Antigen-driven CD4+ T cell and HIV-1 dynamics: Residual viral replication under highly active antiretroviral therapy

Antigen-induced stimulation of the immune system can generate heterogeneity in CD4+ T cell division rates capable of explaining the temporal patterns seen in the decay of HIV-1 plasma RNA levels during highly active antiretroviral therapy. Posttreatment increases in peripheral CD4+ T cell counts are consistent with a mathematical model in which host cell redistribution between lymph nodes and peripheral blood is a function of viral burden. Model fits to patient data suggest that, although therapy reduces HIV replication below replacement levels, substantial residual replication continues. This residual replication has important consequences for long-term therapy and the evolution of drug resistance and represents a challenge for future treatment strategies.

Adherence to antiretroviral therapy and its determinants among persons living with HIV/AIDS in Bayelsa state, Nigeria

Background: A high level of adherence is required to achieve the desired outcomes of antiretroviral therapy. There is paucity of information about adherence to combined antiretroviral therapy in Bayelsa State of southern Nigeria. Objectives: The objectives of the study were to determine the level of adherence to combined antiretroviral therapy among the patients, evaluate the improvement in their immune status and identify reasons for sub-optimal adherence to therapy. Methods: The cross-sectional study involved administration of an adapted and pretested questionnaire to 601 consented patients attending the two tertiary health institutions in Bayesla State, Nigeria: The Federal Medical Centre, Yenagoa and the Niger-Delta University Teaching Hospital Okolobiri. The tool was divided into various sections such as socio-demographic data, HIV knowledge and adherence to combined antiretroviral therapy. Information on the patient's CD4+ T cells count was retrieved from their medical records. Adherence was assessed by asking patients to recall their intake of prescribed doses in the last fourteen days and subjects who had 95-100% of the prescribed antiretroviral drugs were considered adherent. Results: Three hundred and forty eight (57.9%) of the subjects were females and 253 (42.1%) were males. The majority of them, 557 (92.7%) have good knowledge of HIV and combined anti-retroviral therapy with a score of 70.0% and above. A larger proportion of the respondents, 441 (73.4%), had &gt; 95% adherence. Some of the most important reasons giving for missing doses include, &#8220;simply forgot&#8221; 147 (24.5%), and &#8220;wanted to avoid the side-effects of drugs&#8221; 33(5.5%). There were remarkable improvements in the immune status of the subjects with an increment in the proportion of the subjects with CD4+ T cells count of greater than 350 cells/mm3 from 33 (5.5%) at therapy initiation to 338 (56.3%) at study period (p<0.0001). Conclusion: The adherence level of 73.4% was low which calls for intervention and improvement. The combined antiretroviral therapy has significantly improved the immune status of the majority of patients which must be sustained. &#8220;Simply forgot&#8221; was the most important reason for missing doses.

Prolonged cardiac xenograft survival in guinea pig-to-rat model by a highly active cobra venom factor

A highly active cobra venom factor (CVF) was isolated from the venom of Naja kaouthia by sequential column chromatography. It displays strong anticomplementary activity, and has 1515 U of anti complementary activity per mg protein. A single dose of 0.1 mg/kg CVF given i.v. to rats completely abrogated complement activity for nearly 5 days. Given 0.02 mg/kg of CVF. the complement activity of rats was reduced by more than 96.5% in 6 It. In guinea pig-to-rat heart transplant model, rats treated with a single dose of 0.05 mg/kg CVF had significantly prolonged xenograft survival (56.12 +/- 6.27 h in CVF-treated rats vs. 0.19 +/- 0.07 h in control rats, P < 0.001). (C) 2003 Elsevier Ltd. All rights reserved.

Improving a regional chemotherapy service by learning from deaths occurring within 30 days of treatment with systemic anti-cancer therapy.

