HCN1 channels mediate mu opioid receptor long-term depression at insular cortex inputs to the dorsal striatum.

Mu opioid receptors (MORs) are expressed in the dorsal striatum, a brain region that mediates goal-directed (via the dorsomedial striatum) and habitual (via the dorsolateral striatum, DLS) behaviours. Our previous work indicates that glutamate transmission is depressed when MORs are activated in the dorsal striatum, inducing MOR-mediated long-term synaptic depression (MOR-LTD) or short-term depression (MOR-STD), depending on the input. In the DLS, MOR-LTD is produced by MORs on anterior insular cortex (AIC) inputs and MOR-STD occurs at thalamic inputs, suggesting input-specific MOR plasticity mechanisms. Here, we evaluated the mechanisms of induction of MOR-LTD and MOR-STD in the DLS using pharmacology and optogenetics combined with patch-clamp electrophysiology. We found that cAMP/PKA signalling and protein synthesis are necessary for MOR-LTD expression, similar to previous studies of cannabinoid-mediated LTD in DLS. MOR-STD does not utilize these same mechanisms. We also demonstrated that cannabinoid-LTD occurs at AIC inputs to DLS. However, while cannabinoid-LTD requires mTOR signalling in DLS, MOR-LTD does not. We characterized the role of presynaptic HCN1 channels in MOR-LTD induction as HCN1 channels expressed in AIC are necessary for MOR-LTD expression in the DLS. These results suggest a mechanism in which MOR activation requires HCN1 to induce MOR-LTD, suggesting a new target for pharmacological modulation of synaptic plasticity, providing new opportunities to develop novel drugs to treat alcohol and opioid use disorders. KEY POINTS: Mu opioid receptor-mediated long-term depression at anterior insular cortex inputs to dorsolateral striatum involves presynaptic cAMP/PKA signalling and protein translation, similar to known mechanisms of cannabinoid long-term depression. Dorsal striatal cannabinoid long-term depression also occurs at anterior insular cortex inputs to the dorsolateral striatum. Dorsal striatal cannabinoid long-term depression requires mTOR signalling, similar to hippocampal cannabinoid long-term depression, but dorsal striatal mu opioid long-term depression does not require mTOR signalling. Mu opioid long-term depression requires presynaptic HCN1 channels at anterior insular cortex inputs to dorsolateral striatum.

Enriched Pathways of Calcium Regulation, Cellular/Oxidative Stress, Inflammation, and Cell Proliferation Characterize Gluteal Muscle of Standardbred Horses between Episodes of Recurrent Exertional Rhabdomyolysis.

Certain Standardbred racehorses develop recurrent exertional rhabdomyolysis (RER-STD) for unknown reasons. We compared gluteal muscle histopathology and gene/protein expression between Standardbreds with a history of, but not currently experiencing rhabdomyolysis (N = 9), and race-trained controls (N = 7). Eight RER-STD had a few mature fibers with small internalized myonuclei, one out of nine had histologic evidence of regeneration and zero out of nine degeneration. However, RER-STD versus controls had 791/13,531 differentially expressed genes (DEG). The top three gene ontology (GO) enriched pathways for upregulated DEG (N = 433) were inflammation/immune response (62 GO terms), cell proliferation (31 GO terms), and hypoxia/oxidative stress (31 GO terms). Calcium ion regulation (39 GO terms), purine nucleotide metabolism (32 GO terms), and electron transport (29 GO terms) were the top three enriched GO pathways for down-regulated DEG (N = 305). DEG regulated RYR1 and sarcoplasmic reticulum calcium stores. Differentially expressed proteins (DEP ↑N = 50, ↓N = 12) involved the sarcomere (24% of DEP), electron transport (23%), metabolism (20%), inflammation (6%), cell/oxidative stress (7%), and other (17%). DEP included ↑superoxide dismutase, ↑catalase, and DEP/DEG included several cysteine-based antioxidants. In conclusion, gluteal muscle of RER-susceptible Standardbreds is characterized by perturbation of pathways for calcium regulation, cellular/oxidative stress, inflammation, and cellular regeneration weeks after an episode of rhabdomyolysis that could represent therapeutic targets.

