Executive functions were studied in 14 early and continuously treated PKU subjects (age 10.8 years, range 8-13) in comparison with controls matched for IQ, sex, age and socioeconomic status. Brain MRI examination was normal in all PKU patients. Neuropsychological evaluation included Wisconsin Card Sorting Test, Rey-Osterreith Complex Figure Test, Elithorn's Perceptual Maze Test, Weigl's Sorting Test, Tower of London, Visual Search and Motor Motor Learning Test. Whatever the IQ, PKU subjects performed worse than controls in tests exploring executive functions. Subgrouping the PKU subjects according to the quality of dietary control for the entire follow-up period (using 400 micromol/L as cut-off value for blood phenylalanine (Phe) concentration) showed that patients with worse dietary control performed more poorly than both the PKU group with the best dietary control and the control group. However, a mild impairment of executive functions was still found in PKU patients with a good dietary control (Phe <400 micromol/L) compared to controls. Concerning the PKU group as a whole, no linear correlation was found between neuropsychological performance and historical and concurrent biochemical parameters. We conclude that (a) PKU patients, even when treated early, rigorously and continuously, show an impairment of frontal lobe functions; (b) a protracted exposure to moderately high levels of Phe can affect frontal lobe functions independently of the possible effect of the same exposure on IQ; (c) in order to reduce the risk of frontal lobe dysfunction, the target of dietary therapy should be to maintain blood Phe concentration below 400 micromol/L.

Background & Aim-Pancreatitis-associated protein (PAP) is a secretory protein not normally expressed in the healthy pancreas but highly induced during acute pancreatitis. While PAP has been shown to be anti-bacterial and anti-apoptotic in vitro, its definitive biological function in vivo is not clear.

Chronic idiopathic inflammatory bowel disease (IBD) with extensive colonic involvement predisposes to the development of colorectal adenocarcinoma. Among the types of cancer occurring in this setting is an unusually well-differentiated low-grade tubuloglandular adenocarcinoma (LGTGA) that has not been studied systematically thus far. A review of 149 IBD-associated cancer resections performed at our institution yielded 17 patients (11%) with 21 tumors classified as LGTGA based on the following histologic characteristics: very well-differentiated small to medium diameter glands with round or tubular profiles, low-grade cytologic characteristics and absence or paucity of desmoplastic reaction. Twelve patients had ulcerative colitis, 4 Crohn disease, and 1 indeterminate colitis. Their median age was 41.5 years (range, 28 to 58 y). Five patients had separate synchronous cancers of conventional types. LGTGAs ranged from 0.4 to 10 cm in size and varied in gross appearance. They included 5 flat lesions that were not identified visually but were detected either by palpation of the unfixed surgical specimen (1 case) or histologically in random sections (4 cases). The invasive glands usually bore a close histologic resemblance to overlying low-grade or indefinite dysplastic crypts. Twelve carcinomas (57%) with well-defined superficial regions of LGTGA progressed histologically to conventional adenocarcinoma in deeper regions. These tumors were significantly more advanced than 9 carcinomas that maintained low-grade histology throughout. Follow-up of 13 patients (76%) for a mean 4.0 years (range, 0.75 to 9.0 y) disclosed 10 (77%) with favorable outcomes and 3 (23%) with adverse outcomes. Two adverse outcomes were attributable to synchronous advanced-stage conventional cancers and the third to progression from LGTGA to poorly differentiated adenocarcinoma. The mucosa overlying and surrounding LGTGA showed low-grade dysplasia (LGD) in 18 cases (86%), indefinite dysplasia with focal LGD in 1 case (5%), and LGD with focal high-grade dysplasia (HGD) in 2 cases (10%). Immunohistochemical studies disclosed expression of MUC2 in 72%, MUC6 in 0%, CK7 in 69%, and CK20 in 100%. Coexpression of CK7 and CK20 was conserved in regions of conventional adenocarcinoma derived from LGTGA. Silencing of immunohistochemical expression of hMLH1 occurred in 6 of 11 tumors tested (55%), implicating defective DNA replication error repair in their pathogenesis. We conclude that LGTGA is a distinct clinicopathologic entity characterized by direct derivation from LGD mucosa of IBD, very well-differentiated morphology, frequent coexpression of CK7 and CK20, and frequent silencing of hMLH1. Histologic progression from LGTGA to conventional types of adenocarcinoma parallels clinical progression to more aggressive neoplasia. The potential of LGD to give rise directly to LGTGA, and by way of LGTGA to more aggressive cancers, reinforces recommendations in favor of aggressive management of IBD patients diagnosed with LGD.

No abstract

Poor handwriting is a diagnostic criterion for developmental coordination disorder. Typical of poor handwriting is its low overall quality and the high variability of the spatial characteristics of the letters, usually assessed with a subjective handwriting scale. Recently, Dynamic Time Warping (DTW), a technique originally developed for speech recognition, was introduced for pattern recognition in handwriting. The present study evaluates its application to analyze poor handwriting. Forty children attending Dutch mainstream primary schools were recruited and based on their scores on the Concise Evaluation Scale for Children's Handwriting (Dutch abbreviation: BHK), 20 good and 20 poor writers (of whom 13 were scheduled for handwriting intervention) were identified. The groups were matched for age (7-9 years), school grade (grades 2 and 3) and handedness. The children subsequently wrote sequences of the letter 'a' on a graphics tablet in three conditions (normal, fast, and accurate). Classical kinematics were obtained and for each individual letter DTW was used to calculate the distance from the mean shape. The DTW data revealed much higher variability in the letter forms of the poor writers that was independent of the kinematic results of larger trajectories, faster movements, and higher pen pressure. The current results suggest that DTW is a valid and objective technique for letter-form analysis in handwriting and may hence be useful to evaluate the rehabilitation treatments of children suffering from poor handwriting. In education research it may be exploited to explore how children (should) learn to write.

Family videos of 10 children later diagnosed as having autism or pervasive developmental disorders were analysed using a newly devised instrument. The checklist comprises 3 0 individual items and 20 functional categories. It evaluates behaviours in three areas: social interaction, communication and language, functional and symbolic play. The age range covered by home movies was divided into four periods (0-6, 6-12, 12-18 and 18-24 months) and analysed accordingly. The checklist data allow for the derivation of a general developmental profile as well as individual profiles. The most common profile was one in which children made progress from the first to the second or third age period, whereas from the second or third to the fourth period they showed a loss of previously mastered behaviours. The loss was statistically significant in socio-interactive behaviours, less evident in communication/language, and moderate in the area of action schemes and play. Mutual attention (dyadic eye contact), attachment behaviours, emotional reactions and vocalizations were present in almost all the children studied. On the other hand, communicative gestures (pointing, showing, ritualized requests), pretend play and conventional social games were rarely observed. The implications of these results for early diagnosis as well as for theories of early development in autism and severe developmental disorders are briefly discussed.

No abstract

Lingual adenocarcinomas (ADC), either primary or metastatic to the tongue are extraordinarily rare neoplasms. Primary lingual adenocarcinomas are primarily of minor salivary gland origin. Two cases of primary colonic-type adenocarcinomas of the base of the tongue were recently reported for the first time in the English literature. We present an additional case of lingual intestinaltype adenocarcinoma with mucinous features that occurred in association with cervical node metastasis and discuss the clinicopathologic features and histogenetic aspects of this rare entity.