Human milk (HM) provides all nutrients to support an optimal growth and development of the neonate. The composition and structure of HM lipids, the most important energy provider, have an impact on the digestion, uptake and metabolism of lipids. In HM, the lipids are present in the form of dispersed fat globules: large fat droplets enveloped by a phospholipid membrane. Currently, infant milk formula (Control IMF) contains small fat droplets primarily coated by proteins. Recently, a novel IMF concept (Concept IMF) was developed with a different lipid architecture, Nuturis(®), comprising large fat droplets with a phospholipid coating. Confocal laser scanning microscopy (CLSM), with appropriate fluorescent probes, and transmission electron microscopy were used to determine and compare the interfacial composition and structure of HM fat globules, Concept IMF fat droplets and Control IMF fat droplets. The presence of a trilayer-structured HM fat globule membrane, composed of phospholipids, proteins, glycoproteins and cholesterol, was confirmed; in addition exosome-like vesicles are observed within cytoplasmic crescents. The Control IMF fat droplets had a thick protein-only interface. The Concept IMF fat droplets showed a very thin interface composed of a mixture of phospholipids, proteins and cholesterol. Furthermore, the Concept IMF contained fragments of milk fat globule membrane, which has been suggested to have potential biological functions in infants. By mimicking more closely the structure and composition of HM fat globules, this novel IMF concept with Nuturis(®) may have metabolic and digestive properties that are more similar to HM compared to Control IMF.

The bacterial species Staphylococcus aureus, including its methicillin-resistant variant (MRSA), finds its primary ecological niche in the human nose, but is also able to colonize the intestines and the perineal region. Intestinal carriage has not been widely investigated despite its potential clinical impact. This review summarizes literature on the topic and sketches the current state of affairs from a microbiological and infectious diseases' perspective. Major findings are that the average reported detection rate of intestinal carriage in healthy individuals and patients is 20% for S. aureus and 9% for MRSA, which is approximately half of that for nasal carriage. Nasal carriage seems to predispose to intestinal carriage, but sole intestinal carriage occurs relatively frequently and is observed in 1 out of 3 intestinal carriers, which provides a rationale to include intestinal screening for surveillance or in outbreak settings. Colonization of the intestinal tract with S. aureus at a young age occurs at a high frequency and may affect the host's immune system. The frequency of intestinal carriage is generally underestimated and may significantly contribute to bacterial dissemination and subsequent risk of infections. Whether intestinal rather than nasal S. aureus carriage is a primary predictor for infections is still ill-defined.

The RET receptor tyrosine kinase has essential roles in cell survival, differentiation, and proliferation. Oncogenic activation of RET causes the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) and is a frequent event in sporadic thyroid carcinomas. However, the molecular mechanisms underlying RET's potent transforming and mitogenic signals are still not clear. Here, we show that nuclear localization of Bcatenin is frequent in both thyroid tumors and their metastases from MEN 2 patients, suggesting a novel mechanism of RET-mediated function through the B-catenin signaling pathway. We show that RET binds to, and tyrosine phosphorylates, B-catenin and show that the interaction between RET and B-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RETmediated tyrosine phosphorylation, B-catenin escapes cytosolic down-regulation by the adenomatous polyposis coli/ Axin/glycogen synthase kinase-3 complex and accumulates in the nucleus, where it can stimulate B-catenin-specific transcriptional programs in a RET-dependent fashion. We show that down-regulation of B-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. Together, our data show that a Bcatenin-RET kinase pathway is a critical contributor to the development and metastasis of human thyroid carcinoma.

Activating mutations in the RET proto-oncogene are associated with both familial and sporadic medullary thyroid carcinoma (MTC) development; however, the genetic mechanisms underlying MTC tumorigenesis remain largely unknown. Recently, we have identified somatic inactivating mutations in the cell cycle inhibitor gene P18 in human MTC, which coincided with activating RET mutations, suggesting a role for loss of P18 in combination with oncogenic RET in the multistep process of MTC development. Therefore, we crossed transgenic mice expressing oncogenic RET (RET2B) with mice lacking p18 (and p27, another cell cycle inhibitor) and monitored MTC development. RET2B;p18 +/À mice and RET2B;p18 À/À mice developed MTC with a highly increased incidence compared with their corresponding single mutant littermates. In addition, expression of oncogenic RET causes an earlier age of onset and larger MTCs in p18;p27 +/À mice. In a subset of MTCs of RET2B;p18Ink4c expression was completely lost. This loss of p18 Ink4c expression correlated with higher proliferation rates as well as with larger MTCs, indicating that loss of p18 in combination with oncogenic RET not only increases the risk for MTC development but also enhances MTC progression. Our data strongly indicate that oncogenic RET and loss of p18 cooperate in the multistep tumorigenesis of MTC. [Cancer Res 2008;68(5):1329-37]