Maternal high-fat diet aggravates fructose-induced mitochondrial damage in skeletal muscles and causes differentiated adaptive responses on lipid metabolism in adult male offspring.

Maternal high-fat diet (HFD) is associated with metabolic disturbances in the offspring. Fructose is a highly consumed lipogenic sugar; however, it is unknown whether skeletal muscle of maternal HFD offspring respond differentially to a fructose overload. Female Wistar rats received standard diet (STD: 9% fat) or isocaloric high-fat diet (HFD: 29% fat) during 8 weeks before mating until weaning. After weaning, male offspring received STD and, from 120 to 150 days-old, they drank water or 15% fructose in water (STD-F and HFD-F). At 150th day, we collected the oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles. Fructose-treated groups exhibited hypertriglyceridemia, regardless of maternal diet. Soleus of maternal HFD offspring showed increased triglycerides and monounsaturated fatty acid content, independent of fructose, with increased fatty acid transporters and lipogenesis markers. The EDL exhibited unaltered triglycerides content, with an apparent equilibrium between lipogenesis and lipid oxidation markers in HFD, and higher lipid uptake (fatty acid-binding protein 4) accompanied by enhanced monounsaturated fatty acid in fructose-treated groups. Mitochondrial complexes proteins and Tfam mRNA were increased in the soleus of HFD, while uncoupling protein 3 was decreased markedly in HFD-F. In EDL, maternal HFD increased ATP synthase, while fructose decreased Tfam predominantly in STD offspring. Maternal HFD and fructose induced mitochondria ultrastructural damage, intensified in HFD-F in both muscles. Thus, alterations in molecular markers of lipid metabolism and mitochondrial function in response to fructose are modified by an isocaloric and moderate maternal HFD and are fiber-type specific, representing adaptation/maladaptation mechanisms associated with higher skeletal muscle fructose-induced mitochondria injury in adult offspring.

DHA Supplementation Attenuates Inflammation-Associated Gene Expression in the Mammary Gland of Lactating Mothers Who Deliver Preterm.

BACKGROUND: In a randomized trial of DHA supplementation to lactating mothers who delivered preterm, there were significant increases in DHA status in the mother and her infant. OBJECTIVES: Our objective here was to characterize the mammary gland transcriptomes from the above study. We hypothesized that proinflammatory gene expression would be attenuated in the increased DHA group compared with the standard DHA group. METHODS: In the original trial, mothers delivering at <29 wk gestation at the University of Cincinnati Medical Center and intending to express their milk were randomly assigned to supplementation with 200 mg/d DHA (standard group: STD) or 1000 mg/d DHA (experimental group: EXP) within 7 d of delivery. Here, we conducted RNA-seq transcriptome analysis of n = 5 EXP and n = 4 STD extracellular mammary mRNA samples extracted from the fat layer of milk samples obtained 4 wk postenrollment. Transcripts were assessed for differential expression (false discovery rate adjusted P value <0.05) and clustering between EXP compared with STD groups. Ontological analysis of all differentially expressed genes (DEGs) was performed with Toppcluster. RESULTS: There were 409 DEGs. We observed 5 main groups of biological processes that were upregulated, including those associated with improved immune regulation and management of oxidative stress; and 3 main groups of biological processes that were downregulated, including 1 associated with immune dysregulation. For example, we observed upregulation of inflammation-inhibiting genes including NFKB inhibitor alpha (NFKBIA; fold-change (FC), adjusted P value: FC = 1.70, P = 0.007) and interleukin-18 binding protein (IL18BP: FC = 2.2, adjusted P = 0.02); and downregulation of proinflammatory genes including interleukin 7 receptor (IL7R: FC = -1.9, adjusted P = 0.02) and interleukin 1 receptor like 1 (IL1RL1: FC = -13.0, adjusted P = 0.02). CONCLUSIONS: Increased DHA supplementation during lactation can modulate the expression of inflammation-related genes within the mammary gland. This might translate to milk composition with a more optimal inflammasome profile. Future research with a larger clinical trial and greater interrogation of clinical outcomes is warranted.

Effect of sunitinib on testicular oxidative and proinflammatory damage induced by ischemia-reperfusion in rats.

