ITP and dITP exist in all cells. dITP is potentially mutagenic, and the levels of these nucleotides are controlled by inosine triphosphate pyrophosphatase (EC 3.6.1.19). Here we report the cloning, expression, and characterization of a 21.5-kDa human inosine triphosphate pyrophosphatase (hITPase), an enzyme whose activity has been reported in many animal tissues and studied in populations but whose protein sequence has not been determined before. At the optimal pH of 10.0, recombinant hITPase hydrolyzed ITP, dITP, and xanthosine 5-triphosphate to their respective monophosphates whereas activity with other nucleoside triphosphates was low. K m values for ITP, dITP, and xanthosine 5-triphosphate were 0.51, 0.31, and 0.57 mM, respectively, and k cat values were 580, 360, and 640 s ؊1 , respectively. A divalent cation was absolutely required for activity. The gene encoding the hITPase cDNA sequence was localized by radiation hybrid mapping to chromosome 20p in the interval D20S113-D20S97, the same interval in which the ITPA inosine triphosphatase gene was previously localized. A BLAST search revealed the existence of many similar sequences in organisms ranging from bacteria to mammals. The function of this ubiquitous protein family is proposed to be the elimination of minor potentially mutagenic or clastogenic purine nucleoside triphosphates from the cell.

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Hyperglycemia after severe traumatic brain injury (TBI) occurs frequently and is associated with poor clinical outcome and increased mortality. In this review, we highlight the mechanisms that lead to hyperglycemia and discuss how they may contribute to poor outcomes in patients with severe TBI. Moreover, we systematically review the proper management of hyperglycemia after TBI, covering topics such as nutritional support, glucose control, moderated hypothermia, naloxone, and mannitol treatment. However, to date, an optimal and safe glycemic target range has not been determined, and may not be safe to implement among TBI patients. Therefore, there is a mandate to explore a reasonable glycemic target range that can facilitate recovery after severe TBI.

Association studies on the MTHFR polymorphisms (C677T and A1298C) in colorectal cancer (CRC) and colorectal adenoma have shown conflicting results. We performed a meta-analysis to better assess the purported associations. Overall, the 677T allele (10,131 patients and 15,362 controls) showed a small but significant protective effect against CRC compared to the 677C allele [P=0.0003, odds ratio (OR)=0.93; 95% confidence interval (CI) 0.89-0.98, P=0.22 (for heterogeneity)] for a worldwide population. Metaanalyses of other genetic contrasts suggested that the 677T allele is more likely to affect CRC in a recessive genetic model worldwide (P<0.0001, OR=0.86; 95% CI 0.76-0.96, P=0.06) and in Asians (P=0.0005, OR=0.75; 95% CI 0.64-0.88, P=0.71). Similarly, we found a significantly decreased risk of CRC for 1298C polymorphism (4,764 CRC patients and 6,592 controls) for a recessive genetic model worldwide (P=0.005, OR=0.81; 95% CI 0.70-0.94, P=0.40) and in Caucasians (P=0.04, P=0.35). No evidence of association of C677T (4,616 patients and 6,338 controls) and A1298C (1,272 patients and 1,684 controls) with colorectal adenoma were found. The evidence accumulated suggests that MTHFR may represent a low-penetrance susceptible gene for CRC, and that the two polymorphisms might protect against colorectal adenoma developing into cancer. A larger single study is required to further evaluate gene-gene and geneenvironment interactions for MTHFR polymorphisms and the cancer risk in a specific population.

The X-ray repair cross-complementing group 3 (XRCC3) is a highly suspected candidate gene for cancer susceptibility. However, association studies on the XRCC3 polymorphisms (4541A4G, Thr 241 Met, 17893A4G) in cancer have shown conflicting results. Therefore, we performed a meta-analysis to better assess the purported associations. Forty eight eligible case-control studies including 24 975 cancer patients and 34 209 controls were selected for our meta-analysis. Overall, individuals carrying the XRCC3 Met/Met genotype showed a small cancer risk under a recessive genetic model. The subgroup and metaregression analysis demonstrated different scenarios concerning the XRCC3 Met/Met genotype's role in cancer susceptibility for different subgroups. Specially, there was a significantly increased risk of breast cancer (OR, 1.14; P ¼ 0.0004; 95% CI, 1.06 -1.23; P ¼ 0.37 for heterogeneity), elevated but not significant risk of cancer for head and neck, bladder, surprisingly, a significantly decreased risk of non-melanoma skin cancer (OR, 0.76; P ¼ 0.007; 95% CI, 0.62-0.93; P ¼ 0.61 for heterogeneity). A significantly elevated risk of cancer was observed in population-based case-control studies but not in nested or hospital based studies. Similarly, we found a significantly increased risk of cancer for A4541G and a decreased risk for A17893G under dominant genetic models. Our meta-analysis results support that the XRCC3 might represent a lowpenetrance susceptible gene especially for cancer of breast, bladder, head and neck, and non-melanoma skin cancer. A single larger study should be required to further evaluate gene -gene and geneenvironment interactions on XRCC3 polymorphisms and tissue-specific cancer risk in an ethnicity specific population.