lostridium difficile is an anaerobic gram-positive, spore-forming, toxin-producing bacillus that is transmitted among humans through the fecaloral route. The relationship between the bacillus and humans was once thought to be commensal, 1 but C. difficile has emerged as a major enteric pathogen with worldwide distribution. In the United States, C. difficile is the most frequently reported nosocomial pathogen. A surveillance study in 2011 identified 453,000 cases of C. difficile infection and 29,000 deaths associated with C. difficile infection; approximately a quarter of those infections were community-acquired. 2 Nosocomial C. difficile infection more than quadruples the cost of hospitalizations, 3 increasing annual expenditures by approximately $1.5 billion in the United States. 4 In this article, we review the changing epidemiology of this infection, discuss risk factors and preventive strategies, outline current recommendations for treatment, and highlight developing strategies for disease control. Pathogenesis a nd Epidemiol ogy C. difficile colonizes the large intestine and releases two protein exotoxins (TcdA and TcdB) that cause colitis in susceptible persons. Infection is transmitted by spores that are resistant to heat, acid, and antibiotics. The spores are plentiful in health care facilities and are found in low levels in the environment and food supply, allowing for both nosocomial and community transmission. 5 Colonization is prevented by barrier properties of the fecal microbiota; weakening of this resistance by antibiotics is the major risk factor for disease (Fig. 1). Advanced age, antineoplastic chemotherapy, and severe underlying disease also contribute to susceptibility. Symptoms of colitis do not develop in all colonized persons. For example, the majority of infants are colonized with C. difficile but are asymptomatic, 6-8 possibly owing to the lack of toxin-binding receptors in the infant gut, as shown in animal models 9 and as suggested by the common development of antibodies to C. difficile toxins in infants without clinical infection. 7 C. difficile diarrhea is mediated by TcdA and TcdB, which inactivate members of the Rho family of guanosine triphosphatases (Rho GTPases), leading to colonocyte death, loss of intestinal barrier function, and neutrophilic colitis. The organism itself is noninvasive, and infection outside the colon is extremely rare. The two factors that exert a major influence on clinical expression of disease are the virulence of the infecting strain and the host immune response. In the early 2000s, hospitals began reporting dramatic increases in severe C. difficile infection. Isolates were characterized by the Centers for Disease Control and Prevention as toxinotype III, restriction endonuclease analysis group BI, North American pulsed-field gel electrophoresis type NAP1, and polymerase-chain-reaction (PCR) type 027 and were subsequently known as BI/NAP1/027. 10 The BI/NAP1/027 strain is characterized by high-level fluoroquinolone resistance, efficient sporulation, marked...

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Choline is required to make essential membrane phospholipids. It is a precursor for the biosynthesis of the neurotransmitter acetylcholine and also is an important source of labile methyl groups. Mammals fed a choline-deficient diet develop liver dysfunction; however, choline is not considered an essential nutrient in humans. Healthy male volunteers were hospitalized and fed a semisynthetic diet devoid of choline supplemented with 500 mg/day choline for 1 wk. Subjects were randomly divided into two groups, one that continued to receive choline (control), and the other that received no choline (deficient) for three additional wk. During the 5th wk of the study all subjects received choline. The semisynthetic diet contained adequate, but no excess, methionine. In the choline-deficient group, plasma choline and phosphatidylcholine concentrations decreased an average of 30% during the 3-wk period when a choline-deficient diet was ingested; plasma and erthrocyte phosphatidylcholine decreased 15%; no such changes occurred in the control group. In the choline-deficient group, serum alanine aminotransferase activity increased steadily from a mean of 0.42 mukat/liter to a mean of 0.62 mukat/liter during the 3-wk period when a choline-deficient diet was ingested; no such change occurred in the control group. Other tests of liver and renal function were unchanged in both groups during the study. Serum cholesterol decreased an average of 15% in the deficient group and did not change in the control group. Healthy humans consuming a choline-deficient diet for 3 wk had depleted stores of choline in tissues and developed signs of incipient liver dysfunction. Our observations support the conclusion and choline is an essential nutrient for humans when excess methionine and folate are not available in the diet.

We present dynamic light scattering (DLS) and hydrophobic dye-binding data in an effort to elucidate a molecular mechanism for the ability of gastric mucin to form a gel at low pH, which is crucial to the barrier function of gastric mucus. DLS measurements of dilute mucin solutions were not indicative of intermolecular association, yet there was a steady fall in the measured diffusion coefficient with decreasing pH, suggesting an apparent increase in size. Taken together with the observed rise in depolarized scattering ratio with decreasing pH, these results suggest that gastric mucin undergoes a conformational change from a random coil at pH >/= 4 to an anisotropic, extended conformation at pH < 4. The increased binding of mucin to hydrophobic fluorescent with decreasing pH indicates that the change to an extended conformation is accompanied by exposure of hydrophobic binding sites. In concentrated mucin solutions, the structure factor S(q, t) derived from DLS measurements changed from a stretched exponential decay at pH 7 to a power-law decay at pH 2, which is characteristic of a sol-gel transition. We propose that the conformational change facilitates cross-links among mucin macromolecules through hydrophobic interactions at low pH, which in turn leads to a sol-gel transition when the mucin solution is sufficiently concentrated.