C ytotoxic T lymphocyte (CTL)-induced death triggered by the granule exocytosis pathway involves the perforin-dependent delivery of granzymes to the target cell. Gene targeting has shown that perforin is essential for this process; however, CTL defi cient in the key granzymes A and B maintain the ability to kill their targets by granule exocytosis. It is not clear how granzyme AB −/− CTLs kill their targets, although it has been proposed that this occurs through perforin-induced lysis. We found that purifi ed granzyme B or CTLs from wild-type mice induced classic apoptotic cell death. Perforin-induced lysis was far more rapid and involved the formation of large plasma membrane protrusions. Cell death induced by granzyme AB −/− CTLs shared similar kinetics and morphological characteristics to apoptosis but followed a distinct series of molecular events. Therefore, CTLs from granzyme AB −/− mice induce target cell death by a unique mechanism that is distinct from both perforin lysis and apoptosis.
Abstract-Clinical studies suggest that T-type Ca 2ϩ channel blockade may have incremental benefits over conventional L-channel blockade, particularly in microvascular disorders. This study examined functional vasomotor differences in L-and T-channel blockade between large and small vessels and compared the abundance of the L-and T-type channels in these vessels. The inhibition of endothelin-1 and potassium-induced vascular contractile responses by L-channel blockers (verapamil and nifedipine) was compared with combined L-and T-channel blockers (mibefradil and efonidipine) in large (rat aorta) and small (rat mesenteric and human subcutaneous) vessels using wire myography. All 4 of the Ca 2ϩ channel blockers inhibited contractile responses to a similar extent in large rat vessels; however, in rat microvessels, the combined L-and T-channel blockers produced significantly greater inhibition of contraction than L-channel blockers alone. The significance of this differential T-channel effect in microvessels was further supported by the following: (1) a greater abundance of T-channels compared with L-channels in microvessels but not in large vessels; (2) demonstration of divergent Ca 2ϩ channel blocker responses in human microvessels; (3) incremental inhibition of constrictor responses with combined L-and T-Ca 2ϩ channel blockers despite maximal L-channel blockade; (4) the use of structurally diverse Ca 2ϩ channel blockers with varied affinity for L-and T-channels; (5) the use of pharmacodynamically and therapeutically appropriate Ca 2ϩ channel blocker concentrations; (6) confirmation of contractile agonist independent responses; and (7) exclusion of an endothelium-dependent mechanism. We propose that T-type channels play an important role in regulating contractile responses in the microvasculature and, therefore, are a potential therapeutic target.
Millions of southern African livelihoods continue to depend on the successful management and sustainable use of the commons - land and natural resources that are supposedly or actually managed, with varying degrees of success, as common property. This, above all, is the challenge to governance. The poor must tackle it - and governments and development agencies must support their endeavours - in the triple context of knowledge, political economy and power. This paper highlights the major factors and trends in these three areas that we must understand if we are to optimise support for the governance of the commons in southern Africa. If more commons around the region are studied from the same analytical perspectives, it will be easier to share experience and lessons in ways that can usefully inform development and conservation policy and programmes. This is what the Cross-Sectoral Commons Governance in Southern Africa project, reported in this special issue, has tried to do.Southern Africa, commons, governance, knowledge, political economy, power,
The response of human rights to environmental degradation 17 2.3.1 The right to life 18 2.3.2 The right to health 19 2.3.3 The right to water 20 2.3.4 The right to food 21 2.3.5 The right to housing or shelter 21 2.3 .6 The right to property 22 Xl Xlll XVl 1 6 vm Contents 2.4 The development of environmental rights internationally 22 2.4.1 Procedural environmental rights 24 2.4.2 Substantive environmental rights 25 2.4.3 Developments within the United Nations 28 2.5 Conclusion 29 3 Global environmental governance, the global legal architecture and the root causes of environmental degradation 31
This article applies ‘macro’ legal analysis to the challenge of legal reform related to corporate responsibility for human rights violations and degradation of the environment. It recognises that the approaches from different communities of lawyers to the negative impacts on human rights and the environment caused by companies, sometimes operate in isolation from each other, are not always mutually supportive, can lead to a fragmentation of effort, and may not address the root causes of the problem. In particular, this article analyses the extent to which existing approaches tend to address symptoms of the issues, rather than the root causes themselves. It makes the case that in this regard specific root causes exist within the frameworks of corporate law in all jurisdictions and various aspects of international economic law too. To carry out the study, it employs macro legal analysis, a methodology not previously applied in this field, as a means of developing an understanding of the legal frameworks that, it argues, influence corporate decision making that can affect human rights and the environment. It undertakes an analysis that incorporates relevant corporate law, World Trade Organisation (WTO) law, international investment law, the law relating to multilateral development banks (MDBs), and international insurance law. By using this form of anlaysis it is possible to show how legal frameworks can operate in unison, reinforcing each other providing a cumulative effect that can influence corporate decision makers. Finally, based on the results of the analysis, it suggests a possible strategy of macro-level reforms that could be applied to the re-design of relevant legal frameworks to better facilitate the full protection of human rights and to achieve net zero degradation of the environment. As a result it seeks to demonstrate how this approach can be strategically applied by both human rights and environmental lawyers as a common pathway towards effective legal reform.
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