Linkage and Association Analysis of Radiation Damage Repair Genes XRCC3 and XRCC5 with Nevus Density in Adolescent Twins

Previous studies have shown that a deficiency in DNA damage repair is associated with increased cancer risk, and exposure to UV radiation is a major risk factor for the development of malignant melanoma. High density of common nevi (moles) is a major risk factor for cutaneous melanoma. A nevus may result from a mutation in a single UV-exposed melanocyte which failed to repair DNA damage in one or more critical genes. XRCC3 and XRCC5 may have an effect on nevus count through their function as components of DNA repair processes that may be involved directly or indirectly in the repair of DNA damage due to UV radiation. This study aims to test the hypothesis that the frequency of flat or raised moles is associated with polymorphism at or near these DNA repair genes, and that certain alleles are associated with less efficient DNA repair, and greater nevus density. Twins were recruited from schools in south eastern Queensland and were examined close to their 12th birthday. Nurses examined each individual and counted all moles on the entire body surface. A 10cM genome scan of 274 families (642 individuals) was performed and microsatellite polymorphisms in XRCC3 and adjacent to XRCC5 were also typed. Linkage and association of nevus count to these loci were tested simultaneously using a structural-equation modeling approach implemented in MX. There is weak evidence for linkage of XRCC5 to a QTL influencing raised mole count, and also weak association. There is also weak evidence for association between flat mole count and XRCC3. No tests were significant after correction for testing multiple alleles, nor were any of the tests for total association significant. If variation in XRCC3 or XRCC5 influences UV sensitivity, and indirectly affects nevus density, then the effects are small.

Repair-replace strategies for two-dimensional warranty policies

For repairable items sold with free replacement warranty, the actions available to the manufacturer to rectify failures under warranty are to (1) repair the failed item or (2) replace it with a new one. A proper repair-replace strategy can reduce the expected cost of servicing the warranty. In this paper, we study repair-replace strategies for items sold with a two-dimensional free replacement warranty. (C) 2003 Elsevier Ltd. All rights reserved.

A new repair-replace strategy for items sold with a two-dimensional warranty

For repairable items, the manufacturer has the option to either repair or replace a failed item that is returned under warranty. In this paper, we look at a new warranty servicing strategy for items sold with two-dimensional warranty where the failed item is replaced by a new one when it fails for the first time in a specified region of the warranty and all other failures are repaired minimally. The region is characterised by two parameters and we derive the optimal values for these to minimise the total expected warranty servicing cost. We compare the results with other repair-replace strategies reported in the literature. (C) 2003 Elsevier Ltd. All rights reserved.

Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis

DNA mismatch repair is an important mechanism involved in maintaining the fidelity of genomic DNA. Defective DNA mismatch repair is implicated in a variety of gastrointestinal and other turners; however, its role in hepatocellular carcinoma (HCC) has not been assessed. Formalin-fixed, paraffin-embedded archival pathology tissues from 46 primary liver tumors were studied by microdissection and microsatellite analysis of extracted DNA to assess the degree of microsatellite instability, a marker of defective mismatch repair, and to determine the extent and timing of allelic loss of two DNA mismatch repair genes, human Mut S homologue-2 (hMSH2) and human Mut L homologue-1 (hMLH1), and the tumor suppressor genes adenomatous polyposis coli gene (APC), p53, and DPC4. Microsatellite instability was detected in 16 of the tumors (34.8%). Loss of heterozygosity at microsatellites linked to the DNA mismatch repair genes, hMSH2 and/or hMLH1, was found in 9 cases (19.6%), usually in association with microsatellite instability. Importantly, the pattern of allelic loss was uniform in 8 of these 9 tumors, suggesting that clonal loss had occurred. Moreover, loss at these loci also occurred in nonmalignant tissue adjacent to 4 of these tumors, where it was associated with marked allelic heterogeneity. There was relatively infrequent loss of APC, p53, or DPC4 loci that appeared unrelated to loss of hMSH2 or hMLH1 gene loci. Loss of heterozygosity at hMSH2 and/or hMLH1 gene loci, and the associated microsatellite instability in premalignant hepatic tissues suggests a possible causal role in hepatic carcinogenesis in a subset of hepatomas.

Chinese wool auctions: Failed agribusiness reform or future marketing channel?

The spectacular though short-lived operation of China's wool auctions graphically illustrates problems in reforming China's agribusiness sector. A selective coverage of product type and participants, a highly contrived process of price discovery, and an urgent need for parallel reform in related areas all led to the demise of the auctions and are a barrier to their re-emergence as a viable wool marketing channel. Despite the challenges facing wool auctions, this paper argues that they still have much to offer the marketing of wool in China.

