The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms ...observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially expressed in transgenic mice compared with wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders.
It is timely to consider the ethical and social questions raised by progress in pharmacogenomics, based on the current importance of pharmacogenomics for avoidance of predictable side effects of ...drugs, and for correct choice of medications in certain cancers. It has been proposed that the entire population be genotyped for drug-metabolizing enzyme polymorphisms, as a measure that would prevent many untoward and dangerous drug reactions. Pharmacologic treatment targeting based on genomics of disease can be expected to increase greatly in the coming years. Policy and ethical issues exist on consent for large-scale genomic pharmacogenomic data collection, public vs corporate ownership of genomic research results, testing efficacy and safety of drugs used for rare genomic indications, and accessibility of treatments based on costly research that is applicable to relatively few patients. In major psychiatric disorders and intellectual deficiency, rare and de novo deletion or duplication of chromosomal segments (copy number variation), in the aggregate, are common causes of increased risk. This implies that the policy problems of pharmacogenomics will be particularly important for the psychiatric disorders.
In the 1990's there were concerns that methotrexate might increase the risk of post operative complications following elective orthopaedic surgery; as a result many Units initiated policies to ...discontinue methotrexate prior to elective orthopaedic surgery. In 2001 we carried out a controlled study of complications after elective surgery in rheumatoid arthritis (RA) patients who either continued or discontinued methotrexate prior to surgery. In this study we showed that continuation of methotrexate therapy prior to orthopaedic surgery did not increase the risk of infection or surgical complication occurring in patients with RA within one year of surgery. The limitation of this study was that complications later than one year were not studied. Sixty-five patients have been followed up. Thirty-one were fully assessed in clinic and 34 underwent a structured telephone interview. There were no incidences of deep bone infection in any patient group so that there is no evidence that continued methotrexate therapy in the perioperative period increases the risk of late deep infections. We adhere to our original advice that in the absence of renal failure or sepsis, methotrexate therapy should not be stopped before elective orthopaedic surgery in patients with RA whose disease is controlled by the drug before surgery.
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