Use of OKT3 with ciclosporin and steroids for reversal of acute kidney and liver allograft rejection

OKT3 monoclonal antibody therapy was added to preexisting baseline immunosuppressive treatment with ciclosporin and steroids to treat rejection in 52 recipients of cadaveric livers and 10 recipients of cadaveric kidneys. Rejection was controlled in 75% of patients treated, often after high-dose steroid therapy had failed. Rejection recurred during the 17-month follow-up period, after completion of OKT3, in only 25% of the patients who had responded. The safety and effectiveness of this monoclonal therapy, added to ciclosporin and steroids, has been established in this study

The Role of the Neurokinin-1 Receptor in Behaviour and Cognition: an interaction with the Brain Renin Angiotensin System and its implications for Attention Deficit Hyperactivity Disorder

Mice lacking functional neurokinin-1 receptors (NK1R-/-) display several behavioural abnormalities that resemble Attention Deficit Hyperactivity Disorder (ADHD), including locomotor hyperactivity (which is alleviated by ADHD medication), impulsivity and inattentiveness. These findings prompted the proposal that NK1R-/- mice offer a novel murine model of ADHD. The first aim of this thesis was to investigate the influence of non-genetic (epigenetic/environmental) factors on the behaviour of NK1R-/- mice by comparing animals from two different breeding protocols. These studies revealed that certain elements of their impulsivity are influenced by non-genetic factors, but other behaviours are not. The second aim was to compare the behaviour of male and female animals, to determine whether there are sex differences in their behaviour. This study revealed that the hyperactivity of NK1R-/- mice is not evident in females, echoing typical sex differences in ADHD patients. Following this, the behavioural effects of several drugs that target the brain renin angiotensin system (BRAS) are reported. This was prompted by preliminary evidence that the BRAS and NK1R interact in the regulation of locomotor activity. The angiotensin converting enzyme (ACE) inhibitor, captopril, abolished the hyperactivity and impulsivity of (male) NK1R-/- mice, suggesting that ACE could provide a novel therapeutic target for the treatment of ADHD. By contrast, angiotensin receptor antagonism either exacerbated or had no effect on these behaviours, suggesting that captopril's therapeutic effect is not due to a reduction in angiotensin II. Finally, the performance of NK1R-/- mice in the 5-Choice Continuous Performance Test was investigated. NK1R-/- mice displayed performance deficits only during certain phases of training, suggesting that detection of the impulsive or inattentive phenotype might require unpredictable test parameters. Overall, these studies further validate/phenotype the NK1R-/- mouse model of ADHD, and point to an interaction between the BRAS and NK1R in the regulation of ADHD-related behaviours, which warrants further investigation

Perseveration by NK1R-/- ('knockout') mice is blunted by doses of methylphenidate that affect neither other aspects of their cognitive performance nor the behaviour of wild-type mice in the 5-Choice Continuous Performance Test

The underlying cause(s) of abnormalities expressed by patients with attention deficit hyperactivity disorder (ADHD) have yet to be delineated. One factor that has been associated with increased vulnerability to ADHD is polymorphism(s) ofTACR1, which is the human equivalent of the rodent NK1 (substance P-preferring) receptor gene (Nk1r). We have reported previously that genetically altered mice, lacking functional NK1R (NK1R-/-), express locomotor hyperactivity, which was blunted by the first-line treatment for ADHD, methylphenidate. Here, we compared the effects of this psychostimulant (3, 10 and 30 mg/kg, intraperitoneally) on the behaviour of NK1R-/- mice and their wild types in the 5-Choice Continuous Performance Test, which emulates procedures used to study attention and response control in ADHD patients. Methylphenidate increased total trials (a measure of 'productivity') completed by wild types, but not by NK1R-/- mice. Conversely, this drug reduced perseveration by NK1R-/- mice, but not by wild types. Other drug-induced changes in key behaviours were not genotype dependent, especially at the highest dose: for example, % omissions (an index of inattentiveness) was increased, whereas % false alarms and % premature responses (measures of impulsivity) declined in both genotypes, indicating reduced overall response. These findings are discussed in the context of the efficacy of methylphenidate in the treatment of ADHD. Moreover, they lead to several testable proposals. First, methylphenidate does not improve attention in a subgroup of ADHD patients with a functional deficit of TACR1. Second, these patients do not express excessive false alarms when compared with other groups of subjects, but they do express excessive perseveration, which would be ameliorated by methylphenidate