Background: Outwith clinical trials, patient outcomes specifically related to SACT (systemic anti-cancer therapy) are not well reported despite a significant proportion of patients receiving active treatment at the end of life. The NCEPOD reviewing deaths within 30 days of SACT found SACT caused or hastened death in 27% of cases. <br/><br/>Method: Across the Northern Ireland cancer network, 95 patients who died within 30 days of SACT for solid tumours were discussed at the Morbidity and Mortality monthly meeting during 2013. Using a structured template, each case was independently reviewed, with particular focus on whether SACT caused or hastened death. <br/><br/>Results: Lung, GI and breast cancers were the most common sites. Performance status was recorded in 92% at time of final SACT cycle (ECOG PS 0-2 89%).<br/><br/>In 57% the cause of death was progressive disease. Other causes included thromboembolism (13%) and infection (5% neutropenic sepsis, 6% non-neutropenic sepsis). In 26% with death from progressive disease, the patient was first cycle of first line treatment for metastatic disease. In the majority discussion regarding treatment aims and risks was documented. Only one patient was receiving SACT with curative intent, who died from appropriately managed neutropenic sepsis.<br/><br/>A definitive decision regarding SACT's role in death was made in 60%: in 49% SACT was deemed non-contributory and in 11% SACT was deemed the cause of death. In 40% SACT did not play a major role, but a definitive negative association could not be made. <br/><br/>Conclusion: Development of a robust review process of 30-day mortality after SACT established a benchmark for SACT delivery for future comparisons and identified areas for SACT service organisation improvement. Moreover it encourages individual practice reflection and highlights the importance of balancing patients' needs and concerns with realistic outcomes and risks, particularly in heavily pre-treated patients or those of poor performance status.

Biochemical and biophysical properties of a highly active recombinant arginase from Leishmania (Leishmania) amazonensis and subcellular localization of native enzyme

Arginase (L-arginine amidinohydrolase, E.C. 3.5.3.1) is a metalloenzyme that catalyses the hydrolysis Of L-arginine to L-ornithine and urea. In Leishmania spp., the biological role of the enzyme may be involved in modulating NO production upon macrophage infection. Previously, we cloned and characterized the arginase gene from Leishmania (Leishmania) amazonensis. In the present work, we successfully expressed the recombinant enzyme in E. coli and performed biochemical and biophysical characterization of both the native and recombinant enzymes. We obtained K-M and V-max. values of 23.9(+/- 0.96) mM and 192.3 mu mol/min mg protein (+/- 14.3), respectively, for the native enzyme. For the recombinant counterpart, K-M was 21.5(+/- 0.90) mM and V-max was 144.9(+/- 8.9) mu mol/min mg. Antibody against the recombinant protein confirmed a glycosomal cellular localization of the enzyme in promastigotes. Data from light scattering and small angle X-ray scattering showed that a trimeric state is the active form of the protein. We determined empirically that a manganese wash at room temperature is the best condition to purify active enzyme. The interaction of the recombinant protein with the immobilized nickel also allowed us to confirm the structural disposition of histidine at positions 3 and 324. The determined structural parameters provide substantial data to facilitate the search for selective inhibitors of parasitic sources of arginase, which could subsequently point to a candidate for leishmaniasis therapy. (c) 2008 Elsevier B.V. All rights reserved.

Qualidade de vida de indivíduos infectados pelo HIV com ou sem tratmento anti-retroviral

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Representações sociais sobre a Aids e a Terapia Anti-Retroviral: influências no tratamento de pessoas vivendo com HIV/Aids

