Solverson P, Murali SG, Brinkman AS, Nelson DW, Clayton MK, Yen CL, Ney DM. Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria. Am J Physiol Endocrinol Metab 302: E885-E895, 2012. First published January 31, 2012; doi:10.1152/ajpendo.00647.2011.-Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pah enu2 (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3-23 wk of age. The 2 ϫ 2 ϫ 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3-15% increase in energy expenditure, as reflected in oxygen consumption, and a 3-30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO 2 produced/O2 consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice. indirect calorimetry; energy balance; splenomegaly; cytokines; amino acid metabolism

Purpose of Review Hirschsprung’s Disease (HSCR) is characterized by an absence of ganglion cells in the distal hindgut, extending from the rectum to a variable distance proximally, and results from a failure of cranial-caudal neural crest cell migration. Hirschsprung’s-Associated Enterocolitis (HAEC) is a condition with classic manifestations that include abdominal distention, fever and foul-smelling stools, and is a significant and life-threatening complication of HSCR. The purpose of this review is to critically evaluate recent findings regarding the pathophysiology of HAEC. Recent Findings Several recent studies have investigated the etiology of HAEC in humans and mouse models. These studies suggest that alterations in the intestinal barrier, including goblet cell number and function and Paneth cell function, impaired gastrointestinal mucosal immunity, including B-lymphocyte trafficking or function and secretory IgA production, and dysbiosis of the intestinal microbiota may contribute to the development of HAEC. Summary Recent studies add to the body of literature suggesting that the intestinal defects observed in HSCR are not restricted to the aganglionic segment but extend to the mucosal immune system within and beyond the gastrointestinal tract. Future studies further dissecting mechanisms of HAEC and validating these findings in human patients will allow for development of directed therapeutic interventions.

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Complement is necessary for defense against lung infection with Pseudomonas aeruginosa in mice. We studied in vitro interactions between complement and P. aeruginosa and in vivo effects of complement depletion to better understand this relationship. In vitro, P. aeruginosa strain UI-18 was resistant to killing by mouse serum. However, C3 opsonized the organism (via the alternative and mannose binding lectin [MBL] pathways), and C5 convertase activity on the bacterial surface was demonstrated. In vivo, compared with normal mice, complement-deficient mice experienced higher mortality and failed to sterilize their bronchoalveolar space within 24 h of inoculation. These changes did not seem to be a result of decreased inflammation because complementdeficient mice had normal neutrophil recruitment, greater lung myeloperoxidase content, and, by 24 h, a 35-fold higher level of the CXC chemokine KC. Lung static pressure-volume curves were abnormal in infected animals but were significantly more so in complement deficient mice. These data indicate that although P. aeruginosa is resistant to serum killing, C3 opsonization and C5 convertase assembly occur on its surface. This interaction in vivo plays a central role in host survival beyond just recruitment and activation of phagocytes and may serve to limit the inflammatory response to and tissue injury resulting from bacterial infection.Despite advances in diagnosis and treatment, Gram-negative pneumonia is a major health threat in the United States. As of 1999, pneumonia remained the fourth leading cause of death among hospitalized patients, behind the broad categories of cardiovascular disease, cerebrovascular disease, and malignancy (1). For patients developing nosocomial pneumonia, Pseudomonas aeruginosa is the most often identified etiologic organism, accounting for 21% of such infections in a recent survey (2). Well-recognized risk factors for infection with this organism include impaired host immunity, including malignancy; endotracheal intubation and mechanical ventilation; severe burns; and prolonged hospitalization (3).In mouse models of pneumonia, requirements for the cellular and humoral components of the innate immune system have been demonstrated in defense against P. aeruginosa. The NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript presence of neutrophils and the signaling apparatus needed to recruit them into the lung have been shown to be essential for survival during acute infection; native alveolar macrophages alone seem to be insufficient to defend against instilled bacteria (4). The complement system also has been shown to be significant in the response to Pseudomonas pneumonia. Genetically C5-deficient mice exhibit impaired clearance of intrapulmonary P. aeruginosa (5). Although the formation of the membrane attack complex and subsequent complementmediated bacteriolysis may contribute to the role of C5, a need for the anaphylatoxin C5a has been demonstrated in C5a-receptor null mice challenged with intratracheal Pseu...

Pre-operative diabetes status provides useful information that can help to stratify patients in terms of predicted post-operative OS and DFS.