INTRODUCTION: This study aimed to biochemically and histopathologically investigate the effect of sunitinib on oxidative testicular damage induced by ischemia/reperfusion in rats. MATERIAL-METHOD: Experimental animals were divided into three groups of six rats each: testicular torsion-detorsion (TTD), sunitinib+testicular torsion-detorsion (STD), and sham control (SC). Sunitinib (25mg/kg) was administered orally to the STD group by gavage. Normal saline (0.9% NaCl) was administered orally to the TTD and control groups as the solvent. One hour after administration of sunitinib and 0.9% NaCl, all animal groups were done torsion-detorsion. Then, all the rats were killed by high-dose anesthesia, and their testicles were removed. Biochemical and histopathological examinations were performed on the removed testicular tissues. RESULTS: Malondialdehyde; it was observed that the results in the STD group were close to those of the SC group and statistically significant lower compared to the TTD group (p=0.001). The glutathione values were statistically significantly higher in the STD group compared to the TTD group (p<0.001). Nuclear factor kappa B values, revealing a statistically significant difference between the TTD and STD groups (p<0.001). The TNF-α levels were measured and indicating that the results of the STD group were statistically significantly lower than those of the TTD group (p<0.001). Histopathologically, animal tissues given sunitinib were observed to resemble normal tissues. CONCLUSION: Sunitinib was shown to prevent histopathological changes in testicular tissue against ischemia/reperfusion damage.

Insights into the toll-like receptors in sexually transmitted infections.

Toll-like receptors (TLRs) are like soldiers of an innate immune system, which protects vital biological processes against invading pathogens. TLR signalling pathways help in the removal of pathogens and mediate well-established inflammatory processes. However, these processes may also aid in the development or augmentation of an infection or an autoimmune disease. Recent studies have delineated TLR polymorphism's role in the loss of function, making hosts more resistant or vulnerable to the development of an infection. In this review, we have discussed the association of TLRs with sexually transmitted infections (STIs), especially to the pathogen-specific ligands. We have also assessed the impact on TLR downstream signalling and the maintenance of cellular homeostasis during immune responses. Besides, we have discussed the role of TLRs single nucleotide polymorphisms in various STIs. Since TLRs are known to play a part in defence mechanisms and in aiding infections therefore, a thorough understanding of TLRs structure and molecular mechanisms is required to explain how they can influence the outcome of an STI. Such a strategy may lead to the development of novel and useful immunotherapeutic approaches to control pathogen progression and prevent transmission.

Syndecan 4 Upregulation on Activated Langerhans Cells Counteracts Langerin Restriction to Facilitate Hepatitis C Virus Transmission.

Sexually transmitted Hepatitis C virus (HCV) infections and high reinfections are a major concern amongst men who have sex with men (MSM) living with HIV-1 and HIV-negative MSM. Immune activation and/or HIV-1 coinfection enhance HCV susceptibility via sexual contact, suggesting that changes in immune cells or external factors are involved in increased susceptibility. Activation of anal mucosal Langerhans cells (LCs) has been implicated in increased HCV susceptibility as activated but not immature LCs efficiently retain and transmit HCV to other cells. However, the underlying molecular mechanism of transmission remains unclear. Here we identified the Heparan Sulfate Proteoglycan Syndecan 4 as the molecular switch, controlling HCV transmission by LCs. Syndecan 4 was highly upregulated upon activation of LCs and interference with Heparan Sulfate Proteoglycans or silencing of Syndecan 4 abrogated HCV transmission. These data strongly suggest that Syndecan 4 mediates HCV transmission by activated LCs. Notably, our data also identified the C-type lectin receptor langerin as a restriction factor for HCV infection and transmission. Langerin expression abrogated HCV infection in HCV permissive cells, whereas langerin expression on the Syndecan 4 expressing cell line strongly decreased HCV transmission to a target hepatoma cell line. These data suggest that the balanced interplay between langerin restriction and Syndecan 4 transmission determines HCV dissemination. Silencing of langerin enhanced HCV transmission whereas silencing Syndecan 4 on activated LCs decreased transmission. Blocking Heparan Sulfate Proteoglycans abrogated HCV transmission by LCs ex vivo identifying Heparan Sulfate Proteoglycans and Syndecan 4 as potential targets to prevent sexual transmission of HCV. Thus, our data strongly suggest that the interplay between receptors promotes or restricts transmission and further indicate that Syndecan 4 is the molecular switch controlling HCV susceptibility after sexual contact.