Com o advento da Terapia Anti -Retroviral, a Aids assumiu características de doença crônica, em especial nos países onde o acesso aos medicamentos é efetivamente garantido. O Brasil é tomado como modelo por possuir um programa que tem dado boas respostas à epidemia. Em novembro de 1996, foi promulgada, pelo Sistema Único de Saúde (SUS), a lei que dispõe sobre a obrigatoriedade do acesso gratuito a todos os que necessitarem de medicamentos anti -retrovirais. Os resultados obtidos com o tratamento – a redução progressiva da carga viral e a manutenção e/ou restauração do funcionamento do sistema imunológico – têm sido associados a benefícios marcantes na saúde física das pessoas soropositivas e permitido que elas retomem e concretizem seus projetos de vida. Porém, o acesso universal aos medicamentos que possibilita o tratamento para portadores do HIV gratuitamente ainda enfrenta problemas de adesão. Em uma compreensão mais restrita, adesão pode ser definida como o comportamento de uma pessoa – tomar remédio, seguir uma dieta ou fazer mudanças no estilo de vida – que corresponde às recomendações da equipe de saúde. Nesse contexto, esse estudo se propõe a analisar as representações sociais de sujeitos soropositivos sobre o tratamento anti-retroviral e suas implicações no processo de adesão a este tratamento, caracterizando as imagens e os sentidos que estes sujeitos soropositivos que aderiram ou não aderiram à terapia anti -retroviral possuem sobre este tipo de tratamento e as implicações na sua vida, destacando as objetivações e as ancoragens que compõem suas representações sociais. A metodologia foi pautada nas formulações teóricas sobre pesquisa qualitativa, priorizando -se a entrevista no enfoque do Método de Explicitação do Discurso Subjacente (MEDS), realizadas na Unidade de Referência em Doenças Infecciosas e Parasitárias Especiais (UREDIPE), vinculada à Secretaria de Estado de Saúde do estado do Pará (SESPA) e no Hospital Universitário João de Barros Barreto (HUJBB), mais especificamente na Clinica de Doenças Infecciosas e Parasitárias (DIP).

Anti dermatophytic therapy: prospects for the discovery of new drugs from natural products

Millions of people and animals suffer from superficial infections caused by a group of highly specialized filamentous fungi, the dermatophytes, which only infect keratinized structures. With the appearance of AIDS, the incidence of dermatophytosis has increased. Current drug therapy used for these infections is often toxic, long-term, and expensive and has limited effectiveness; therefore, the discovery of new anti dermatophytic compounds is a necessity. Natural products have been the most productive source for new drug development. This paper provides a brief review of the current literature regarding the presence of dermatophytes in immunocompromised patients, drug resistance to conventional treatments and new anti dermatophytic treatments.

Evaluation of inadequate anti-retroviral treatment in patients with HIV/AIDS

Introduction: Since the emergence of antiretroviral therapy, the survival of patients infected with human immunodeficiency virus has increased. Non-adherence to this therapy is directly related to treatment failure, which allows the emergence of resistant viral strains. Methods: A retrospective descriptive study of the antiretroviral dispensing records of 229 patients from the Center for Health Care, University Hospital, Federal University of Juiz de Fora, Brazil, was conducted between January and December 2009. Results: The study aimed to evaluate patient compliance and determine if there was an association between non-adherence and the therapy. Among these patients, 63.8% were men with an average age of 44.0 +/- 9.9 years. The most used treatment was a combination of 2 nucleoside reverse transcriptase inhibitors with 1 non-nucleoside reverse transcriptase inhibitor (55.5%) or with 2 protease inhibitors (28.8%). It was found that patients taking lopinavir/ritonavir with zidovudine and lamivudine had a greater frequency of inadequate treatment than those taking atazanavir with zidovudine and lamivudine (85% and 83.3%, respectively). Moreover, when the combination of zidovudine/lamivudine was used, the patients were less compliant (chi(2) = 4.468, 1 degree of freedom, p = 0.035). Conclusions: The majority of patients failed to correctly adhere to their treatment; therefore, it is necessary to implement strategies that lead to improved compliance, thus ensuring therapeutic efficacy and increased patient survival.

Novel Use of Dual Anti-Inflammatory Therapy to Overcome Drug Resistance and Improve Functional Recovery Following Spinal Cord Injury

