Clinical applications of the Model for End-Stage Liver Disease (MELD) in hepatic medicine.

The Model for End-Stage Liver Disease (MELD) score incorporates serum bilirubin, creatinine, and the international normalized ratio (INR) into a formula that provides a continuous variable that is a very accurate predictor of 90-day mortality in patients with cirrhosis. It is currently utilized in the United States to prioritize deceased donor organ allocation for patients listed for liver transplantation. The MELD score is superior to other prognostic models in patients with end-stage liver disease, such as the Child-Turcotte-Pugh score, since it uses only objective criteria, and its implementation in 2002 led to a sharp reduction in the number of people waiting for liver transplant and reduced mortality on the waiting list without affecting posttransplant survival. Although mainly adopted for use in patients waiting for liver transplant, the MELD score has also proved to be an effective predictor of outcome in other situations, such as patients with cirrhosis going for surgery and patients with fulminant hepatic failure or alcoholic hepatitis. Several variations of the original MELD score, involving the addition of serum sodium or looking at the change in MELD over time, have been examined, and these may slightly improve its accuracy. The MELD score does have limitations in situations where the INR or creatinine may be elevated due to reasons other than liver disease, and its implementation for organ allocation purposes does not take into consideration several conditions that benefit from liver transplantation. The application of the MELD score in prioritizing patients for liver transplantation has been successful, but further studies and legislation are required to ensure a fair and equitable system.

A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility.

A glycosylated polypeptide, ß-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm in mucosal fluids of the female reproductive tract. Here, we report a sequence variant in DEFB126 that has a two-nucleotide deletion in the open reading frame, which generates an abnormal mRNA. The allele frequency of this variant sequence was high in both a European (0.47) and a Chinese (0.45) population cohort. Binding of the Agaricus bisporus lectin to the sperm surface glycocalyx was significantly lower in men with the homozygous variant (del/del) genotype than in those with either a del/wt or a wt/wt genotype, suggesting an altered sperm glycocalyx with fewer O-linked oligosaccharides in del/del men. Moreover, sperm from del/del carriers exhibited an 84% reduction in the rate of penetration of a hyaluronic acid gel, a surrogate for cervical mucus, compared to the other genotypes. This reduction in sperm performance in hyaluronic acid gels was not a result of decreased progressive motility (average curvilinear velocity) or morphological deficits. Nevertheless, DEFB126 genotype and lectin binding were correlated with sperm performance in the penetration assays. In a prospective cohort study of newly married couples who were trying to conceive by natural means, couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence. This common sequence variation in DEFB126, and its apparent effect of impaired reproductive function, will allow a better understanding, clinical evaluation, and possibly treatment of human infertility.

The capsule encoding the viaB locus reduces interleukin-17 expression and mucosal innate responses in the bovine intestinal mucosa during infection with Salmonella enterica serotype Typhi.

The viaB locus contains genes for the biosynthesis and export of the Vi capsular antigen of Salmonella enterica serotype Typhi. Wild-type serotype Typhi induces less CXC chemokine production in tissue culture models than does an isogenic viaB mutant. Here we investigated the in vivo relevance of these observations by determining whether the presence of the viaB region prevents inflammation in two animal models of gastroenteritis. Unlike S. enterica serotype Typhimurium, serotype Typhi or a serotype Typhi viaB mutant did not elicit marked inflammatory changes in the streptomycin-pretreated mouse model. In contrast, infection of bovine ligated ileal loops with a serotype Typhi viaB mutant resulted in more fluid accumulation and higher expression of the chemokine growth-related oncogene alpha (GROalpha) and interleukin-17 (IL-17) than did infection with the serotype Typhi wild type. There was a marked upregulation of IL-17 expression in both the bovine ligated ileal loop model and the streptomycin-pretreated mouse model, suggesting that this cytokine is an important component of the inflammatory response to infection with Salmonella serotypes. Introduction of the cloned viaB region into serotype Typhimurium resulted in a significant reduction of GROalpha and IL-17 expression and in reduced fluid secretion. Our data support the idea that the viaB region plays a role in reducing intestinal inflammation in vivo.