Association of Attitudes and Beliefs towards Antiretroviral Therapy with HIV-Seroprevalence in the General Population of Kisumu, Kenya

Since antiretroviral therapy (ART) became available in the developed world, the prevalence of unprotected sex and the incidence of sexually transmitted infections (STIs) and HIV have increased. We hypothesized that a similar phenomenon may be occurring in sub-Saharan Africa concomitant with the scale-up of HIV treatment.We conducted a general population-based survey in Kisumu, Kenya. Participants completed an interview that included demographics as well as ART-related attitudes and beliefs (AB) and then underwent HIV serological testing. Exploratory and confirmatory factor analyses of AB about ART indicated two factors: 1) ART-related risk compensation (increased sexual risk taking now that ART is available); and 2) a perception that HIV is more controllable now that ART is available. Logistic regression was used to determine associations of these factors with HIV-seroprevalence after controlling for age.1,655 (90%) of 1,844 people aged 15-49 contacted, including 749 men and 906 women, consented to participate in the study. Most participants (n = 1164; 71%) had heard of ART. Of those who had heard of ART, 23% believed ART was a cure for HIV. ART-related risk compensation (Adjusted (A)OR = 1.45, 95% CI 1.16-1.81), and a belief that ART cures HIV (AOR = 2.14, 95% CI 1.22-3.76) were associated with an increased HIV seroprevalence in men but not women after controlling for age. In particular, ART-related risk compensation was associated with an increased HIV-seroprevalence in young (aged 15-24 years) men (OR = 1.56; 95% CI 1.12-2.19).ART-related risk compensation and a belief that ART cures HIV were associated with an increased HIV seroprevalence among men but not women. HIV prevention programs in sub-Saharan Africa that target the general population should include educational messages about ART and address the changing beliefs about HIV in the era of greater ART availability

Analysis of chemokine and chemokine receptor expression in squamous cell carcinoma of the head and neck (SCCHN) cell lines

The purpose of this work was to analyze chemokine and chemokine receptor expression in untreated and in irradiated squamous cell carcinoma of the head and neck (SCCHN) tumor cell lines, aiming at the establishment of assays to test for the relevance of chemokine and chemokine receptor expression in the response of SCCHN to radiotherapy and radiochemotherapy. Five low passage and 10 established SCCHN lines, as well as two normal cell lines, were irradiated at 2 Gy or sham-irradiated, and harvested between 1 and 48 h after treatment. For chemokines with CC and CXC structural motifs and their receptors, transcript levels of target and reference genes were quantified relatively by real-time PCR. In addition, CXCL1 and CXCL12 protein expression was analyzed by ELISA. A substantial variation in chemokine and chemokine receptor expression between SCCHN was detected. Practically, all cell lines expressed CCL5 and CCL20, while CCL2 was expressed in normal cells and in some of the tumor cell lines. CXCL1, CXCL2, CXCL3, CXCL10, and CXCL11 were expressed in the vast majority of the cell lines, while the expression of CXCL9 and CXCL12 was restricted to fibroblasts and few tumor cell lines. None of the analyzed cell lines expressed the chemokines CCL3, CCL4, or CCL19. Of the receptors, transcript expression of CCR1, CCR2, CCR3, CCR5, CCR7, CCXR2, and CCXR3 was not detected, and CCR6, CXCR1, and CXCR4 expression was restricted to few tumor cells. Radiation caused up- and down-regulation with respect to chemokine expressions, while for chemokine receptor expressions down-regulations were prevailing. CXCL1 and CXCL12 protein expression corresponded well with the mRNA expression. We conclude that the substantial variation in chemokine and chemokine receptor expression between SCCHN offer opportunities for the establishment of assays to test for the relevance of chemokine and chemokine receptor expression in the response of SCCHN to radiotherapy and radiochemotherapy

Induction and persistence of an immune intestinal imbalance by intestinal y-irradiation in the rat