Over 1.2 million Americans are currently living with a traumatic spinal cord injury (SCI). Despite the need for effective therapies, there are currently no proven effective treatments that can improve recovery of function in SCI patients. Many therapeutic compounds have shown promise in preclinical models of SCI, but all of these have fallen short in clinical trials. P-glycoprotein (Pgp) is an active transporter expressed on capillary endothelial cell membranes at the blood-spinal cord barrier (BSCB). Pgp limits passive diffusion of blood-borne drugs into the CNS, by actively extruding drugs from the endothelial cell membrane. Pgp can become pathologically up-regulated, thus greatly impeding therapeutic drug delivery (‘multidrug resistance’). Importantly, many drugs that have been evaluated for the treatment of SCI are Pgp substrates. We hypothesized that Pgp-mediated drug resistance diminishes the delivery and efficacy of neuroprotective drugs following SCI. We observed a progressive, spatial spread of Pgp overexpression within the injured spinal cord. To assess Pgp function, we examined spinal cord uptake of systemically-delivered riluzole, a drug that is currently being evaluated in clinical trials as an SCI intervention. Blood-to-spinal cord riluzole penetration was reduced following SCI in wild-type but not Pgp-null rats, highlighting a critical role for Pgp in mediating spinal cord drug resistance after injury. Others have shown that pro-inflammatory signaling drives Pgp up-regulation in cancer and epilepsy. We have detected inflammation in both acutely- and chronically-injured spinal cord tissue. We therefore evaluated the ability of the dual COX-/5-LOX inhibitor licofelone to attenuate Pgp-mediated drug resistance following SCI. Licofelone treatment both reduced spinal cord Pgp levels and enhanced spinal cord riluzole bioavailability following SCI. Thus, we propose that licofelone may offer a new combinatorial treatment strategy to enhance spinal cord drug delivery following SCI. Additionally, we assessed the ability of licofelone, riluzole, or both to enhance recovery of locomotor function following SCI. We found that licofelone treatment conferred a significant improvement in hindlimb function that was sustained through the end of the study. In contrast, riluzole did not improve functional outcome. We therefore conclude that licofelone holds promise as a potential neuroprotective intervention for SCI.

Honeycomb nanogold networks with highly active sites

The formation of macroporous honeycomb gold using an electrochemically generated hydrogen bubble template is described. The synthesis procedure induces the formation of highly active surfaces with enhanced electrocatalytic and surface enhanced Raman scattering properties.

Pd and Pt ions as highly active sites for the water-gas shift reaction over combustion synthesized zirconia and zirconia-modified ceria

Noble metal substituted ionic catalysts were synthesized by solution combustion technique. The compounds were characterized by X-ray diffraction, FT-Raman spectroscopy, and X-ray photoelectron spectroscopy. Zirconia supported compounds crystallized in tetragonal phase. The solid solutions of ceria with zirconia crystallized in fluorite structure. The noble metals were substituted in ionic form.The water-gas shift reaction was carried out over the catalysts.Negligible conversions were observed with unsubstituted compounds. The substitution of a noble metal ion was found to enhance the reaction rate. Equilibrium conversion was obtained below 250 degrees C in the presence of Pt ion substituted compounds. The formation of Bronsted acid-Bronsted base pairs was proposed to explain the activity of zirconia catalysts. The effect of oxide ion vacancies on the reactions over substituted ceria-zirconia solid solutions was established. (c)2010 Elsevier B.V. All rights reserved.

A Single-Stage Water-Gas Shift Reaction over Highly Active and Stable Si- and Al-Substituted Pt/CeO2 Catalysts

Ce0.88Si0.1Pt0.02O2-d and Ce0.88Al0.1Pt0.02O2-d catalysts were synthesized by using a low-temperature sonochemical method and characterized by using XRD, TEM, XPS, FTIR, and BET surface analyzer. The catalytic activities of these compounds were investigated for the watergas shift reaction in the temperature range of 140-440 degrees C. The substitution of Si in Ce0.98Pt0.02O2-d increased the releasing capacity of lattice oxygen, whereas the substitution of Al decreased the reducibility of Ce0.98Pt0.02O2-d, as evidenced by hydrogen temperature-programmed reduction studies. However, both the catalysts showed a considerable improvement in terms of activity and stability compared to Ce0.98Pt0.02O2-d. The combined activity measurement and characterization results suggest that the increase in the oxygen vacancy, which acts as a dissociation center for water, is the primary reason for the improvement in the activity of modified Ce0.98Pt0.02O2-d. Both the catalysts are 100?% selective toward H2 production, and approximately 99?% conversion of CO to CO2 was observed at 260 and 270 degrees C for Ce0.88Si0.1Pt0.02O2-d and Ce0.88Al0.1Pt0.02O2-d, respectively. These catalysts do not deactivate during the daily startup/shutdown operations and are sustainable even after prolonged reaction. Notably, these catalysts do not require any pretreatment or activation during startup/shutdown operations.