Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-ß/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation.

Disruption of the TGF-ß pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-ß signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-ß pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-ß pathway member expression levels and ß-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-ß member expression with lower ß-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-ß pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and ß-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.

Hyperglycemia is associated with increased risk of morbidity and mortality after colectomy for cancer.

BACKGROUND: The relationship of hyperglycemia to general surgery outcomes is not well-understood. We studied the association of operative day and postoperative day 1 (POD1) blood glucose (BG) with outcomes after open colectomy for cancer. STUDY DESIGN: We retrospectively analyzed the 2000-2005 Veterans Affairs Surgical Quality Improvement Program database, linked with Veterans Affairs Decision Support System BG values. Median BG was categorized as hypoglycemic (<80 mg/dL); normoglycemic (BG 80-120 mg/dL); or mildly (BG 121-160 mg/dL), moderately (BG 161-200 mg/dL), or severely (BG >200 mg/dL) hyperglycemic. The relationship of BG to postoperative outcomes was assessed with multivariable logistic regression. RESULTS: We identified 9,638 colectomies. We excluded 511 procedures for emergency status or preoperative coma, mechanical ventilation, or sepsis. After excluding patients without recorded BG, we analyzed operative day and POD1 BG in 7,576 and 5,773 procedures, respectively. On multivariable analysis, operative day moderate hyperglycemia was associated with surgical site infection (odds ratio = 1.44; 95% CI, 1.10-1.87). POD1 severe hyperglycemia was associated with cardiac arrest (odds ratio = 2.31; 95% CI, 1.08-4.98) and death (odds ratio = 1.97; 95% CI, 1.23-3.15). POD1 mild (odds ratio = 2.20; 95% CI, 1.05-4.60), moderate (odds ratio = 3.44; 95% CI, 1.51-7.84), and severe (odds ratio = 3.94; 95% CI, 1.64-9.58) hyperglycemia and hypoglycemia (odds ratio = 6.74; 95% CI, 1.75-25.97) were associated with myocardial infarction. Associations were similar in diabetic and nondiabetic patients. CONCLUSIONS: Even mild hyperglycemia was associated with adverse outcomes after colectomy, suggesting that a perioperative BG target of 80 to 120 mg/dL, although avoiding hypoglycemia, might be appropriate. Randomized clinical trials are needed to confirm these findings.

Urachal remnant small bowel obstruction: report of two adult cases.

This report describes two separate cases of adult patients with intestinal obstruction caused by an urachal remnant. While reports of infected urachal cysts causing intra-abdominal pathology are not uncommon, intestinal obstruction caused by urachal remnants is exceedingly rare in the pediatric population and has never been described in adults. Both of these patients required surgical intervention with excision of the urachal remnant and subsequent resolution of the small bowel obstruction.

Early immunoneutralization of calcitonin precursors attenuates the adverse physiologic response to sepsis in pigs.

OBJECTIVE: The 116 amino acid prohormone procalcitonin and some of its component peptides (collectively termed calcitonin precursors) are important markers and mediators of sepsis. In this study, we sought to evaluate the effect of immunoneutralization of calcitonin precursors on metabolic and physiologic variables of sepsis in a porcine model. DESIGN: A prospective, controlled animal study. SETTING: A university research laboratory. SUBJECTS: 30-kg Yorkshire pigs. INTERVENTIONS: Sepsis was induced in 15 pigs by intraperitoneal instillation of a suspension of cecal content (1 g/kg animal body weight) and a toxinogenic Escherichia coli solution (2 x 10(11) colony-forming units). During induction of sepsis, seven pigs received an intravenous infusion of purified rabbit antiserum, reactive to the aminoterminal portion of porcine prohormone procalcitonin. Another eight control pigs received an intravenous infusion of purified nonreactive rabbit antiserum. For all 15 animals, physiologic data (urine output, core temperature, arterial pressure, heart rate, cardiac index, and stroke volume index) and metabolic data (serum blood urea nitrogen and creatinine, arterial lactate, and pH) were collected or recorded hourly until death at 15 hrs. MEASUREMENTS AND MAIN RESULTS: In this large-animal model of rapidly lethal peritonitis, serum calcitonin precursors were significantly elevated. Amino-prohormone procalcitonin-reactive antiserum administration resulted in a significant improvement or a beneficial trend in a majority of the measured physiologic and metabolic derangements induced by sepsis. Specifically, arterial pressure, cardiac index, stroke volume index, pH, and creatinine were all significantly improved, while urine output and serum lactate had beneficial trends. Treated animals also experienced a statistically significant increase of short-term survival. CONCLUSIONS: These data from a large-animal model with polymicrobial sepsis demonstrate the salutary effect of early immunoneutralization of calcitonin precursors on physiologic and metabolic variables. Immunologic blockade of calcitonin precursors may offer a novel therapeutic approach to human sepsis.