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In multiple endocrine neoplasia syndrome Type 2 (MEN2), medullary thyroid carcinoma (MTC) and pheochromocytoma (PC) are associated with hereditary activating germ-line mutations in the RET proto-oncogene. Also in a large percentage of sporadic MTCs and PCs, somatic RET mutations appear to be involved in tumor formation. In one single MEN2 family an extensive variety in disease expression may be observed, indicating that additional genetic events are responsible for progression of the disease towards a more aggressive phenotype. However, these additional mutations in both hereditary and sporadic MTC and PC development are largely unknown. Here, we show for the first time the presence of somatic mutations in the cell cycle regulator P18 in human RET-associated MTCs and PCs. Each of these mutations causes an amino acid substitution in the cyclin dependent kinaseinteracting region of P18 INK4C . Since these mutations partly inhibited P18 INK4C function and reduced its stability, our findings implicate P18 as a tumor suppressor gene involved in human MTC and PC development. ' 2008 Wiley-Liss, Inc.Key words: P18 INK4C; medullary thyroid carcinoma; RET; tumor suppressor gene; multistep tumorigenesis Multiple endocrine neoplasia Type 2 (MEN2) is an autosomal dominantly inherited cancer syndrome. The clinical expression of MEN2 varies, although all patients develop medullary thyroid carcinoma (MTC) or its precursor C-cell hyperplasia (CCH). MEN2 can be subdivided in MEN2A, MEN2B and familial MTC (FMTC). MEN2A is characterized by MTC, pheochromocytoma (PC), and hyperparathyroidism. MEN2B is characterized by MTC, PC and mucosal ganglioneuromas (in the colon, lips and tongue). FMTC patients solely develop MTC. MTC originates from the calcitonin producing neuroendocrine C-cells in the thyroid gland, and PC originates from the neuroendocrine chromaffin cells in the adrenal medulla. 1 MEN2 patients carry an activating germ-line mutation in the RET proto-oncogene, leading to constitutive activation of its encoded transmembrane receptor tyrosine kinase RET. The MEN2 phenotype correlates strongly with specific RET mutations. 2,3 In MEN2A the mutations affect cysteine residues in the extracellular domain of the protein. The most commonly affected Cysteine is C634. 4,5 In MEN2B, the most common mutation (in 95% of the cases) results in a Methionine to Threonine substitution at position 918 in the intracellular domain of the protein. [6][7][8] Somatic RET mutations have been detected in 23-69% of sporadic MTC, the vast majority of which has the M918T mutation, as well as in 10-15% of sporadic PC, with M918T in 50% of the cases. 9 Carriers of the same germ-line RET mutation, both related and unrelated, can develop MTC and PC at widely varying ages, suggesting that in addition to the mutated RET gene, other oncogenic events are required for the development of these tumors. The most frequently detected chromosomal alteration in MTC and PC is loss of a specific part or of the entire short arm of chromosome 1. [10][11][12] The most comm...

Background Lipid droplets in human milk have a mode diameter of ∼4 μm and are surrounded by a native phospholipid-rich membrane. Current infant milk formulas (IMFs) contain small lipid droplets (mode diameter ∼0.5 μm) primarily coated by proteins. A concept IMF was developed mimicking more closely the structure and composition of human milk lipid droplets. Objectives This randomized, controlled, double-blind equivalence trial evaluates the safety and tolerance of a concept IMF with large, milk phospholipid–coated lipid droplets (mode diameter 3–5 μm) containing vegetable and dairy lipids in healthy, term infants. Methods Fully formula-fed infants were enrolled up to 35 d of age and randomly assigned to 1 of 2 formulas until 17 wk of age: 1) Control IMF with small lipid droplets containing vegetable oils (n = 108); or 2) Concept IMF with large, milk phospholipid–coated lipid droplets comprised of 48% dairy lipids (n = 115). A group of 88 breastfed infants served as reference. Primary outcome was daily weight gain during intervention. Additionally, number and type of adverse events, growth, and tolerance parameters were monitored. Results Equivalence of daily weight gain was demonstrated (Concept compared with Control IMF: −1.37 g/d; 90% CI: −2.71, −0.02; equivalence margin ± 3 g/d). No relevant group differences were observed in growth, tolerance and number, severity, or relatedness of adverse events. We did observe a higher prevalence of watery stools in the Concept than in the Control IMF group between 5 and 12 wk of age (P < 0.001), closer to the stool characteristics observed in the breastfed group. Conclusions An infant formula with large, milk phospholipid–coated lipid droplets containing dairy lipids is safe, well tolerated, and supports an adequate growth in healthy infants. This trial was registered in the Dutch Trial Register (www.trialregister.nl) as NTR3683.

Changes in FM% occur mainly in the first 3 months of life, and FM%, visceral and abdominal subcutaneous fat do not change between 3 and 6 months, supporting the concept of a critical window for adiposity development in the first three months of life. In addition, our study provides longitudinal reference data of FM%, FFM, visceral fat and abdominal subcutaneous fat during the first 6 months of life.