Late presentation to HIV/AIDS testing, treatment or continued care: clarifying the use of CD4 evaluation in the consensus definition.

OBJECTIVES: Late presentation to HIV/AIDS services compromises treatment outcomes and misses opportunities for biomedical and behavioural prevention. There has been significant heterogeneity in how the term 'late presentation' (LP) has been used in the literature. In 2011, a consensus definition was reached using CD4 counts to define and measure late presenters and, while it is useful for clinical care, the consensus definition has several important limitations that we discuss in this article. METHODS: Using the spectrum of engagement in HIV care presented by Gardner and colleagues, this article highlights issues and opportunities associated with use of the consensus definition. RESULTS: The consensus definition is limited by three principal factors: (1) the CD4 count threshold of 350 cells/µL is being increasingly questioned as the biomedical justification grows for earlier initiation of treatment; (2) CD4 evaluations are conducted at multiple services providing HIV care; thus it remains unclear to which service the patient is presenting late; and (3) the limited availability of CD4 evaluation restricts its use in determining the prevalence of LP in many settings. CONCLUSIONS: The consensus definition is useful because it describes the level of disease progression and allows for consistent evaluation of the prevalence and determinants of LP. Suggestions are provided for improving the application of the consensus definition in future research.

Changing global essential medicines norms to improve access to AIDS treatment: lessons from Brazil.

Brazil's large-scale, successful HIV/AIDS treatment programme is considered by many to be a model for other developing countries aiming to improve access to AIDS treatment. Far less is known about Brazil's important role in changing global norms related to international pharmaceutical policy, particularly international human rights, health and trade policies governing access to essential medicines. Prompted by Brazil's interest in preserving its national AIDS treatment policies during World Trade Organisation trade disputes with the USA, these efforts to change global essential medicines norms have had important implications for other countries, particularly those scaling up AIDS treatment. This paper analyses Brazil's contributions to global essential medicines policy and explains the relevance of Brazil's contributions to global health policy today.

Assessing health impact assessment: multidisciplinary and international perspectives.

Health impact assessment (HIA) seeks to expand evaluation of policy and programmes in all sectors, both private and public, to include their impact on population health. While the idea that the public's health is affected by a broad array of social and economic policies is not new and dates back well over two centuries, what is new is the notion-increasingly adopted by major health institutions, such as the World Health Organisation (WHO) and the United Kingdom National Health Services (NHS)-that health should be an explicit consideration when evaluating all public policies. In this article, it is argued that while HIA has the potential to enhance recognition of societal determinants of health and of intersectoral responsibility for health, its pitfalls warrant critical attention. Greater clarity is required regarding criteria for initiating, conducting, and completing HIA, including rules pertaining to decision making, enforcement, compliance, plus paying for their conduct. Critical debate over the promise, process, and pitfalls of HIA needs to be informed by multiple disciplines and perspectives from diverse people and regions of the world.

Defining equity in health.

STUDY OBJECTIVE: To propose a definition of health equity to guide operationalisation and measurement, and to discuss the practical importance of clarity in defining this concept. DESIGN: Conceptual discussion. Setting, Patients/Participants, and Main results: not applicable. CONCLUSIONS: For the purposes of measurement and operationalisation, equity in health is the absence of systematic disparities in health (or in the major social determinants of health) between groups with different levels of underlying social advantage/disadvantage-that is, wealth, power, or prestige. Inequities in health systematically put groups of people who are already socially disadvantaged (for example, by virtue of being poor, female, and/or members of a disenfranchised racial, ethnic, or religious group) at further disadvantage with respect to their health; health is essential to wellbeing and to overcoming other effects of social disadvantage. Equity is an ethical principle; it also is consonant with and closely related to human rights principles. The proposed definition of equity supports operationalisation of the right to the highest attainable standard of health as indicated by the health status of the most socially advantaged group. Assessing health equity requires comparing health and its social determinants between more and less advantaged social groups. These comparisons are essential to assess whether national and international policies are leading toward or away from greater social justice in health.

Understanding and responding to youth substance use: the contribution of a health and human rights framework.

This article examines the utility of a health and human rights framework for conceptualizing and responding to the causes and consequences of substance use among young people. It provides operational definitions of "youth" and "substances," a review of current international and national efforts to address substance use among youths, and an introduction to human rights and the intersection between health and human rights. A methodology for modeling vulnerability in relation to harmful substance use is introduced and contemporary international and national responses are discussed. When governments uphold their obligations to respect, protect, and fulfill human rights, vulnerability to harmful substance use and its consequences can be reduced.

Frameworks matter: ecosocial and health and human rights perspectives on disparities in women's health--the case of tuberculosis.

Frameworks matter. To understand, intervene in, and improve the health of girls and women requires more than just good intentions and an eclectic list of "risk factors" or policy prescriptions, even if dressed up in notions of "gender." In this article, we present two frameworks-ecosocial and health and human rights-that, if considered singly and in combination, we believe could prove useful to furthering work on understanding and addressing societal patterns of health, disease, and well-being. After explicitly summarizing our theoretical stances, we sketch the kinds of questions these frameworks invite us to consider, with reference to a particular case example: women and tuberculosis. By taking on the challenge of articulating and applying our frameworks, separately and in relation to each other, we hope to deepen understanding and generate new ideas that can make a difference for the health of girls and women.

HIV/AIDS and human rights revisited.