During radiotherapy for pelvic or abdominal cancer, the intestine is a critical dose-limiting organ. Despite precautions in treatment (planning and delivery), patients develop radiation-induced bowel injury during and for several months after treatment. Radiation enteropathy therefore remains an important obstacle to the radiocurability of abdominal tumors continues to impair patients' quality of life. An inflammatory process associated to immune imbalance has been hypothesized for the development of chronic radiation enteritis. The development of delayed radiation effects involves a continuous process starting immediately at the time of irradiation. The chronic inflammatory reactions are typically characterized by a large infiltrate of immune cells (macrophages, lymphocytes). The balance of cytokines production is crucial to immune response to disease prevention and CD4+ T cells play a prominent role in the disease progression. The persistence of disease susceptibility and resistance depends on the profiles of the cytokines secreted by Th1 and Th2 cells. In the early time, we showed that abdominal single irradiation (10Gy) or fractionated colorectal ?-irradiation (4Gy/fractions, 3 fractions/week and total dose 52Gy) modified the Th1 and Th2 cytokines expression characterized by Th1 cytokines (IFN-gamma/IP10) repression. The Th2 shift occurred via regulation of the level of cytokine-mediators through transcriptional modulation and STAT signaling. During the acute phase, the immune imbalance is associated to an infiltration of macrophages and neutrophiles. This Th1/Th2 imbalance may be attributed to a different radiosensitivity (Th1 more radiosensitive than Th2) and the secretion of a feed-back inhibitor of Th1 polarization potentiating the Th2 profile. In long term (6 months after radiotherapy) the intestinal response may be also driven by the Th2- type responses. The molecular mechanism of this immune imbalance persistence remained unknown. Interestingly, irradiation created an immunosuppressive effect characterized by IL10/STAT3 pathway repression, the pathway known to regulate Th1/Th2 balance. A decrease of the CD4+CD25+FOXP3+ regulatory T cells (Tregs) frequency in the mesenteric lymph nodes may be at the genesis of the IL-10 repression. These results raise the question of whether the Th2 polarization post-irradiation (acute and delayed time) in the intestine involve a highway code of the T cell trafficking induced by a homeostastatic differential chemokines and an alteration of the microvasculature. The assumed loss of tolerance induced by reduced frequency of Treg may be deleterious for Th inactivation and antibacterial responses. These findings suggest the importance to reduce irradiation effects during and after radiotherapy based on immune deviation

Treatment of PuO2 Lung Contamination using a Dry Powder Formulation of DTPA

Lung contamination can result from accidental release of actinides such as Pu and Am. The therapeutic approach to reduce the effective radiation dose is to remove the α-emitting radionuclides from the body by promoting their decorporation. DTPA is the recommended treatment of internal contamina-tion by plutonium. The present work investigates the decorporation efficacy of a dry powder formulation of CaNa3-DTPA on a pulmonary contamination with PuO2. Sprague-Dawley rats were exposed to PuO2 aerosols, and 2 hours later received an intratracheal insufflation of CaNa3-DTPA (18.2 ± 1.4 µmol /kg) formulated into porous particles. Urines were collected daily for 7 days. Initial lung deposit (ILD) was determined by X ray spectrometry counting 7 days post-inhalation. Fourteen days post-inhalation, rats were euthanized, liver, femurs and lungs were collected and broncho alveolar lavages (BAL) were carried out. The total alpha activity of samples was measured by liquid scintillation counting in BAL, BAL cells and BAL fluids. The ILDs of untreated rats and DTPA-treated rats were respectively 15.6 ± 2.3 and 13.6 ± 2.3 kBq. The cumulative activity urinary excretion over 7 days was 7-fold higher after DTPA administration as compared to untreated rats, and represented approximately 7% of the ILD for DTPA-treated animals. In the main retention tissues, liver and skeleton, the deposit of activity in DTPA-treated rats was less than 5% of the one of untreated animals (1.13% of ILD in liver of untreated rats vs 0.05% in DTPA-treated rats; 2.75% in skeleton vs 0.1%). Distribution of alpha activity within lungs was determined. Activity recovered in BAL fluids from DTPA-treated rats was 7.3-times lower than in BAL fluids from untreated animals. Although the activity associ-ated with BAL cells tended to decrease, the difference between the 2 groups remained non significant, suggesting that pulmonary surfactant and/or serum-derived proteins represented the major accessible lung compartment for DTPA decorporation. However, no significant decrease in whole lung activity was ob-tained. Our study shows the efficacy of a dry DTPA powder on actinide decorporation. By inhibiting ac-tinide deposit in skeleton and liver, a limitation of the dose delivered to these tissues is expected, thus limiting the risks for radiation-induced diseases. In addition, DTPA treatment modified distribution of activity within lungs. It is generally admitted that soluble compounds leading to more homogeneous irra-diation of the lungs cause higher damage than insoluble forms. The decorporation of the most soluble fraction of radionuclide present in BAL fluids, could thus limit lung damage

