC. We also 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. CONCLUSIONS: Our 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.

Differential regulation of indoleamine-2,3-dioxygenase (IDO) by HIV type 1 clade B and C Tat 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. We hypothesize 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. Our 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, our 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.

Methamphetamine enhances HIV-1 infectivity in monocyte derived dendritic cells.

The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. We report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection is mediated by downregulation of extracellular-regulated kinase (ERK2) and the upregulation of p38 mitogen-activated protein kinase (MAPK). A p38 inhibitor (SB203580) specifically reversed the Meth-induced upregulation of the CCR5 HIV-1 coreceptor. The dopamine D2 receptor antagonist RS +/- sulpiride significantly reversed the Meth-induced upregulation of CCR5, demonstrating that the Meth-induced effect is mediated via the D2 receptor. These studies report for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression. Further, Meth mediates its regulatory effects via dopamine receptors and via downregulating ERK2 with a reciprocal upregulation of p38 MAPK. Elucidation of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in high-risk Meth-using HIV-1-infected subjects.

Prevalence of drug resistance and associated mutations in HIV-positive Puerto Ricans: sex variations.

INTRODUCTION: A cross sectional study was conducted from 2002-2004 to record the evolution of HIV-1 infection in Puerto Rico by monitoring the expression of antiretroviral resistance-associated mutations. METHODS: Samples were analyzed by using the TRUGENE HIV-1 Genotyping Kit and the OpenGene DNA Sequencing System. RESULTS: Mutations in the HIV-1 virus were detected in 92.7% of men and 94.8% of women. Of these, 75.1% of men and 72.4% of women had HIV-1 with resistance to at least one medication. The average number of HIV mutations was 6.1 in men and 5.3 in women. In 2002 and 2003, strains were most frequently resistant to the antiretroviral drugs zalcitabine, lamivudine and didanosine, while in 2004, strains were most frequently resistant to zalcitabine, lamivudine, and efavirenz. The most prevalent mutations in the reverse transcriptase gene were M184V, K103N, T215Y, and M41L. The most prevalent mutations in the protease gene were L63P, M361, L90M, A71V, and L101. CONCLUSIONS: Significant differences between men and women were recorded in the levels of HIV-1 expressed mutations and resistance. When comparing these results with data from 2000 and 2001, results indicate that expression of resistant mutations has remained constant.

Chronic exposure of human macrophages in vitro to morphine and methadone induces a putative tolerant/dependent state.

We have shown previously that whereas acute exposure of cultured murine peritoneal macrophages inhibits phagocytosis, chronic exposure results in a putative tolerant/dependent state. We now report similar observations using human cultured monocyte-derived macrophages (hMDM) from a control population and from methadone patients. With hMDM, acute exposure to morphine and methadone inhibited phagocytosis in a dose-dependent manner. In contrast, chronic exposure resulted in eventual normalization of phagocytosis, indicating that a putative tolerant state to the opiates had developed. When opiates were withdrawn from chronically-exposed, tolerized hMDM, phagocytosis was once again depressed. The duration of withdrawal-induced depression lasted several hours, which is much longer than evidenced previously with murine macrophages. These data identify well with various in vivo studies on immune effects of opiate withdrawal; and, in so-doing, supplement ongoing speculation that opiate withdrawal is likely to have serious impact on host defenses of street heroin addicts.

Induction of a Soluble Anti-HIV-1 factor (s) with IFN-γ, IL-10, and ß-Chemokine Modulating Activity by an Influenza-Bacterial Polyantigenic Mixture.

Partial immune restoration may be obtained with highly active antiretroviral therapy (HAART), but specific anti-HIV-1 immune responses do not appear to improve substantially. We have demonstrated that a soluble factor(s) induced by a mixture of inactivated influenza and bacterial vaccines called polyantigenic immunomodulator (PAI), possesses strong immunoregulatory and anti-HIV-1 activities. In the present study, we show that culture fluids from both PAI-stimulated peripheral blood mononuclear cells (PBMC) and CD8+ T-cells of HIV-1 infected patients were able to suppress HIV-1 replication in an MHC-unrestricted fashion. The PAI-induced antiviral activity was eliminated when culture fluids were pre-heated at 100°C for 10 min. and it is associated with induction of IFN-γ, MIP-1α, MIP-1ß, and RANTES production, but inhibition of IL-10. Furthermore, this induction is dependent on the immunological status (CD4:CD8 ratio) of the HIV-1 infected patient. Taken together, our results suggest that the MHC-unrestricted HIV-1 suppression that is induced by culture fluids from PAI-stimulated PBMC may result from the stimulation of immune cell subpopulations to produce a heat-labile antiviral soluble factor(s), which in turn modulate cytokine and ß-chemokine production. The identification of this PAI-induced soluble factor(s) may have major therapeutic potential.

Impaired cytokine production and suppressed lymphocyte proliferation activity in HCV-infected cocaine and heroin ("speedball") users.