Nanocarriers For Vaginal Drug Delivery.

BACKGROUND: Vaginal drug delivery approach represents one of the imperative strategies for local and systemic delivery of drugs. The peculiar dense vascular networks, mucus permeability, and range of physiological characteristics of the vaginal cavity have been exploited for therapeutic benefit. Furthermore, the vaginal drug delivery has been curtailed due to the influence of different physiological factors like acidic pH, constant cervical secretion, microflora, cyclic changes during periods along with turnover of mucus of varying thickness. OBJECTIVE: This review highlights advancement of nanomedicine and its prospective progress towards the clinic. METHODS: Relevant literature reports and patents related to topics are retrieved and used. RESULT: The extensive literature search and patent revealed that nanocarriers are efficacious over conventional treatment approaches. CONCLUSION: Recently, nanotechnology based drug delivery approach has promised better therapeutic outcomes by providing enhanced permeation and sustained drug release activity. Different nanoplatforms based on drugs, peptides, proteins, antigens, hormones, nucleic material, and microbicides are gaining momentum for vaginal therapeutics.

Inflammatory cytokine biomarkers of asymptomatic sexually transmitted infections and vaginal dysbiosis: a multicentre validation study.

OBJECTIVES: Vaginal dysbiosis and STIs are important drivers of the HIV epidemic and reproductive complications. These conditions remain prevalent, partly because most cases are asymptomatic. We have shown that inflammatory cytokines interleukin (IL)-1α, IL-1ß and interferon-γ-induced protein (IP)-10 are biomarkers for detecting asymptomatic STIs and vaginal dysbiosis (bacterial vaginosis (BV) or intermediate microbiota). This study aimed to validate the performance of these biomarkers in African women recruited regardless of symptoms. METHODS: IL-1α, IL-1ß and IP-10 were measured in menstrual cup secretions, endocervical, lateral vaginal wall and vulvovaginal swabs from 550 women from Pretoria, Soweto and Cape Town, South Africa and Bondo, Kenya using Luminex and ELISA. STIs were assessed by PCR, BV by Nugent scoring and vaginal microbiota by 16S rRNA sequencing. RESULTS: Across four study populations and four types of genital specimens, the performance of IL-1α, IL-1ß and IP-10 for identification of women with STIs, BV or intermediate microbiota was consistent. Of the genital samples assessed, biomarkers measured in lateral vaginal wall swabs performed best, correctly classifying 76%(95% CI 70% to 81%) of women according to STI, BV or intermediate microbiota status (sensitivity 77%, specificity 71%) and were more accurate than clinical symptoms (sensitivity 41%, specificity 57%) (p=0.0003). Women incorrectly classified as STI/BV positive using the biomarkers had more abundant dysbiosis-associated bacteria, including Prevotella bivia and Gardnerella sp, detected by 16S rRNA sequencing, but not Nugent scoring. Including vaginal pH with the cytokine biomarkers improved the accuracy of the test (82% (95% CI 75% to 88%) correctly classified), although pH alone had poor specificity (61%). CONCLUSIONS: An inexpensive, point-of-care screening test including IL-1α, IL-1ß and IP-10 (and potentially pH) could be used in resource-limited settings to identify women with asymptomatic STIs and dysbiosis. These women could then be referred for aetiological testing, followed by specific treatment.

[Evaluation of the composition of the microbiota of the urethra in men with sexually transmitted infections].