Early Inflammatory Changes in Lung Following PuO2 or Pu Nitrate Contamination in the Rat

Increases in cancer incidence and mortality among workers overexposed to alpha-emitting radionuclides, such as plutonium (Pu), have been described with lung tumors of epithelial origin being the most common. However, the question of mechanisms leading to tumor formation following inhalation of radionuclides remains. The main factor controlling tumor incidence seems to be associated with radiation dose distribution, the more homogenous the distribution, the higher the incidence of cancer. In addition, some evidence exists regarding the role of the inflammatory response as a cofactor of tumorigenesis. The present study aims to determine the early inflammatory changes following pulmonary Pu contamination with the insoluble compound, PuO2 or the moderately soluble compound, Pu nitrate. Adult male Sprague-Dawley rats were exposed to PuO2 aerosols using a nose-only inhalation procedure (Initial lung deposit 4.7-43.4 kBq), or received intratracheal administration of Pu nitrate (25 kBq). Fourteen days post contamination, rats were euthanized and bronchoalveolar lavages (BAL) carried out. Activity was measured by liquid scintillation in lungs, femurs and liver. Distribution of activity within lung compartments was also studied. Activation of alveolar macrophages was evaluated by measurement of inflammatory mediators in supernatants collected 24h after plating and intracellular acid phosphatase activity determination, as well as by CD68 immunolabelling on lungs. The higher solubility of Pu nitrate as compared to PuO2 is illustrated by higher activity deposits in skeleton and liver, and lower retention in lungs. However, at this time point, lung distribution does not vary between the 2 compounds, the majority of activity being retained in the cellular fraction of BAL, mainly macrophages. Activation of macrophages is observed in the two groups of contaminated animals, with an enhanced production of TNF-alpha, MCP-1, CINC-1 and MIP-2, and an increased acid phosphatase activity, as compared to sham-contaminated rats. The level of activation was found to be dependant on the initial lung deposit following PuO2 contamination. Our results provide evidence for an early inflammatory response following Pu lung contamination and the role of macrophages whatever the solubility of the Pu compound

Intracellular Pu Decorporation in Rat by Different DTPA Formulations

Cellular internalisation of DTPA appears negligible. Thus, a fast urinary excretion of Pu-DTPA is observed after treatments, but a slow excretion also occurs, explained by Pu-DTPA retention within the interstitium (2.5% of Pu-DTPA, half-life 1 week). One day after 14C-DTPA i.v., 1-2% of the activity was retained in perfused soft tissues, demonstrating its cellular internalisation, whereas blood DTPA was 0.025%. Encapsulation of DTPA has been proposed to improve its cellular internalisation, and a nearly total liver decorporation was obtained using stealth® 100 nm-liposomes. This study estimates intracellular decorporation of Pu by different DTPA formulations. First, a biokinetic study was performed after Pu-DTPA i.v., to help interpretation of decorporation data. About 99% of Pu was excreted via urines for the first 3 days, followed by residual excretion. Similar Pu activities were measured in skeleton, liver, kidneys and urine of day 7 (0.1%). These values, quite different than those measured after Pu-citrate i.v., demonstrated the great stability of Pu-DTPA, in extra and intracellular environments. When DTPA solutions were given i.v., 1 hour after Pu-citrate i.v., both fast and slow excretion (half-life 3-4 days) of Pu-DTPA were observed. The ratio between fast and slow excretions increased with DTPA dosage and, at similar dosage, this ratio was much lower after pulmonary insufflation of dry DTPA powder than after i.v.. Therefore, fast excretion depends on DTPA concentration in blood, whereas slow excretion, associated with intracellular DTPA, depends on total DTPA administered. This was confirmed after specific liver or lung contamination. Then, most of the urinary decorporation involved a slow process observed for 1 month. Moreover, half-life of slow excretion appeared to vary depending on tissues. In a last experiment, a treatment was performed 1 day before Pu-citrate i.v. (30 and 300µmol.kg-1). A decorporation similar to a standard treatment (30µmol.kg-1, i.v. at+1h) was observed for the highest dosage (~50%), whereas a 25 % decorporation was obtained for the lowest dosage. Altogether, these results underline the importance of intracellular DTPA in the decorporation process which will be discuss in terms of modelling and radioprotection