Familial PDGFRA-mutation syndrome: somatic and gastrointestinal phenotype.

Germline activating platelet-derived growth factor receptor alpha (PDGFRA) mutations have been described in four families. All the index patients have presented with multiple mesenchymal tumors of the gastrointestinal tract. We identified a fifth family with four first-degree relatives that harbor a PDGFRA exon 18 (D846V) germline mutation. The affected kindred have a unique phenotype including coarse facies and skin, broad hands and feet, and previously undescribed premature tooth loss. While the index patient presented with multiple small bowel inflammatory fibroid polyps (IFPs) and has a gastric gastrointestinal stromal tumor (GIST), no tumors have yet been identified in other family members. We describe the pathology, genetics, the incomplete penetrance and variable expressivity of the familial PDGFRA-mutation syndrome referencing the mouse knock-in Pdgfra model. We speculate on the role of the telocyte, a recently described CD34, PDGFRA+ stromal cell, in the development of inflammatory fibroid polyps and the somatic phenotype.

One bite or two? A prospective trial comparing colonoscopy biopsy technique in patients with chronic ulcerative colitis.

BACKGROUND AND STUDY AIMS: Surveillance for mucosal dysplasia in patients with chronic ulcerative colitis requires numerous biopsies (often over 40). The aim of the present study was to determine if two biopsies could be obtained with jumbo forceps before removing them from the instrument (double biopsy technique), as opposed to one biopsy per pass, without sacrificing the histological quality of the biopsy material. METHODS: Twelve patients with chronic ulcerative colitis underwent colonoscopy, and four-quadrant biopsies were obtained at 10 cm intervals. For biopsies at each interval, two quadrants were obtained using the double biopsy technique and the other two quadrants were obtained individually. Two pathologists blinded to the biopsy technique examined each biopsy for technical and diagnostic qualities. The primary outcome was the histological adequacy in the evaluation of dysplasia. RESULTS: A total of 468 biopsies were obtained. A higher proportion of double-biopsy specimens were inadequate for dysplasia assessment compared with single-biopsy specimens (OR=2.78, 95% CI 1.37 to 5.59; P=0.005). In the double biopsy technique group, 14 samples were deemed inadequate due to actual tissue specimen loss, compared with eight samples in the single biopsy technique. However, when analysis was repeated using only the retrieved specimens, the double biopsy technique continued to be at higher risk of obtaining inadequate specimens (OR=14.5, 95% CI 2.1 to 98.7; P=0.006). CONCLUSIONS: The results of the present study suggest that the double biopsy technique is vulnerable to specimen loss and reduced histological quality, and the adoption of this technique as an equivalent method for tissue sampling may be premature.

Acute-phase serum amyloid A: perspectives on its physiological and pathological roles.

Serum amyloid A (SAA), a protein originally of interest primarily to investigators focusing on AA amyloidogenesis, has become a subject of interest to a very broad research community. SAA is still a major amyloid research topic because AA amyloid, for which SAA is the precursor, is the prototypic model of in vivo amyloidogenesis and much that has been learned with this model has been applicable to much more common clinical types of amyloid. However, SAA has also become a subject of considerable interest to those studying (i) the synthesis and regulation of acute phase proteins, of which SAA is a prime example, (ii) the role that SAA plays in tissue injury and inflammation, a situation in which the plasma concentration of SAA may increase a 1000-fold, (iii) the influence that SAA has on HDL structure and function, because during inflammation the majority of SAA is an apolipoprotein of HDL, (iv) the influence that SAA may have on HDL's role in reverse cholesterol transport, and therefore, (v) SAA's potential role in atherogenesis. However, no physiological role for SAA, among many proposed, has been widely accepted. None the less from an evolutionary perspective SAA must have a critical physiological function conferring survival-value because SAA genes have existed for at least 500 million years and SAA's amino acid sequence has been substantially conserved. An examination of the published literature over the last 40 years reveals a great deal of conflicting data and interpretation. Using SAA's conserved amino acid sequence and the physiological effects it has while in its native structure, namely an HDL apolipoprotein, we argue that much of the confounding data and interpretation relates to experimental pitfalls not appreciated when working with SAA, a failure to appreciate the value of physiologic studies done in the 1970-1990 and a current major focus on putative roles of SAA in atherogenesis and chronic disease. When viewed from an evolutionary perspective, published data suggest that acute-phase SAA is part of a systemic response to injury to recycle and reuse cholesterol from destroyed and damaged cells. This is accomplished through SAA's targeted delivery of HDL to macrophages, and its suppression of ACAT, the enhancement of neutral cholesterol esterase and ABC transporters in macrophages. The recycling of cholesterol during serious injury, when dietary intake is restricted and there is an immediate and critical requirement of cholesterol in the generation of myriads of cells involved in inflammation and repair responses, is likely SAA's important survival role. Data implicating SAA in atherogenesis are not relevant to its evolutionary role. Furthermore, in apoE(-/-) mice, domains near the N- and C- termini of SAA inhibit the initiation and progression of aortic lipid lesions illustrating the conflicting nature of these two sets of data.