OBJECTIVE: to conduct a comparative study of the composition of the microbiota of the urethra in men with sexually transmitted infections (STIs), and healthy men. MATERIAL AND METHODS: The study included 103 men aged 18 to 45 years: 42 men with urethritis caused by STIs and 61 clinically healthy men. Identification of pathogenic and conditionally pathogenic microorganisms in scrapings from the urethra was performed by PCR in real time (test system Androflor (DNA-Technology, Moscow). RESULTS: In the analysis of the total bacterial mass, it was found that the bacterial contamination of the urethral biotope in patients with STI was significantly higher than in the group of healthy men (5.8 Lg10 and 4.7 Lg10, respectively), with the highest level of bacterial contamination was detected in patients infected with N. gonorrhoeae (6.4 Lg10). Patients with STIs had significantly lower levels of relative Staphylococcus spp., Streptococcus spp., Corynebacterium spp. and their amounts in General compared to clinically healthy men: according to ROC analysis, the best diagnostic indicator (0.93+/-0.04, p<0.001), distinguishing a group of healthy individuals from patients with STI, was the amount of Staphylococcus spp., Streptococcus spp. and Corynebacterium spp. ("Amount Of Normoflor"). In patients infected with C. trachomatis, compared with clinically healthy men, the relative number was significantly higher of Bacteroides spp. / Porphyromonas spp. / Prevotella spp., Peptostreptococcus spp. / Parvimonas spp.; in patients infected with N. gonorrhoeae - Anaerococcus spp. and in patients infected with M. genitalium - Megasphaera spp. / Veillonella spp. / Dialister spp., Anaerococcus spp., Peptostreptococcus spp. / Parvimonas spp. and Eubacterium spp. CONCLUSION: An increase in the total bacterial contamination of the urethra in STI was found, most pronounced in infection with Neisseria gonorrhoeae. The best diagnostic indicator that distinguishes normal microbiota from the microbiota of patients with STIs is the sum of Staphylococcus spp., Streptococcus spp. and Corynebacterium spp. In patients with clinical signs of an inflammatory reaction and the presence of STIs, a decrease in the normoflora in all types of STIs and an increase in obligate anaerobic bacteria - Megasphaera spp. / Veillonella spp. / Dialister spp., Bacteroides spp. / Porphyromonas spp. / Prevotella spp., Anaerococcus spp., Peptostreptococcus spp. / Parvimonas spp. and Eubacterium spp.

A High-throughput Bead-based Affinity Assay Enables Analysis of Genital Protein Signatures in Women At Risk of HIV Infection.

Women at high risk of HIV infection, including sex workers and those with active genital inflammation, have molecular signatures of immune activation and epithelial barrier remodeling in samples of their genital mucosa. These alterations in the local immunological milieu are likely to impact HIV susceptibility. We here analyze host genital protein signatures in HIV uninfected women, with high frequency of condom use, living in HIV-serodiscordant relationships. Cervicovaginal secretions from women living in HIV-serodiscordant relationships (n = 62) were collected at three time points over 12 months. Women living in HIV-negative seroconcordant relationships (controls, n = 25) were sampled at one time point. All study subjects were examined for demographic parameters associated with susceptibility to HIV infection. The cervicovaginal samples were analyzed using a high-throughput bead-based affinity assay. Proteins involved in epithelial barrier function and inflammation were increased in HIV-serodiscordant women. By combining several methods of analysis, a total of five proteins (CAPG, KLK10, SPRR3, elafin/PI3, CSTB) were consistently associated with this study group. Proteins analyzed using the affinity set-up were further validated by label-free tandem mass spectrometry in a partially overlapping cohort with concordant results. Women living in HIV-serodiscordant relationships thus had elevated levels of proteins involved in epithelial barrier function and inflammation despite low prevalence of sexually transmitted infections and a high frequency of safe sex practices. The identified proteins are important markers to follow during assessment of mucosal HIV susceptibility factors and a high-throughput bead-based affinity set-up could be a suitable method for such evaluation.

Contribution of the swine model in the study of human sexually transmitted infections.

The pig has garnered more and more interest as a model animal to study various conditions in humans. The growing success of the pig as an experimental animal model is explained by its similarities with humans in terms of anatomy, genetics, immunology, and physiology, by their manageable behavior and size, and by the general public acceptance of using pigs for experimental purposes. In addition, the immunological toolbox of pigs has grown substantially in the last decade. This development led to a boost in the use of pigs as a preclinical model for various human infections including sexually transmitted diseases (STIs) like Chlamydia trachomatis. In the current review, we discuss the use of animal models for biomedical research on the major human STIs. We summarize results obtained in the most common animal models and focus on the contributions of the pig model towards the understanding of pathogenesis and the host immune response. In addition, we present the main features of the porcine model that are particularly relevant for the study of pathogens affecting human female and male genital tracts. We also inform on the technological advancements in the porcine toolbox to facilitate new discoveries in this biologically important animal model. There is a continued need for improvements in animal modeling for biomedical research inclusive STI research. With all its advantages and the highly improved toolbox, the porcine model can play a crucial role in STI research and open the door to new exciting discoveries.