HCV-infected "speedball" users (n = 30) were selected from an original cohort of 400 intravenous drug users for cytokine analysis. Cytokine concentrations (TNF-alpha, IL-1beta, IL-6, IFN-gamma, IL-2, IL-4, IL-10 and IL-12) were determined in plasma and peripheral blood mononuclear cells (PBMC) cultures derived ex vivo from these patients. In addition, lymphocyte proliferation was measured in 49 HCV-positive "speedball" users. TNF-alpha, IL-6, IFN-gamma, IL-2, IL-4, IL-10, IL-12 cytokines and not IL-1beta were significantly increased in plasma from HCV-positive "speedball" users compared with healthy controls. Except for IL-10, all other cytokines measured were augmented in phytohemagglutinin-stimulated PBMC cultures from HCV-positive "speedball" users. Likewise, overproduction of cytokines TNF-alpha, IL-1beta, IL-6 and IFN-gamma, was consistently detected when PBMC cultures from HCV-positive "speedball" users were stimulated with a biological response modifier. However, HCV-infected "speedball" users showed significant reduction in lymphoproliferative activity. Compared with healthy subjects, there was a consistent overproduction of both TH1 and TH2 type cytokines in the plasma and PBMC's of HCV-infected "speedball" users. Furthermore, there was a persistent reduction of lymphoproliferative activity in this group. These immunologic abnormalities, coupled with the range of response between the two TH-types in HCV-infected "speedball" users, suggest impairment in the regulatory mechanism of the TH1-TH2 system.

Distribution of naïve (CD45RA+) and memory (CD45RO+) T-cells in HIV-infected Puerto Rican population.

HIV infection usually results in a gradual deterioration of the immune system. It is evident that early recognition of progression markers during HIV infection from asymptomatic to symptomatic state is needed. In the present cross-sectional study, peripheral blood lymphocytes from 63 HIV-infected Puerto Rican individuals were analyzed by two-color flow cytometry to study the co-expression CD45RA and CD45RO on both CD4+ and CD8+ T-cells and its correlation with age, gender, CD4 count, CD4:CD8 ratio, anti-retroviral therapy, clinical status, and viral load. Measurement of T-cell subsets in these patients showed an excessive increase of CD3+CD8+, CD8+CD45RA+, and CD8+CD45RO+ T-cells as disease progresses. In contrast, it was also observed a significant decrease in CD3+CD4+, CD4+CD45RA+ and CD4+CD45RO+ T-cells. The distribution of CD8+CD45RA+ T-cells did not change significantly between HIV and AIDS cases suggesting that this T-cell subset is not a good progression marker. Interestingly, CD4+CD45RA+ T-cells were significantly difference between genders, and CD44+CD45RA+ and CD8+CD45RO+ T-cells were influenced by age. In conclusion, the distribution of naïve/memory CD4+ T-cells and memory CD8+ T-cells significantly correlate with HIV infection in disease progression. It is also important to mention that these T-cell subpopulations may be influenced by both gender and age. Overall, these results suggest that a loss in the generation of new immune response and function may be occurring during disease progression. This study open new windows of understanding that will be beneficial for future studies on immunopathogenesis, diagnosis, prognosis, and treatment monitoring for HIV/AIDS.

Distribution of naïve (CD45RA+) and memory (CD45RO+) T-cells in HIV-infected Puerto Rican population

HIV infection usually results in a gradual deterioration of the immune system. It is evident that early recognition of progression markers during HIV infection from asymptomatic to symptomatic state is needed. In the present cross-sectional study, peripheral blood lymphocytes from 63 HIV-infected Puerto Rican individuals were analyzed by two-color flow cytometry to study the co-expression CD45RA and CD45RO on both CD4+ and CD8+ T-cells and its correlation with age, gender, CD4 count, CD4:CD8 ratio, anti-retroviral therapy, clinical status, and viral load. Measurement of T-cell subsets in these patients showed an excessive increase of CD3+CD8+, CD8+CD45RA+, and CD8+CD45RO+ T-cells as disease progresses. In contrast, it was also observed a significant decrease in CD3+CD4+, CD4+CD45RA+ and CD4+CD45RO+ T-cells. The distribution of CD8+CD45RA+ T-cells did not change significantly between HIV and AIDS cases suggesting that this T-cell subset is not a good progression marker. Interestingly, CD4+CD45RA+ T-cells were significantly difference between genders, and CD44+CD45RA+ and CD8+CD45RO+ T-cells were influenced by age. In conclusion, the distribution of naïve/memory CD4+ T-cells and memory CD8+ T-cells significantly correlate with HIV infection in disease progression. It is also important to mention that these T-cell subpopulations may be influenced by both gender and age. Overall, these results suggest that a loss in the generation of new immune response and function may be occurring during disease progression. This study open new windows of understanding that will be beneficial for future studies on immunopathogenesis, diagnosis, prognosis, and treatment monitoring for HIV/AIDS.

Cirugía de angiofibroma nasofaringeo juvenil / Surgery of of juvenile nasopharyngeal angiofibroma

En el presente trabajo, analizamos los distintos tratamientos quirúrgicos que se llevaron a cabo en 6 casos de angiofibroma nasofaríngeo juvenil (ANJ). Las vías quirúrgicas que se utilizaron fueron la nasal paralateral, la transpalatina, de Rouge-Denker, y la vía natural oral. Analizamos el criterio actual sobre la preparación prequirúrgica, la utilización de las distintas técnicas actuales, haciendo mención especial del "degloving". Se hace referencia a la relación entre los diferentes estadios del tumor: tamaño y localización, y consecuentemente las distintas técnicas a emplear