Disease progression in patients with virological suppression in response to HAART is associated with the degree of immunological response

OBJECTIVE: To determine if immunological response is associated with disease progression in patients with virological suppression after initiating HAART. DESIGN: A cohort study of 1084 treatment-naive participants in the British Columbia HIV/AIDS Drug Treatment Program who had achieved viral loads < 500 copies/ml at 3-9 months after initiating triple-drug therapy. METHODS: Cox proportional hazards was used to model the association with disease progression of baseline variables, change in CD4 cell counts and CD4 cell count strata at 6 months. Logistic regression analysis was used to examine associations with two definitions of poor immunological response. RESULTS: Patients were followed for a median of 51.4 months. In univariate analyses, increases in CD4 cell counts of < 25 cells/microl and absolute CD4 cell counts of < 200 cells/microl were associated with an increased risk of death or new AIDS events. Two mulitivariate models, one including baseline CD4 cell count and change in CD4 cell count from baseline and the other including only absolute CD4 cell counts at 6 months, were found to predict disease progression in this setting. Increases in CD4 cell count of < 25 cells/microl were associated with increasing age and inversely associated with low baseline CD4 cell counts, high baseline viral loads and good adherence to therapy. CD4 cell counts of < 200 cells/microl at 6 months were associated with low baseline CD4 cell counts and having AIDS at baseline. CONCLUSION: Patients with virological suppression are still at risk for HIV disease progression if adequate immunological responses are not achieved.     

Binding mechanism of doxorubicin in ion-exchange albumin microcapsules

The absorption efficiency of cross-linked albumin microcapsules was evaluated as a function of various experimental conditions in an attempt to elucidate the doxorubicin binding mechanism of these microcapsules. The amount of drug absorbed augmented with increasing doxorubicin concentration until saturation was reached. Neither a Langmuir nor a Freundlich isotherm relationship was observed, indicating that the fixation of doxorubicin on the microcapsule walls did not follow a common physical adsorption process. Decreasing the mean particle diameter of the microcapsules increased the absorption rate and the total amount of doxorubicin absorbed, as expected. The absorption rate was enhanced by the elevation of the stirring rate of the aqueous drug solution. Furthermore, the presence of electrolytes in this aqueous solution profoundly altered the absorption profile of doxorubicin. Increasing the NaCl concentration in the solution reduced the total amount of drug absorbed. Moreover, the nature of the cation used also affected the absorption profile. These results suggested that there is a competitive fixation of the cation on the binding sites (identified as R-COO groups) available to the drug molecules. The weakly cross-linked microcapsules acted as cation-exchange resins which can exchange their labile sodium with the protonated drug present in the solution. This was also confirmed by the results of the titrimetric assay of the acidic microcapsules with NaOH.     

Anchorage Efficacy of Palatally-inserted Miniscrews in Molar Distalization with a Periodontally/Miniscrew-anchored Distal Jet

AIM: As a clinical pilot study using the skeletonized, periodontally/miniscrew-anchored Distal Jet appliance, this study aimed to verify the positional stability of the palatally-inserted paramedian miniscrews when subjected to loading for several months, hence to assess the efficacy of the supporting anchorage design. MATERIAL AND METHOD: Sixteen miniscrews (8-9 mm in length, 1.6 mm in diameter, polished surface) were inserted in the anterior region of the palate at paramedian locations. Once they had been in place for 1 week, skeletonized Distal Jets for bilateral molar distalization were anchored to the first premolars and necks of the miniscrews using composite. The appliances' coil spring systems were activated to a distalization force of 200-240 cN. The miniscrews were processed histologically after minimally-invasive explantation. RESULTS: Forces acting reciprocally on the anchorage unit result in significant anchorage loss in the palatally-inserted titanium miniscrews used for added anchorage support: we observed ventral movement in the vicinity of the miniscrew heads of 0.95+/-0.82 mm (the mean; p = 0.005), and extrusion of 0.21+/-0.28 mm (p = 0.040). In the process they tipped 2.65 degrees +/-6.23 degrees in relation to the palatal plane and 2.15 degrees +/-5.76 degrees in relation to the anterior cranial base. We observed no evidence of direct screw-to-bone contact in any of the explanted miniscrews. CONCLUSIONS: Titanium miniscrews with a polished surface, 1.6 mm in diameter and 8-9 mm long, do not provide stationary anchorage in molar distalization with the periodontally/miniscrew-anchored Distal Jet. When subjected for several months to load from forces that act in reciprocity to the force systems occurring during molar distalization, they fail to remain completely stationary in position in the palatal locations in which they were inserted. However, the combined anchorage setup is sufficient, intraorally and regardless of patient compliance, to largely compensate for the mesially-acting forces that occur reciprocal to molar distalization.     