Distribution and factors associated with salivary secretory leukocyte protease inhibitor concentrations.

OBJECTIVES: This cross-sectional study examined the distribution and correlates of salivary secretory leukocyte protease inhibitor (SLPI) concentrations within a multinational cohort of men. METHODS: Extracellular SLPI was measured in oral gargle cell supernatants of 378 men from three countries using an ELISA-based assay. Risk factor data were collected by a questionnaire. Factors associated with SLPI were assessed using linear and logistic regression for continuous and categorical SLPI, respectively. RESULTS: Among men aged 18-73 years, the median SLPI concentration was 492.0 ng ml-1 (range: 2.3-1919.9). In multivariable modeling, men in Brazil and younger men (18-30 years) were more likely to have higher levels of SLPI [adjusted odds ratio (aOR) 3.84; 95% confidence interval (CI): 1.94-7.59, and aOR 3.84; 95% CI: 1.98-7.43, respectively]. Men with a self-reported sexually transmitted diseases diagnosis in the past 6 months were more likely to have higher SLPI levels (aOR 2.98; 95% CI: 1.1-7.83) and men reporting bleeding/swollen gums were less likely to have higher SLPI (aOR 0.34; 95% CI: 0.15-0.79). Similar results were observed for linear regression models. CONCLUSIONS: Secretory leukocyte protease inhibitor concentrations varied significantly by country and decreased with increasing age. The interaction between SLPI, modifiable factors, and oral infections that influence cancer risk warrants further investigation.

Association of Sexual Debut in Adolescents With Microbiota and Inflammatory Markers.

OBJECTIVE: To investigate the association of sexual debut and vaginal, anorectal, and oral microbiota and vaginal inflammatory markers in female adolescents. METHODS: We conducted a school-based study in adolescents in Antwerp, Belgium. During three visits over 8 months, participants answered questionnaires and self-collected vaginal, anorectal, and oral swabs. Five Lactobacillus species, Lactobacillus genus, Gardnerella vaginalis, and Atopobium vaginae were quantified; and seven inflammatory markers were measured in the vaginal specimens. In the oral and anorectal specimens, Lactobacillus genus, G vaginalis, and A vaginae were ascertained. RESULTS: Of the 93 adolescents (mean age 16.2 years) at the first visit, 41 (44.1%) had passed sexual debut (penile-vaginal intercourse) and five (5.4%) had sexual experience without passing sexual debut. Having sexual experience at the first visit was not found to be associated with species presence or concentrations (acknowledging an underpowered study because the required sample size was not attained). Modeling the longitudinal data on all girls showed that sexual debut was associated with increased odds of vaginal and anorectal G vaginalis (P=.021; P=.030) and A vaginae (P=.041; P=.012) with increments of interleukins (interleukin [IL]-1α P<.001, IL-1ß P=.046, IL-8 P=.033) and chemokines (regulated on activation, normal T cell expressed and secreted P<.001; macrophage inflammatory protein-1ß P=.040), whereas no difference was seen when modeling (before-after) the girls initiating and girls staying without sexual intercourse. The association of sexual intercourse with IL-1α (P<.001), IL-1ß (P=.030), and IL-8 (P=.002) at the first visit was (greater than 70%) mediated by vaginal G vaginalis and A vaginae concentrations. CONCLUSION: Sexual debut in adolescents is associated with an inflammatory vaginal reaction and with the presence of bacterial vaginosis-related species. Strategies preventing the colonization of bacterial vaginosis-related organisms during early sexual debut are urgently needed and may prevent acquisition of sexually transmitted infections including human immunodeficiency virus in early life.

Association of interleukin-8 gene polymorphisms in HIV patients with opportunistic infections in Limpopo Province, South Africa.