Arsenic inhibits the repair of DNA damage induced by benzo(a)pyrene

In order to study the effect of arsenic on DNA damage, Sprague-Dawley rats were dosed with sodium arsenite (10 mg/kg) with or without 800 mug of benzo(a)pyrene (BP) by intramammilary injection. The animals were sacrificed on day 1, 3, 5, 10 and 27 and the mammary gland tissues were collected for DNA adduct measurement using a P-32 post-labeling assay. Animals dosed with arsenic alone did not show any DNA adducts. DNA adduct levels in rats dosed with BP alone reached a maximum level by day 5, reducing to 13% of this level by day 27. Adduct levels in rats dosed with arsenic and BP also reached a maximum by day 5 but only 80% of the level observed in the BP group. However, 84% of this amount still remained by day 27. The First Nucleotide Change (FNC) technique was used for the screening of 115 samples of various tissues from mice that had been chronically exposed to sodium arsenate for over 2 years revealed that inorganic arsenic did not attack the two putative hotspots (codons 131 and 154) of the hOGG1 gene. These results support the hypothesis that arsenic exerts its biological activity through DNA repair inhibition. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Iatrogenic bile duct injury: The scourge of laparoscopic cholecystectomy

Background: Laparoscopic cholecystectomy (LC) has become the first-line surgical treatment of calculous gall-bladder disease and the benefits over open cholecystectomy are well known. In the early years of LC, the higher rate of bile duct injuries compared with open cholecystectomy was believed to be due to the 'learning curve' and would dissipate with increased experience. The purpose of the present paper was to review a tertiary referral unit's experience of bile duct injuries induced by LC. Methods: A retrospective analysis was performed on all patients referred for management of an iatrogenic bile duct injury from 1981 to 2000. For injuries sustained at LC, details of time between LC and recognition of the injury, time from injury to definitive repair, type of injury, use of intraoperative cholangiography (IOC), definitive repair and postoperative outcome were recorded. The type of injury sustained at open cholecystectomy was similarly classified to allow the severity of injury to be compared. Results: There were 131 patients referred for management of an iatrogenic bile duct injury that occurred at open cholecystectomy (n = 62), liver resection (n = 5) and at LC (n = 64). Only 39% of bile duct injuries were recognized at the time of LC. Following conversion to open operation, half the subsequent procedures were considered inappropriate. When the injury was not recognized during LC, 70% of patients developed bile leak/peritonitis, almost half of whom were referred, whereas the rest underwent a variety of operative procedures by the referring surgeon. The remainder developed jaundice or abnormal liver function tests and cholangitis. An IOC was performed in 43% of cases, but failed to identify an injury in two-thirds of patients. The bile duct injuries that occurred at LC were of greater severity than with open cholecystectomy. Following definitive repair, there was one death (1.6%). Ninety-two per cent of patients had an uncomplicated recovery and there was one late stricture requiring surgical revision. Conclusions: The early prediction that the rate of injury during LC would decline substantially with increased experience has not been fulfilled. Bile duct injury that occurs at LC is of greater severity than with open cholecystectomy. Bile duct injury is recognized during LC in less than half the cases. Evidence is accruing that the use of cholangiography reduces the risk and severity of injury and, when correctly interpreted, increases the chance of recognition of bile duct injury during the procedure. Prevention is the key but, should an injury occur, referral to a specialist in biliary reconstructive surgery is indicated.

Macrophages, myofibroblasts and neointimal hyperplasia after coronary artery injury and repair

Macrophages participate in the restenosis process through the release of cytokines, metalloproteinases and growth factors. Studies of peritoneal granulation tissue suggest that macrophages may be precursors of myofibroblasts. This study examined the contribution of monocyte/macrophage lineage cells to neointimal cellular mass in a porcine model of thermal vascular injury. Thermal coronary artery injury caused medial smooth muscle cell necrosis and transformation of the media into an extracellular matrix barrier. The neointimal hyperplasia that developed over the injury sites was evaluated by light microscopy, electron microscopy and immunohistochemistry. At day 3, blood monocytes were adhered to the vessel wall and infiltrated the fibrotic media. At day 14, 42 +/- 3.9% of neointimal cells had a monocytic nuclear morphology and expressed macrophage-specific antigen SWC3 (identified by monoclonal antibody DH59B). Moreover, 9.2+/-1.8% of neointimal cells co-expressed SWC3 and alpha-smooth muscle actin and had ultrastructural characteristics intermediate between macrophages and myofibroblasts. At day 28, 10.5 +/- 3.5%, of cells expressed SWC3 and 5.2+/-1.8% of cells co-expressed SWC3 and alpha-smooth muscle actin. This study indicates that hematopoietic cells of monocyte/macrophage lineage abundantly populate the neointima in the process of lesion formation and may be precursors of neointimal myofibroblasts after thermal vascular injury. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Repair of three pathologic fractures in a dog with multiple myeloma

Three pathological fractures occurred secondary to osteolytic lesions of multiple myeloma. Two long bone fractures were each stabilised using interlocking nail fixation augmented with polymethyl meth acral ate bone cement. One vertebral fracture was stabilised using Steinmann pins and PMMA. Successful stabilisation, rapid return to function and improvement in quality of life occurred in all fractures. The patient survived approximately eight months on concurrent chemotherapy.