Tooth root dentin mineralization defects in a mouse model of hypophosphatasia.

Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PP(i) ), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PP(i) , resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in Alpl(-/-) mice, a model for infantile HPP. In Alpl(-/-) mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in Alpl(-/-) mice. TNAP was found to be highly expressed by mature odontoblasts, and Alpl(-/-) molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in Alpl(-/-) dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in Alpl(-/-) mice, was present in the generally unmineralized Alpl(-/-) mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in Alpl(-/-) mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to Alpl(-/-) mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PP(i) during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients.

Sources of influence on medical practice.

OBJECTIVES: To explore the opinion of general practitioners on the importance and legitimacy of sources of influence on medical practice. METHODS: General practitioners (n=723) assigned to Primary Care Teams (PCTs) in two Spanish regions were randomly selected to participate in this study. A self administered questionnaire was sent by mail and collected by hand. The dependent variable collected the opinion on different sources that exert influence on medical practice. Importance was measured with a 9 item scale while legitimacy was evaluated with 16 items measured with a 1 to 7 point Likert scale. RESULTS: The most important and legitimate sources of influence according to general practitioners were: training courses and scientific articles, designing self developed protocols and discussing with colleagues. The worst evaluated were: financial incentives and the role played by the pharmaceutical industry. CONCLUSIONS: The development of medical practice is determined by many factors, grouped around three big areas: organisational setting, professional system and social setting. The medical professional system is the one considered as being the most important and legitimate by general practitioners. Other strategies of influence, considered to be very important by the predominant management culture (financial incentives), are not considered to be so by general practitioners. These results, however, are not completely reliable as regards the real network of influences existing in medical practice, which reflect instead different "value systems".