Opportunistic infections (OIs) are common among human immunodeficiency virus (HIV) patients; however, genetic susceptibility to these infections has not been studied. Recent studies have shown that interleukin-8 (IL-8) A/T genotype carriers are more susceptible to a variety of diseases. In this study, we showed the effects of IL-8 gene polymorphisms on OIs and symptoms such as sexually transmitted diseases (STDs), tuberculosis (TB), diarrhea, shortness of breath, weight loss, and viral load, in HIV and acquired immunodeficiency syndrome patients. Genomic DNA was purified from mouthwash samples collected from patients attending HIV centers in the Vhembe district. The IL-8 (-251) A/T locus was genotyped using allele-specific polymerase chain reaction followed by agarose gel electrophoresis. The results showed a weak association between the IL-8 AA genotype and OIs such as STDs (P = 0.143), diarrhea (P = 0.906), and TB (P = 0.762). Significant associations were found between the IL-8 AT genotype and weight loss (P = 0.019), shortness of breath (P = 0.043), and skin problems (P = 0.003). Low viral load was also found to be significantly associated with IL-8 AA genotype (P = 0.009). The present study suggests that different IL-8 genotypes are associated with resistance to various OIs. However, further studies using larger samples sizes are needed to confirm this hypothesis.

Relationship between female genital tract infections, mucosal interleukin-17 production and local T helper type 17 cells.

T helper type 17 (Th17) cells play an important role in immunity to fungal and bacterial pathogens, although their role in the female genital tract, where exposure to these pathogens is common, is not well understood. We investigated the relationship between female genital tract infections, cervicovaginal interleukin-17 (IL-17) concentrations and Th17 cell frequencies. Forty-two cytokines were measured in cervicovaginal lavages from HIV-uninfected and HIV-infected women. Frequencies of Th17 cells (CD3(+) CD4(+) IL-17a(+)) were evaluated in cervical cytobrushes and blood by flow cytometry. Women were screened for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis and herpes simplex virus 2 by PCR, and candidal infections and bacterial vaginosis by Gram stain. Women with bacterial sexually transmitted infections (STIs), specifically chlamydia and gonorrhoea, had higher genital IL-17 concentrations than women with no STI, whereas women with candidal pseudohyphae/spores had lower IL-17 concentrations compared with women without candidal infections. Viral STIs (herpes simplex virus 2 and HIV) were not associated with significant changes in genital IL-17 concentrations. Genital IL-17 concentrations correlated strongly with other inflammatory cytokines and growth factors. Although Th17 cells were depleted from blood during HIV infection, cervical Th17 cell frequencies were similar in HIV-uninfected and HIV-infected women. Cervical Th17 cell frequencies were also not associated with STIs or candida, although few women had a STI. These findings suggest that IL-17 production in the female genital tract is induced in response to bacterial but not viral STIs. Decreased IL-17 associated with candidal infections suggests that candida may actively suppress IL-17 production or women with dampened IL-17 responses may be more susceptible to candidal outgrowth.

Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections.

Pathogens have evolved highly specialized mechanisms to infect hosts. Several microorganisms modulate the eukaryotic cell surface to facilitate their engulfment. Once internalized, they hijack the molecular machinery of the infected cell for their own benefit. At different stages of phagocytosis, particularly during invasion, certain pathogens manipulate pathways governed by small GTPases. In this review, we focus on the role of Rho proteins on curable, sexually transmitted infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Treponema pallidum. Despite the high, worldwide frequencies of these sexually-transmitted diseases, very little is known about the strategies developed by these microorganisms to usurp key eukaryotic proteins that control intracellular signaling and actin dynamics. Improved knowledge of these molecular mechanisms will contribute to the elucidation of how these clinically important pathogens manipulate intracellular processes and parasitize their hosts.

Microbicides for the prevention of sexually transmitted HIV infection.

