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This article explores the nature and extent of barriers to access to justice that older persons experience, including those with mental health conditions. It finds that access to justice-the right to fair, prompt and responsive decisions by administrative decision-makers and equal access to courts and tribunals to obtain timely and effective remedies-is not only an important right in itself but also enables the enjoyment of many other human rights. Yet older persons, particularly those with mental health conditions, face a significant "justice gap." Ageist attitudes, laws and practices interact with other forms of bias such as mentalism, sexism, ableism, racism, homophobia, and heterosexism exacerbating older persons' disadvantage and marginalization, particularly those with mental health conditions, and older indigenous persons. These discriminatory practices, together with the phenomena of elder abuse, all severely limit older persons' access to timely and responsive justice. International and national standards, both general and specific to older persons, have been shown to be inadequate to respond to this justice gap. An international standard in the form of a binding legal obligation that specifically addresses older persons' rights of access to justice is needed urgently as part of a new international treaty on the human rights of older persons. [ABSTRACT FROM AUTHOR]

Innate immune responses are a major barrier to safe systemic gene therapy with adenovirus (Ad) vectors. We show that intravenous (IV) injection of rats with Ad5 vectors causes a novel rapid shock reaction that involves hypotension, hemoconcentration, tissue edema, and vasocongestion, with notable pathology in the pancreas and the gastrointestinal system. We show for the first time that this reaction is dependent on platelet-activating factor (PAF), a lipid signaling molecule that is a known shock inducer. Ad upregulated PAF within 5 minutes in vivo, and antagonists of the PAF receptor were able to prevent Ad-induced shock. Ad upregulated PAF via the reticuloendothelial system (RES), because splenectomy or depletion of phagocytes blocked the ability of Ad to induce both PAF and shock. Rats were considerably more sensitive to Ad-induced shock than were mice, but PAF mediated shock in both species. Other Ad-induced innate immune responses such as cytokine induction and thrombocytopenia were not mediated by PAF. In summary, systemic IV injection of Ad stimulates the RES to upregulate PAF within a matter of minutes, which results in shock. The identification of this novel pathway suggests strategies to improve the safety of systemic gene therapy with Ad vectors. [ABSTRACT FROM AUTHOR]

When adenovirus vectors are injected intravenously, they are quickly taken up by Kupffer cells in the liver. We report that this causes rapid necrosis of Kupffer cells in mice at doses of 1011 particles/kg or higher. By 10 min after intravenous vector injection, Kupffer cells were permeable to propidium iodide and trypan blue. This coincided with a sharp rise in serum lactate dehydrogenase. Ultrastructural examination showed degeneration of Kupffer cells, including complete disappearance of chromatin by 1 h. After an initial intravenous injection of vector, dead Kupffer cells were unable to take up a second dose of vector, and hepatic transgene expression from the second dose was augmented. Death of Kupffer cells did not affect serum levels of IL-6 or IL-12. There was no immediate change in the number of Kupffer cells in the liver, but a significant decline was found by 4 h after injection of vector. Interestingly, substantial numbers of vector-containing Kupffer cells were found in pulmonary capillaries, indicating that they had been swept out of the liver. Together these results show that an intravenous injection of adenovirus vector causes synchronous and surprisingly rapid Kupffer cell death.Molecular Therapy (2006) 13, 108–117; doi: 10.1016/j.ymthe.2005.08.007 [ABSTRACT FROM AUTHOR]

After an intravascular injection, adenoviral vectors are normally taken up by the reticuloendothelial system in the liver, where they rapidly trigger an innate response. However, we have previously found that the biodistribution of adenoviral vectors is altered in cirrhotic rats due to the presence of pulmonary intravascular macrophages, which cause a shift in vector uptake from the liver to the lungs. We now report that this is correlated with fatal pulmonary hemorrhagic edema in cirrhotic rats. In addition, cirrhotic rats reacted to vector with enormous increases in TNF-α and IL-6 and markedly prolonged coagulation times. Although we also saw fatal reactions to high doses of adenoviral vectors in normal rats, the time course and symptoms were very different, and pulmonary hemorrhagic edema was seen only in cirrhotic rats. Because abnormal pulmonary reticuloendothelial uptake is known to occur in humans during cirrhosis and other diseases, there is the potential that intravascular administration of adenoviral vectors might cause lung pathology in such patients. [Copyright &y& Elsevier]

When adenoviral vectors are administered systemically, they are quickly taken up by phagocytes of the reticuloendothelial system, including Kupffer cells (KCs) in the liver. We have recently shown in mice that E1/E3-deleted Ad5 vectors cause rapid KC death, followed by a slower depletion of KCs from the liver (Mol. Ther. 13:108-117, 2006). KCs lost membrane integrity within 10 min after i.v. injection of Ad5 vectors, and this eventually resulted in significant depletion of KCs from the liver. In the current study, we investigated which features of the adenoviral fiber contribute to KC toxicity by administering Ad5 vectors with the fiber partially or completely replaced by the type 35 fiber. When compared to the type 5 fiber, the type 35 fiber does not bind to CAR, has a much shorter shaft, and lacks a putative heparin-binding domain (KKTK) in the shaft. We also directly examined the role of the KKTK domain in the Ad5 shaft. All vectors were provided by Cell Genesys, Inc. and were described in Hum. Gene Ther. 14:777-787, 2003.C57Bl/6 mice were injected i.v. with vectors and F4/80+ KCs in the liver were counted at 18 h. An Ad5 vector dose of 1011 vp/kg depleted KCs by approximately 80%. KCs were depleted to a similar extent when the type 5 fiber head was replaced with the type 35 fiber head (5S35H), indicating that the type 5 and type 35 fiber heads were interchangeable and that CAR binding was not essential. However, when the type 5 shaft was replaced with the type 35 shaft, no KC depletion was seen, regardless of whether the fiber was completely replaced (35F) or only the shaft was replaced (35S5H). In addition, KC depletion was also absent with an Ad5 vector that had the shaft KKTK sequence replaced with GAGA (S*). This indicated that the shaft length did not determine toxicity, but rather that the putative heparin-binding domain was involved. Of note, all of the vectors were capable of producing KC depletion to some degree when injected at higher doses (1012 vp/kg), indicating that none of the alterations provided absolute protection against KC toxicity.In summary, we found that the type 5 fiber shaft made a major contribution to KC toxicity. Vectors that lacked the KKTK motif or contained the type 35 fiber shaft were impaired in their ability to deplete KCs. There was no obvious contribution from the type 5 fiber head, and CAR binding played no apparent role in KC toxicity. This information is likely to prove valuable in developing less toxic adenoviral vectors for systemic administration.Molecular Therapy (2006) 13, S145–S145; doi: 10.1016/j.ymthe.2006.08.441 [ABSTRACT FROM AUTHOR]

An abstract of the article "In Vivo Studies on the Toxicity of Adenovirus Vectors for Kupffer Cells," by Elanchezhiyan Manickan, Jeffrey S. Smith, Jie Tian, and Andrew P. Byrnes is presented.