Influence of oil droplet surface charge on the performance of antibody--emulsion conjugates.

Targeted drug delivery requires binding of (and subsequent uptake by) the carrier to target cells. The purpose of our present study is to compare the binding and uptake of emulsions with different electric surface properties to SK-BR3 cell line, which over-expresses the HER2 receptor. Cationic emulsion was prepared by incorporating 0.25% w/w of the cationic lipid, stearylamine in the formulation while the anionic emulsion formulation was identical but lacking stearylamine. Immunoemulsions were prepared by conjugating the 2-iminothiolane derivative of the monoclonal antibody trastuzumab (Herceptin) through the reactive maleimide group of the octadecyl-4-(maleimidomethyl)cyclohexane-carboxylic amide linker which was incorporated in the oil phase of the anionic and cationic emulsions. Cationic emulsion exhibited a droplet size of approximately 130 nm and a zeta potential of +50 mV compared to anionic emulsion with a droplet size of approximately 140 nm and a zeta potential of -30 mV which decreased to -5 mV following antibody coupling. There was no significant difference in the coupling efficiency of trastuzumab to anionic and cationic emulsions which was in the range of 60-70%. The cationic emulsion and immunoemulsion appeared to be physically stable over a long period of time, as indicated by particle-size measurements while the droplets of the anionic immunoemulsion coalesced with time resulting in phase separation within 20 days storage at 4 degrees C. The results of binding and uptake to cells showed that both cationic and anionic immunoemulsions bind and internalized to cells much more than the respective blank emulsions. The enhanced penetration of the probe coumarin-6 with both immunoemulsions clearly indicated that the internalization process was mainly controlled by a cell-receptor endocytosis mechanism mediated by the binding affinity of trastuzumab to the cell surface receptor since the uptake of the cationic immunoemulsion was not significantly different from the uptake of the anionic immunoemulsion. However, only the cationic immunoemulsion might be considered for further investigation in view of its long standing physical stability.     

The design and evaluation of a novel targeted drug delivery system using cationic emulsion-antibody conjugates.

In an attempt to design a targeted drug delivery system to tumors' over-expressing H-ferritin specifically recognized by a monoclonal antibody, AMB8LK, a cationic emulsion - AMB8LK conjugate was prepared. A novel cross-linker molecule bearing maleimide group was synthesized and added to cationic emulsion formulation for AMB8LK Fab' fragment covalent coupling. NMR spectroscopy confirmed the cross-linker synthesis and the preservation of the active maleimide function. SDS gel-electrophoresis results corroborated the formation of the Fab' fragment. Different densities of Fab' fragments (10-200 Fab'/oil droplet) were conjugated to emulsion droplet interface and no changes in the physico-chemical properties were observed ( approximately 120 nm size and zeta potential of approximately +30 mV). The coupling efficiency ranged from 55% to 70% and was visualized by TEM showing gold particles attached to the droplet interface. Cell culture studies demonstrated specific binding to cells as confirmed by the occurrence of the marked reduction in binding when free AMB8LK Mab was incubated before adding the AMB8LK-emulsion conjugate to the cells. The coupling of AMB8LK Fab' fragment to the cationic emulsion increased the cells uptake by 50% as compared to non-conjugated respective cationic emulsion. Appropriate conditions were, thus, identified for coupling AMB8LK Fab' fragment to cationic emulsion without altering the specificity and affinity of the Mab fragment to the tumor antigen.     

