Biomedical subjects
John C Murray
Publications and source records attributed to John C Murray.
Antenatal screening for sexually transmitted infections in remote Australia.
BACKGROUND: Antenatal screening for, and prompt management of, sexually transmitted infections (STI) can prevent adverse maternal, fetal and perinatal outcomes. This is particularly important in areas of high STI endemicity. AIMS: To assess adherence with antenatal STI screening guidelines in a large remote region, and whether completeness of antenatal syphilis screening improved after the onset of a regional syphilis outbreak in April 2001. METHODS: Data from the regional antenatal syphilis screening database from 1997 to 2002 were analysed to identify time trends in the completeness of antenatal syphilis screening. Adherence to antenatal screening guidelines was assessed by examining pathology request forms of women undergoing antenatal syphilis screening to determine whether screening for gonorrhoea, chlamydia, hepatitis B and HIV had also been carried out. Logistic regression was used to analyse associations between adherence to the guidelines and patient's age and race, and health service characteristics. RESULTS: Adherence to syphilis screening guidelines improved from 44.6% in 1997 to 68.9% in 2001 and 81.4% in 2002. After controlling for the time interval between the first antenatal syphilis test and date of delivery, being younger and Aboriginal, and delivering after the syphilis outbreak had been identified were positively associated with adherence to syphilis screening guidelines. Proportions of antenates screened for gonorrhoea/chlamydia, hepatitis B and HIV at booking and for gonorrhoea/chlamydia in the third trimester were 69%, 91%, 68% and 77%, respectively. Aboriginal women were more likely to have been screened for gonorrhoea and chlamydia. Women seen by a doctor were more likely to have undergone HIV screening than those who saw a nurse. CONCLUSIONS: Significant improvement in adherence to antenatal syphilis screening guidelines occurred after identification of a syphilis outbreak. This achievement is reason for optimism regarding the potential to achieve more complete antenatal screening of other STI.
Early melanoma detection: nonuniform dermoscopic features and growth.
BACKGROUND: Dermoscopy alone is not sufficient to detect all early melanomas. Total body photos reveal growth of melanomas but also reveal growth of melanocytic nevi. OBJECTIVE: We set out to determine whether a simplified algorithm on the basis of nonuniform dermoscopic features combined with growth noted from baseline total body photos targeted the early melanocytic neoplasms most likely to be malignant. METHODS: Lesions removed during follow-up of patients with total body photographs were reviewed and 169 melanocytic lesions were identified for which both gross clinical and dermoscopic photos were available. The images were evaluated separately by 3 academic dermatologists, without knowledge of the given pathologic diagnosis, for uniformity (consistent gradient of features from center to edge) and change (specifically, that which could indicate melanoma growth in normal skin or within a nevus). RESULTS: Using a minimum of 2 out of 3 agreement for uniformity and change, 12 of 16 melanomas (including all 5 superficially invasive tumors) were graded as nonuniform and changed. The 4 melanomas not included in this category were in situ. The predicted odds of melanoma for lesions scored as both nonuniform and changed was 4.06 (P >.0195). If 3 out of 3 agreement was used, the odds ratio increased to 6 (P >.0010). CONCLUSION: An algorithm on the basis of dermoscopic nonuniformity and change suggestive of growth as determined by total body photography segregates melanocytic neoplasms most likely to be malignant.
In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes.
The 3-unsubstituted isoxazole ring in the anti-inflammatory drug leflunomide undergoes a unique N-O bond cleavage to the active alpha-cyanoenol metabolite A771726, which resides in the same oxidation state as the parent. In vitro studies were conducted to characterize drug-metabolizing enzyme(s) responsible for ring opening and to gain insight into the mechanism of ring opening. Under physiological conditions, leflunomide was converted to A771726 in rat and human plasma (rat plasma,t1/2 = 36 min; human plasma, t1/2 = 12 min) and whole blood (rat blood, t1/2 = 59 min; human blood, t1/2 = 43 min). Human serum albumin also catalyzed A771726 formation, albeit at a much slower rate (t1/2 = 110 min). Rat and human liver microsomes also demonstrated NADPH-dependent A771726 formation (human liver microsomes, Vmax = 1797 pmol/min/mg and Km = 274 microM). Leflunomide metabolism in microsomes was sensitive to furafylline treatment, suggesting p4501A2 involvement. 3-Methylleflunomide, which contained a 3-methyl substituent on the isoxazole ring, was resistant to ring opening in base, plasma, blood, and liver microsomes. In microsomes, two monohydroxylated metabolites were formed, and metabolite identification studies established the 3- and the 5-methyl groups on the isoxazole ring as sites of hydroxylation. These results indicate that the C3-H in leflunomide is essential for ring opening. Although A771726 formation in human liver microsomes or recombinant p4501A2 required NADPH, its formation was greatly reduced by oxygen or carbon monoxide, suggesting that the isoxazole ring opening was catalyzed by the p450Fe(II) form of the enzyme. A mechanism for the p450-mediated ring scission is proposed in which the isoxazole ring nitrogen or oxygen coordinates to the reduced form of the heme followed by charge transfer from p450Fe(II) to the C=N bond or deprotonation of the C3-H, which results in a cleavage of the N-O bond.