Partner notification in the context of HIV: an interest-analysis.

Codes of confidentiality play an essential role in the intimate discourses in many learned professions. Codes with various prescriptions exist. The Hippocratic Oath for example, prescribes rewards to the secret keeper, for keeping secret what ought to be kept secret, and punishments for failing. In public health practice, partner notification, arguably is one endeavor that tests the durability of this secret keeping doctrine of the health professional. We present an interest-analysis of partner notification in the context of HIV service rendition. Using principles-based analysis, the interests of the individual, the state/public health, and the bioethicist's are discussed. The public health interests in partner notification, which are usually backed by state statutes and evidence, are premised on the theory that partners are entitled to knowledge. This theory posits that knowledge empowers individuals to avoid continuing risks; knowledge of infection allows for early treatment; and that knowledgeable partners can adapt their behavior to prevent further transmission of infection to others. However, persons infected with HIV often have counter interests. For instance, an infected person may desire to maintain the privacy of their health status from unnecessary disclosure because of the negative impacts of disclosure, or because notification without a matching access to HIV prevention and treatment services is detrimental. The interest of the bioethicist in this matter is to facilitate a resolution of these conflicted interests. Our analysis concludes that governmental interests are not absolute in comparison with the interests of the individual. We reiterate that any effort to morally balance the benefits of partner notification with its burdens ought to first recognize the multivalent nature of the interests at play.

Protective effects of NIM811 in transient focal cerebral ischemia suggest involvement of the mitochondrial permeability transition.

Cerebral ischemia followed by reperfusion activates numerous pathways that lead to cell death. One such pathway involves the release of large quantities of the excitatory amino acid glutamate into the synapse and activation of N-methyl-D-aspartate receptors. This causes an increase in mitochondrial calcium levels ([Ca(2+)](m)) and a production of reactive oxygen species (ROS), both of which may induce the mitochondrial permeability transition (MPT). As a consequence, there is eventual mitochondrial failure culminating in either apoptotic or necrotic cell death. Thus, agents that inhibit MPT might prove useful as therapeutic interventions in cerebral ischemia. In this study, we have investigated the neuroprotective efficacy of the novel compound NIM811. Similar in structure of its parent compound cyclosporin A, NIM811 is a potent inhibitor of the MPT. Unlike cyclosporin A, however, it is essentially void of immunosuppressive actions, allowing the role of MPT to be clarified in ischemia/reperfusion injury. The results of these studies demonstrate that NIM811 provides almost 40% protection in a model of transient focal cerebral ischemia. This was associated with a nearly 10% reduction in mitochondrial reactive species formation and 34% and 38% reduction of cytochrome c release in core and penumbra, respectively. Treatment with NIM811 also increased calcium retention capacity by approximately 20%. Interestingly, NIM811 failed to improve ischemia-induced impairment of bioenergetics. The neuroprotective effects of NIM811 were not due to drug-induced alterations in cerebral perfusion after ischemia. Activation of MPT appears to be an important process in ischemia/reperfusion injury and may be a therapeutic target.

Market incentives, human lives, and AIDS vaccines.

For many, an AIDS vaccine holds the promise of intervening in a widespread epidemic because it is not predicated on changing economic structures and social contexts underlying vulnerability to HIV for millions of individuals. Yet 20 years into the AIDS epidemic, there is still no vaccine. Based on interviews of AIDS vaccine researchers, watchdog organizations, and ethics groups from the United States, South Africa, and Kenya conducted between August and December of 2003, this paper explores possible answers to the question of why there is no vaccine, looking in particular at contradictions between a biomedical research industry increasingly driven by market incentives and a disease that primarily affects individuals living in low-income countries with little vaccine purchasing power. Producing a vaccine that could be effective in low-income regions requires new kinds of initiatives that can coordinate research nationally and globally, and circumvent current regulatory mechanisms that dictate against the development and dissemination of low-profit medical technologies. Until such initiatives are supported, however, vaccine research will continue at a devastatingly slow pace at the cost of millions of lives annually.

Precarious connections: making therapeutic production happen for malaria and tuberculosis.

