Orally Active Multi-Functional Antioxidants Delay Cataract Formation in Streptozotocin (Type 1) Diabetic and Gamma-Irradiated Rats

Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation.Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed

Document Destruction and Civil Litigation in Victoria

This review was commissioned by the Victorian Attorney-General,The Hon Rob Hulls MP, following the recent case of McCabe in the Supreme Court of Victoria. Mrs McCabe suffered from lung cancer which she attributed to the smoking over many years of cigarettes produced by British American Tobacco Australia Services Limited (BAT). She sued BAT for personal injuries caused by its alleged negligence, and claimed damages.At the trial, the trial judge struck out BAT’s defence, thus awarding the case to Mrs McCabe. He did so on the basis that BAT had failed to comply with a series of discovery orders he had earlier made, requiring the company to produce various documents relevant to Mrs McCabe’s case.BAT was unable to produce many of these documents because over a period of years they had been destroyed pursuant to a number of document retention policies devised by the Company. BAT appealed to the Court of Appeal against the decision of the trial judge to strike out its defence. The Court allowed the appeal and in doing so made new law for Victoria on the key issue of principle which had arisen, of what the position should be when documents relevant to litigation have been destroyed in advance of the formal commencement of legal proceedings. On this question the Court of Appeal said that the document destruction in McCabe was not unlawful because it took place before the commencement of litigation.The Court also said that decisions of the type made by the trial judge in McCabe to strike out a defence would only be justified in future cases if the precommencement destruction amounted to an attempt to pervert the course of justice or, if open, contempt of court.The broad policy conclusion reached by this review is that the exercise of a trial judge’s discretion in civil litigation to rule on the consequences of failure by parties to comply with discovery rules should not be limited to circumstances in which formal legal proceedings have been commenced. It should extend to certain pre-commencement situations.The main reasons for this general conclusion are to ensure fairness in civil litigation; to enable the courts to decide cases on the basis of as much relevant evidence and information as possible; and to preserve and enhance the overall integrity and reputation of the civil justice process and therefore the justice system as a whole. Destruction of relevant documents is a serious matter and can adversely affect individual parties to litigation as well as damage community confidence in the system of justice itself. This can be so whether the destruction occurs after or before the commencement of litigation.To deal with this important issue, a three-pronged approach is proposed in this report. First, there should be a new statutory provision applicable to civil proceedings in all the Victorian courts, giving judicial officers very similar discretionary powers in dealing with pre-commencement document destruction as those available if destruction occurs after proceedings have been formally commenced. The second proposal is that Victoria should have a new statutory criminal offence dealing with the destruction of documentary material which is relevant to a judicial proceeding. This statute would deal with the worst and most blatant instances of the destruction of material relevant to civil litigation and would cover highly negligent destructions as well as intentional ones. It should cover cases of pre-commencement destruction as well as those post-commencement of proceedings.The third key proposal is that there should be a new professional conduct regulation, as there now is in New South Wales, to apply where advice is given by lawyers to clients about document retention and destruction and also to situations where lawyers themselves are in possession or control of material which is relevant to actual or reasonably anticipated litigation. This regulation would be aimed at guiding the day-to-day operations of legal practitioners in this area, both solicitors and barristers, as distinct from dealing with a particular case before a court or an actual allegation of destruction so serious that it could give rise to possible criminal liability.The particular Recommendations are set out in the next section of the report.They are expressed in reasonably broad, general terms. This is because the main thrust of this review has been to identify the key public and legal policy issues which arise in this area and to suggest what the appropriate responses might be.The drafting of any specific statutory and regulatory provisions should be left to the relevant experts, depending upon decisions that the Attorney-General and the Government as a whole may make in relation to the Recommendations

Document Destruction and Civil Litigation in Victoria

This review was commissioned by the Victorian Attorney-General,The Hon Rob Hulls MP, following the recent case of McCabe in the Supreme Court of Victoria. Mrs McCabe suffered from lung cancer which she attributed to the smoking over many years of cigarettes produced by British American Tobacco Australia Services Limited (BAT). She sued BAT for personal injuries caused by its alleged negligence, and claimed damages.At the trial, the trial judge struck out BAT’s defence, thus awarding the case to Mrs McCabe. He did so on the basis that BAT had failed to comply with a series of discovery orders he had earlier made, requiring the company to produce various documents relevant to Mrs McCabe’s case.BAT was unable to produce many of these documents because over a period of years they had been destroyed pursuant to a number of document retention policies devised by the Company. BAT appealed to the Court of Appeal against the decision of the trial judge to strike out its defence. The Court allowed the appeal and in doing so made new law for Victoria on the key issue of principle which had arisen, of what the position should be when documents relevant to litigation have been destroyed in advance of the formal commencement of legal proceedings. On this question the Court of Appeal said that the document destruction in McCabe was not unlawful because it took place before the commencement of litigation.The Court also said that decisions of the type made by the trial judge in McCabe to strike out a defence would only be justified in future cases if the precommencement destruction amounted to an attempt to pervert the course of justice or, if open, contempt of court.The broad policy conclusion reached by this review is that the exercise of a trial judge’s discretion in civil litigation to rule on the consequences of failure by parties to comply with discovery rules should not be limited to circumstances in which formal legal proceedings have been commenced. It should extend to certain pre-commencement situations.The main reasons for this general conclusion are to ensure fairness in civil litigation; to enable the courts to decide cases on the basis of as much relevant evidence and information as possible; and to preserve and enhance the overall integrity and reputation of the civil justice process and therefore the justice system as a whole. Destruction of relevant documents is a serious matter and can adversely affect individual parties to litigation as well as damage community confidence in the system of justice itself. This can be so whether the destruction occurs after or before the commencement of litigation.To deal with this important issue, a three-pronged approach is proposed in this report. First, there should be a new statutory provision applicable to civil proceedings in all the Victorian courts, giving judicial officers very similar discretionary powers in dealing with pre-commencement document destruction as those available if destruction occurs after proceedings have been formally commenced. The second proposal is that Victoria should have a new statutory criminal offence dealing with the destruction of documentary material which is relevant to a judicial proceeding. This statute would deal with the worst and most blatant instances of the destruction of material relevant to civil litigation and would cover highly negligent destructions as well as intentional ones. It should cover cases of pre-commencement destruction as well as those post-commencement of proceedings.The third key proposal is that there should be a new professional conduct regulation, as there now is in New South Wales, to apply where advice is given by lawyers to clients about document retention and destruction and also to situations where lawyers themselves are in possession or control of material which is relevant to actual or reasonably anticipated litigation. This regulation would be aimed at guiding the day-to-day operations of legal practitioners in this area, both solicitors and barristers, as distinct from dealing with a particular case before a court or an actual allegation of destruction so serious that it could give rise to possible criminal liability.The particular Recommendations are set out in the next section of the report.They are expressed in reasonably broad, general terms. This is because the main thrust of this review has been to identify the key public and legal policy issues which arise in this area and to suggest what the appropriate responses might be.The drafting of any specific statutory and regulatory provisions should be left to the relevant experts, depending upon decisions that the Attorney-General and the Government as a whole may make in relation to the Recommendations