In their article, Sofia Gruskin and Daniel Tarantola demonstrate how, as the number of people living with HIV and with AIDS continues to grow in nations with different economies, social structures, and legal systems, HIV/AIDS-related human rights issues are not only becoming more apparent, but also increasingly diverse. In the 1980s, the relationship of HIV/AIDS to human rights was only understood as it involved people with HIV or AIDS and the discrimination to which they were subjected. The concerns included mandatory HIV testing; restrictions on international travel; barriers to employment and housing, access to education, medical care, or health insurance; and the many issues raised by named reporting, partner notification, and confidentiality. Almost 20 years into the epidemic, these issues remain serious and most often have not been resolved. In the 1990s, however, there was increased understanding of the importance of human rights as a factor in determining people's vulnerability to HIV infection and their consequent risk of acquiring HIV infection and their chances of accessing appropriate care and support. And most recently, human rights have also come to be understood to be directly relevant to every element of the risk/vulnerability paradigm. Gruskin and Tarantola identify three situations and three levels of governmental obligations that should be considered when identifying the specific needs and related rights of individuals in the context of HIV/AIDS. They conclude that policymakers, program managers, and service providers must become more comfortable using human rights norms and standards to guide and limit government action in all matters affecting the response to HIV/AIDS; and that those involved in HIV/AIDS advocacy must become more familiar with the practicalities of using international human rights law when they strive to hold governments accountable.

Nitric oxide mediated modulation of norepinephrine transport: identification of a potential target for S-nitrosylation.

1. Carrier mediated uptake (uptake-1) transport of norepinephrine (NE) plays a key role in the regulation of sympathetic neurotransmission. Recent investigations indicate that nitric oxide (NO) may modulate uptake-1 activity, possibly in a cyclic GMP independent manner. 2. Carrier mediated transport of [(3)H-NE] and [(3)H-dopamine, DA] was examined in CHO cells transfected with cDNA for the NE and DA transporters (NET, DAT) respectively. 3. While exposure to the NO donor S-nitroso-N-acetylpenicillamine (100 microM, SNAP) significantly reduced [(3)H-NE] uptake (P<0.001), no effect on [(3)H-DA] transport was apparent. 4. Comparison of the amino acid sequences for NET and DAT identified cysteine residue 351 in NET, which was not present in DAT. Site-directed mutagenesis of Cys 351 to Ser produced a functional NET that was resistant to the inhibitory effects of SNAP. 5. The presence of SNAP mediated nitrosylation of the cysteine residue in an 8-mer model peptide based around Cys 351 in NET was confirmed by both biochemical and mass spectroscopic means. 6. These data indicate the potential regulatory role for NO in modulating sympathetic neurotransmission, and further confirm the importance of non-cyclic GMP dependent mechanisms in mediating the actions of NO.

Reduced myocardial nerve growth factor expression in human and experimental heart failure.

Maintenance of cardiac performance is tightly controlled by the autonomic nervous system. In congestive heart failure (CHF), although the adverse pathophysiological effects of cardiac sympathetic overactivity are increasingly recognized, the paradoxical finding of reduced sympathetic innervation density in the failing heart remains unexplained. Given these observations, we tested the hypothesis that a reduction in the myocardial production of nerve growth factor (NGF), which is important for the maintenance of sympathetic neuronal survival, could explain the conflicting neurochemical and neuroanatomical profile of CHF. In healthy humans (n=11), there was a significantly greater transcardiac venoarterial plasma NGF gradient than in CHF patients (n=11, P<0.05). In a rat model of CHF, a 40% reduction (P<0.05) NGF mRNA expression was apparent in association with a 24% reduction in tissue NGF content (P<0.05). In conjunction, evidence of reduced sympathetic innervation in the failing heart was apparent, as measured histologically by catecholamine fluorescence and by expression of the neuronal NGF receptor trkA. Norepinephrine (10 micromol/L) exposure reduced both NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that myocardial NGF downregulation may represent an adaptive response to sympathetic overactivity. These data indicate that NGF expression in the heart is dynamic and may be altered in cardiovascular disease states. In CHF, reduced NGF expression may account for alterations in sympathetic neuronal function and neuroanatomy. The full text of this article is available at http://www.circresaha.org.

Catechol-O-methyltransferase activity in CHO cells expressing norepinephrine transporter.

1. We examined the existence of catecholamine metabolizing enzymes (catechol-O-methyltransferase, COMT, and monoamine oxidase, MAO) in CHO cells transfected with norepinephrine (NE) transporter (NET) cDNA. 2. NET activity was studied by incubating cells with [3H]-NE (0. 5 microCi ml-1, 20 min) in a Na+ containing medium. Incubation with [3H]-NE lead to [3H] accumulation at 47797+/-4864 d.p.m. per well. Specific inhibitors of NET abolished this uptake. 3. During post-uptake incubation, [3H] leaked rapidly from cells and the extracellular phase comprised 89% of total radioactivity within 40 min. Both [3H] retention and [3H] 'leakage' were largely unaffected by inhibitors for MAO. In contrast, COMT inhibitors, U-0521 and Ro 41-0960, dose-dependently increased intracellular [3H]-NE retention with a maximal increase of 4.5 fold. The EC50 for Ro 41-0960 was 139-times lower than that of U-0521. U-0521 largely inhibited [3H] 'leakage' and doubled the apparent Vmax for [3H]-NE uptake. 4. Addition of U-0521 during uptake incubation increased intracellular NE content by 8 fold. Normetanephrine, the COMT-dependent metabolite of NE, was formed in large quantities during post-uptake incubation. U-0521 significantly inhibited the formation of NMN with an equal preservation of intracellular NE. 5. CHO cells expressing NET possess COMT activity, which is responsible for the metabolism of NE to form lipophilic metabolite normetanephrine. The apparent 'properties' of the NET function expressed in CHO cells changed, after inhibition of COMT, in such a way closer to that described in the native neuronal preparations.