Idealized cultural beliefs about gender: implications for mental health

Background In this paper, we examined the relationship between culture-specific ideals (chastity, masculinity, caste beliefs) and self-esteem, shame and depression using an idealized cultural model proposed by Mahalingam (2006, In: Mahalingam R (ed) Cultural psychology of immigrants. Lawrence Erlbaum, Mahwah, NJ, pp 1–14). Methods Participants were from communities with a history of extreme male-biased sex ratios in Tamilnadu, India (N = 785). Results We hypothesized a dual-process model of self-appraisals suggesting that achieving idealized cultural identities would increase both self-esteem and shame, with the latter leading to depression, even after controlling for key covariates. We tested this using structural equation modeling. The proposed idealized cultural identities model had an excellent fit (CFI = 0.99); the effect of idealized identities on self-esteem, shame and depression differed by gender. Conclusions Idealized beliefs about gender relate to psychological well-being in gender specific ways in extreme son preference communities. We discuss implications of these findings for future research and community-based interventions.     

Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy

OBJECTIVE: To characterize the temporal changes in mortality and life expectancy among HIV-positive individuals initiating antiretroviral therapy in British Columbia, Canada, from 1993 to 2004. METHODS: This analysis was restricted to 2238 antiretroviral-naive HIV-positive individuals who started antiretroviral therapy between January 1993 and September 2004. The primary analysis endpoint was all-cause mortality stratified by four time periods: 1993-1995, 1996-1998, 1999-2001, and 2002-2004. Cox proportional hazard models, with associated 95% confidence intervals (CI), were used to estimate the hazard of death. Abridged life tables were constructed to compare life expectancies at the age of 20 years. RESULTS: Product limit estimates of the cumulative mortality rate at 12 months after therapy initiation decreased from 15.8% (+/- 1.6%) in 1993-1995 to 6.1% (+/- 1.1%) in 2002-2004. Life expectancy at the age of 20 years has increased from 9.1 years (+/- 2.3 years) in 1993-1995 to 23.6 years (+/- 4.4 years) in 2002-2004. Subjects in 1993-1995 were more likely to die than those who started therapy in 2002-2004 (hazard ratio 2.78; 95% CI 1.92-3.85). Patients who initiated dual therapy or therapies containing three or more antiretroviral drugs were, respectively, 1.49 (95% CI 1.23-1.82) and 2.56 (95% CI 2.13-3.13) times less likely to die than those who started on monotherapy. CONCLUSION: A significant and progressive decrease in mortality and increase in life expectancy were observed over the 12-year study period. The increase in life expectancy and decrease in mortality were directly associated with the use of modern forms of HAART.     

Determinants of nevirapine hypersensitivity and its effect on the association between hepatitis C status and mortality in antiretroviral drug-naive HIV-positive patients

OBJECTIVE: To assess risks factors and outcomes associated with nevirapine hypersensitivity reactions, and to determine the effect of hypersensitivity as a modifier of the association between hepatitis C virus (HCV) infection and mortality among antiretroviral drug-naive patients. METHODS: The primary endpoint was hypersensitivity reactions in a population-based cohort of antiretroviral therapy-naive HIV-individuals, 18 years or older in British Columbia, Canada, who started triple antiretroviral therapy with nevirapine between May 1997 and June 2003. Univariate and multivariate analyses were performed to identify predictors of nonaccidental mortality in the subgroup of patients with known HCV serostatus. RESULTS: A total of 66 (9.6%) of 685 patients met the definition for hypersensitivity reactions. In the univariate logistic regression analysis, no variables were identified as risk factors. In multivariate survival analyses conducted to identify characteristics associated with nonaccidental mortality, patients with both HCV coinfection and hypersensitivity reactions had a higher risk of death (hazard ratio, 7.12; 95% confidence interval, 2.73-18.53; P < 0.001) compared with those who did not have HCV coinfection or hypersensitivity reaction. CONCLUSION: Results of this study suggest that the hypersensitivity reaction behaves as an effect modifier of the association between HCV infection and mortality in this cohort of antiretroviral drug-naive HIV-positive patients. These results support the current recommendation against the use of nevirapine in HIV/HCV-coinfected patients.