Evidence for hyperacute rejection of human liver grafts: The case of the canary kidneys

Sequential liver and kidney transplantation from the same donor was performed in 2 patients. The kidney in Patient 1, which was transplanted after the liver, was hyperacutely rejected and removed 6 hours later. The first liver as well as another liver transplanted 3 days later developed widespread hemorrhagic necrosis. Although the cytotoxic crossmatch of preoperative recipient serum with both donors was negative, patchy widespread IgM and C(1q) deposits were found in all 3 organs. In Patient 2, who had a strongly positive cytotoxic crossmatch with his donor, the liver suffered a massive but reversible injury, while the kidney never functioned. Both patients developed a coagulopathy a few minutes after liver revascularization. The kidneys in these cases had served like the canaries which miners once used to detect a hostile environment and their presence made more understandable how an indolent version of hyperacute rejection of the liver can take place

Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor 'knockout' mice.

Mice with functional ablation of the neurokinin-1 receptor gene (NK1R(-/-)) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT)

Invited Review: IPCC, Agriculture and Food - A Case of Shifting Cultivation and History.

Since 1990 the Intergovernmental Panel on Climate Change (IPCC) has produced five Assessment Reports (ARs), in which agriculture as the production of food for humans via crops and livestock have featured in one form or another. A constructed data base of the ca. 2,100 cited experiments and simulations in the five ARs were analysed with respect to impacts on yields via crop type, region and whether or not adaptation was included. Quantitative data on impacts and adaptation in livestock farming have been extremely scarce in the ARs. The main conclusions from impact and adaptation are that crop yields will decline but that responses have large statistical variation. Mitigation assessments in the ARs have used both bottom-up and top-down methods but need better to link emissions and their mitigation with food production and security. Relevant policy options have become broader in later ARs and included more of the social and non-production aspects of food security. Our overall conclusion is that agriculture and food security, which are two of the most central, critical and imminent issues in climate change, have been dealt with in an unfocussed and inconsistent manner between the IPCC five ARs. This is partly a result of agriculture spanning two IPCC working groups but also the very strong focus on projections from computer crop simulation modelling. For the future, we suggest a need to examine interactions between themes such as crop resource use efficiencies and to include all production and non-production aspects of food security in future roles for integrated assessment models

Enhancement of 5-aminolaevulinic acid-induced photodynamic therapy in normal rat colon using hydroxypyridinone iron-chelating agents.

© Cancer Research Campaign 1998Full text is available as a scanned copy of the original print version.Currently, the clinical use of 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PPIX) for photodynamic therapy (PDT) is limited by the maximum tolerated oral ALA dose (60 mg kg(-1)). This study investigates whether hydroxypyridinone iron-chelating agents can be used to enhance the tissue levels of PPIX, without increasing the administered dose of ALA. Quantitative charge-coupled device (CCD) fluorescence microscopy was employed to study PPIX fluorescence pharmacokinetics in the colon of normal Wistar rats. The iron chelator, CP94, when administered with ALA was found to produce double the PPIX fluorescence in the colonic mucosa, compared with the same dose of ALA given alone and to be more effective than the other iron chelator studied, CP20. Microspectrofluorimetric studies demonstrated that PPIX was the predominant porphyrin species present. PDT studies conducted on the colonic mucosa showed that the simultaneous administration of 100 mg kg(-1) CP94 i.v. and 50 mg kg(-1) ALA i.v. produced an area of necrosis three times larger than similar parameters without the iron-chelating agent with the same light dose. It is possible, therefore, to increase the amount of necrosis produced by ALA-induced PDT substantially, without increasing the administered dose of ALA, through the simultaneous administration of the iron-chelating agent, CP94.Engineering and Physical Sciences Research Council.DUSA Pharmaceutical