Davis, Paul Andrew

Abstract Antimitochondrial antibodies (AMA) recognizing the acetyltransferase (E2) of the pyruvate dehydrogenase (PDH) complex have been previously well-documented and the immunodominant epitope mapped. In this study, we demonstrate that sera from patients with primary biliary cirrhosis (PBC) react with another lipoic acid containing acyltransferase enzyme, namely the E2 of the branched chain alpha-ketoacid dehydrogenase (BCKD) complex. Indeed, 85/120 (71%) sera from patients with PBC reacted with BCKD-E2 by immunoblotting against purified BCKD complex. In contrast, sera from patients with chronic active hepatitis or progressive sclerosing cholangitis as well as sera from healthy volunteers did not react with any component enzymes of the BCKD complex. More importantly, BCKD enzyme activity was inhibited after incubation of the BCKD complex with either PBC sera against BCKD-E2 or with affinity purified antisera to BCKD-E2. Enzyme activity was unaltered by control sera or with PBC sera that reacted with PDH-E2 but not BCKD-E2. Furthermore, immunoblots of purified mitochondria probed with PBC sera absorbed with BCKD-E2 demonstrated that BCKD-E2 and PDH-E2 are each recognized by distinct AMA populations which do not cross-react. In addition, affinity purified PBC sera against BCKD-E2 did not react with PDH-E2 nor inhibit PDH enzyme activity, thus providing further evidence that BCKD-E2 and PDH-E2 are recognized by separate AMA. These data further suggest that the BCKD-E2 epitope recognized by AMA contains, or is close to, a functional domain of this enzyme. The availability of cDNA clones encoding BCKD-E2 and PDH-E2 will allow the study of how key metabolic enzymes may be involved in the immunology and pathology of PBC.

Objective To analyse the trends in opportunistic PSA screening in A ustralia, focusing on younger men (<55 years of age), to examine the effects of this screening on transrectal ultrasonography ( TRUS )‐guided biopsy rates and to determine the nature of prostate cancers ( PC as) being detected. Subjects and Methods All men who received an opportunistic screening PSA test and TRUS ‐guided biopsy between 2001 and 2008 in A ustralia were analysed using data from the A ustralian C ancer registry ( A ustralian I nstitute of H ealth and W elfare) and Medicare databases. The V ictorian cancer registry was used to obtain G leason scores. Age‐standardized and age‐specific rates were calculated, along with the incidence of PC a, and correlated with G leason scores. Results A total 5 174 031 PSA tests detected 128 167 PC as in the period 2001–2008. During this period, PSA testing increased by 146% (a mean of 4629 tests per 100 000 men annually), with 80 and 59% increases in the rates of TRUS ‐guided biopsy and incidence of PC a, respectively. The highest increases in PSA screening occurred in men <55 years old and up to 1101 men had to be screened to detect one incident case of PC a (0.01%). Screening resulted in two thirds of men aged <55 years receiving a negative TRUS biopsy. There was no correlation with G leason >7 tumours in patients aged <55 years. Conclusion Despite the ongoing controversy about the merits of PCa screening, there was an increase in PSA testing, especially in men <55 years old, leading to a modestly higher incidence of PC a in A ustralia. Overall, PSA screening was associated with high rates of negative TRUS ‐biopsy and the detection of low/intermediate grade PCa among younger patients.