The One Health Movement has been a primary advocate for collaboration across disciplinary and organizational sectors in the study of infectious diseases. There is potentially much to be gained by incorporating the interrelations of animal and human ecosystems, as well as the expertise of veterinary, medical, and public health practitioners. Too often, however, the idea rather than the realities of collaboration become valorized within One Health approaches. Paying little to no attention to the motivations, ontologies, and politics of collaborative arrangements, however, is a critical mistake, one that diminishes considerably One Health framework explanatory powers. Using Anna Tsing's framework of friction, in this paper I take the examples of malaria and tuberculosis pharmaceuticals collaborations, often called Product Development Partnerships, to argue for the need to attend to the conditions under which collaborations across divergent disciplines, geographies, organizations, and institutions might work productively and when they do not.

Glutamate receptor antagonists modulate heat shock protein response in focal brain ischemia.

Neurons and glia reacting to ischemic injury exhibit delayed expression of heat shock proteins (HSPs). We tested the hypothesis that glutamate receptor antagonists alter neuronal and glial activation during focal cerebral ischemia, as shown by spatio-temporal changes in HSP immunoreactivity. Rats underwent focal ischemia by permanent occlusion of the middle cerebral artery. All animals were pre-treated with NBQX (30 mg kg-1), a competitive antagonist of the AMPA/kainate receptor, or CGS-19755 (10 mg kg-1), a competitive NMDA receptor antagonist, and euthanatized after 6 or 24 h of ischemia to demonstrate regional immunoreactivity of HSP-72 or 32 in brain. Neurons immunolabeled for HSP-72 appeared in the penumbral region adjacent to the infarct at 24 h and increased in number and distribution after pretreatment with NBQX or CGS-19755. Immunolabeling for HSP-32 revealed that pre-treatment with CGS-19755 caused ramified glia to infiltrate the ischemic cortex at 6 h, a pattern that was not seen in ischemic controls until 24 h. Blockade of the NMDA or AMPA/kainate receptor modulates cellular stress responses in both neurons and glia within the developing infarct. We conclude that early, rather than delayed, expression of HSP-32 is a sensitive indicator of glial activation induced specifically by CGS-19755.

Calpain cleaves methionine aminopeptidase-2 in a rat model of ischemia/reperfusion.

Ischemic stroke results in multiple injurious signals within a cell including dysregulation of calcium homeostasis. Consequently, there is an increase in the enzymatic activity of the calpains, calcium dependent proteases that are thought to contribute to neuronal injury. In addition, cellular stress due to ischemia/reperfusion also triggers a decrease in protein translation through activation of the unfolded protein response (UPR). In the present study we found that methionine aminopeptidase 2 (MetAP2), a critical component of the translation initiation complex, is a calpain substrate. In vitro calpain assays demonstrated that while MetAP2 has autoproteolytic activity, calpain also produces a stable proteolytic fragment at 50kDa using recombinant MetAP2. This 50kDa fragment, in addition to a 57kDa fragment was present in in vitro digestions of rat brain homogenates. Production of these fragments was inhibited by calpastatin, the endogenous and specific inhibitor of calpain. Using an in vivo middle cerebral artery occlusion (MCAO) model only the 57kDa fragment of MetAP2 was observed. These data suggest that calpain activation in stroke may regulate MetAP2-mediated protein translation giving calpains a larger role in the cellular stress response than previously determined.

Drug partnerships and global practices.

Tuberculosis poses one of the biggest threats to individuals living with HIV in most low-income regions of the world, and the increase of multi-drug resistant tuberculosis (MDR-TB) in South Africa, Eastern Europe, and elsewhere makes this threat that much more critical. Despite the extent of the problem, new drugs for tuberculosis have not been developed for over four decades, largely because tuberculosis occurs primarily among the poor in low-income regions and the market for tuberculosis drugs is not lucrative enough to warrant time and resource commitments by pharmaceutical companies. In the wake of sustained global criticism of pharmaceutical-state practices, however, new partnerships for drug development (PDPs) are forming to address critical shortages of drugs for diseases like tuberculosis that have been termed 'neglected' precisely because they have not seen new treatments for so long. This paper examines some of these partnerships, tracing some of the dynamic developments as well as challenges in forging alternative pathways to new drug and vaccine production.

The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia.

Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable 'upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia-reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.