The impetus for, and efforts in the past 20 years toward a women-initiated method for preventing sexual transmission of HIV has been previously well described. To date, four classes of topical agents categorized by mechanism of action as: surfactants, buffers, cell entry blockers and antiretroviral agents have undergone advanced clinical testing. Thus far, only coitally linked use of 1% tenofovir gel has demonstrated moderate effectiveness in preventing HIV and HSV-2 infection and has generated renewed hope for microbicide development. Studies of new antiviral agents, novel delivery mechanisms and combination/multipurpose products that address challenges of adherence and enhance the effectiveness of tenofovir gel are already underway to further enhance sexual and reproductive health needs of men and women and efforts to prevent HIV infection.

Aspectos epidemiológicos da AIDS em Florianópolis/SC, Brasil / Epidemiological aspects of AIDS in the city of Florianopolis, Brazil / Aspectos epidemiológicos del sida en Florianópolis/SC, Brasil

O estudo teve como objetivo descrever os aspectos epidemiológicos das pessoas com 13 anos e mais, com AIDS, residentes em Florianópolis/SC entre 1986 e 2006. Estudo descritivo, transversal, com coleta das variáveis: ano de diagnóstico, sexo, idade, categoria de exposição, escolaridade, cor da pele e Regional de Saúde de residência, no Sistema Nacional de Agravos de Notificação e Sistema de Informação sobre Mortalidade. Constata-se a magnitude da AIDS em homens, com ensino fundamental, de cor da pele branca, idade entre 20 e 49 anos e heterossexuais. Observou-se a vulnerabilidade feminina na redução da razão entre os sexos masculino/feminino no período avaliado. Apresentam-se a base social e a especificidade dos doentes de AIDS em Florianópolis/SC, e sugerem-se investimentos no diagnóstico territorial na Estratégia de Saúde da Família e acompanhamento dos sistemas de informação pelas Regionais de Saúde, para avaliar a eficiência e a efetividade das estratégias de prevenção à AIDS em Florianópolis/SC.

The purpose is to describe epidemiological aspects of people living with AIDS for 13 years or over in the city of Florianopolis, Brazil, from 1986 to 2006. It's a descriptive and cross-sectional study, with the following data collected: year of diagnosis, gender, age, exposure category, education level, skin color and the registration of the residence at the Regional Health Program, in the National Notifiable Diseases System and in the Information System about Mortality. It was realized the magnitude of men infected by AIDS, with a basic education, white color, age between 20 and 49 years, and heterosexuals. It was noticed the female vulnerability concerning to the reduction of rational between male and female during the period in question. It shows the social base and the specificity of AIDS patients in Florianopolis, suggesting the investments on the territorial diagnosis in the Health Family Strategy and a follow up at the Regional Health Program, in order to evaluate the efficiency and effectiveness of the strategies in preventing AIDS in Florianopolis.

Este estudio objetivó describir los aspectos epidemiológicos de las personas mayores de 13 años, residentes en Florianópolis/SC, que contrajeron SIDA, de 1986 a 2006. Estudio transversal, con la colección de las variables: año de diagnóstico; sexo; edad; categoría de exposición; nivel de educación; color de la piel; la Autoridad Regional de Salud de residencia, en el Sistema Nacional de Agravos de Notificação y Sistema de Informação sobre Mortalidade. Se constató la magnitud de SIDA en hombres, con escuela secundaria completa, que eran de raza blanca, de entre 20 y 49 años y heterosexuales. Se observó la vulnerabilidad femenina en la reducción de la relación entre los géneros femenino masculino/femenino en el período del estudio. Se presenta la base social y la especificidad de los pacientes con SIDA en Florianópolis/SC, se sugiere el diagnóstico de la inversión territorial en la Estrategia de Salud de la Familia y la supervisión de los sistemas de información en los distritos de salud para evaluar la eficiencia y la eficacia de las estrategias la prevención del SIDA en Florianópolis/SC.

Human papillomavirus in HNSCC: recognition of a distinct disease type.

Strong epidemiologic and molecular data now support the conclusion that human papillomavirus (HPV) infection is responsible for a distinct form of head and neck squamous cell carcinoma (HNSCC), independent from the traditional risk factors of tobacco and alcohol use. Patients with HPV-positive HNSCC have a different clinical presentation and better clinical outcomes than those with HPV-negative HNSCC. A diagnosis of HPV-positive HNSCC is associated not only with therapeutic relevance, but also has important implications for future prevention and screening strategies.