[Dens invaginatus. Review of the literature and diagnostic and therapeutic guidelines]

Dens invaginatus is a clinically relevant malformation of teeth resulting from an infolding of enamel and dentine into the dental structure during tooth formation, hence the former denomination "dens in dente". The dens invaginatus shows multiple morphological variations of crown and root formation. This frequently leads to caries, pulpal and periodontal involvement with necrosis and loss of attachment. Therefore, early diagnosis and prevention are of utmost importance. Due to the complexity of the malformation, treatment options in former days were limited. This article presents a profound review of the literature regarding etiology, epidemiology and histology. It discusses clinical appearance and diagnosis and it provides guidelines for decision-making and treatment of invaginated teeth.

The murine Fgfrl1 receptor is essential for the development of the metanephric kidney

Fgfrl1 is a novel member of the fibroblast growth factor receptor family. Its extracellular domain resembles the four conventional Fgfrs, while its intracellular domain lacks the tyrosine kinase domain necessary for Fgf mediated signal transduction. During embryonic development Fgfrl1 is expressed in the musculoskeletal system, in the lung, the pancreas and the metanephric kidney. Targeted disruption of the Fgfrl1 gene leads to the perinatal death of the mice due to a hypoplastic diaphragm, which is unable to inflate the lungs. Here we show that Fgfrl1-/- embryos also fail to develop the metanephric kidney. While the rest of the urogenital system, including bladder, ureter and sexual organs, develops normally, a dramatic reduction of ureteric branching morphogenesis and a lack of mesenchymal-to-epithelial transition in the nephrogenic mesenchyme result in severe renal dysgenesis. The failure of nephron induction might be explained by the absence of the tubulogenic markers Wnt4, Fgf8, Pax8 and Lim1 at E12.5 of the mutant animals. We also observed a loss of Pax2 positive nephron precursor cells and an increase of apoptosis in the cortical zone of the remnant kidney. Fgfrl1 is therefore essential for mesenchymal differentiation in the early steps of nephrogenesis.

Comparison of the receptor FGFRL1 from sea urchins and humans illustrates evolution of a zinc binding motif in the intracellular domain

BACKGROUND: FGFRL1, the gene for the fifth member of the fibroblast growth factor receptor (FGFR) family, is found in all vertebrates from fish to man and in the cephalochordate amphioxus. Since it does not occur in more distantly related invertebrates such as insects and nematodes, we have speculated that FGFRL1 might have evolved just before branching of the vertebrate lineage from the other invertebrates (Beyeler and Trueb, 2006). RESULTS: We identified the gene for FGFRL1 also in the sea urchin Strongylocentrotus purpuratus and cloned its mRNA. The deduced amino acid sequence shares 62% sequence similarity with the human protein and shows conservation of all disulfides and N-linked carbohydrate attachment sites. Similar to the human protein, the S. purpuratus protein contains a histidine-rich motif at the C-terminus, but this motif is much shorter than the human counterpart. To analyze the function of the novel motif, recombinant fusion proteins were prepared in a bacterial expression system. The human fusion protein bound to nickel and zinc affinity columns, whereas the sea urchin protein barely interacted with such columns. Direct determination of metal ions by atomic absorption revealed 2.6 mole zinc/mole protein for human FGFRL1 and 1.7 mole zinc/mole protein for sea urchin FGFRL1. CONCLUSION: The FGFRL1 gene has evolved much earlier than previously assumed. A comparison of the intracellular domain between sea urchin and human FGFRL1 provides interesting insights into the shaping of a novel zinc binding domain.

Fish possess multiple copies of fgfrl1, the gene for a novel FGF receptor

FGFRL1 is a novel FGF receptor that lacks the intracellular tyrosine kinase domain. While mammals, including man and mouse, possess a single copy of the FGFRL1 gene, fish have at least two copies, fgfrl1a and fgfrl1b. In zebrafish, both genes are located on chromosome 14, separated by about 10 cM. The two genes show a similar expression pattern in several zebrafish tissues, although the expression of fgfrl1b appears to be weaker than that of fgfrl1a. A clear difference is observed in the ovary of Fugu rubripes, which expresses fgfrl1a but not fgfrl1b. It is therefore possible that subfunctionalization has played a role in maintaining the two fgfrl1 genes during the evolution of fish. In human beings, the FGFRL1 gene is located on chromosome 4, adjacent to the SPON2, CTBP1 and MEAEA genes. These genes are also found adjacent to the fgfrl1a gene of Fugu, suggesting that FGFRL1, SPON2, CTBP1 and MEAEA were preserved as a coherent block during the evolution of Fugu and man.

Three members of the connective tissue growth factor family CCN are differentially regulated by mechanical stress

Expression of connective tissue growth factor (CTGF), a member of the CCN gene family, is known to be significantly induced by mechanical stress. We have therefore investigated whether other members of the CCN gene family, including Cyr61 and Nov, might reveal a similar stress-dependent regulation. Fibroblasts growing under stressed conditions within a three-dimensional collagen gel showed at least a 15 times higher level of Cyr61 mRNA than cells growing under relaxed conditions. Upon relaxation, the decline of the Cyr61 mRNA to a lower level occurred within 2 h, and was thus quicker than the response of CTGF. The regulation was fully reversible when stress was reapplied. Thus, Cyr61 represents another typical example of a stress-responsive gene. The level of the Nov mRNA was low in the stressed state, but increased in the relaxed state. This CCN gene therefore shows an inverted regulation relative to that of Cyr61 and CTGF. Inhibition of protein kinases by means of staurosporine suppressed the stress-induced expression of Cyr61 and CTGF. Elevated levels of cAMP induced by forskolin mimicked the effects of relaxation on the regulation of Cyr61, CTGF and Nov. Thus, adenylate cyclase as well as one or several protein kinases might be involved in the mechanoregulation of these CCN genes.

Zyxin interacts with the SH3 domains of the cytoskeletal proteins LIM-nebulette and Lasp-1

Zyxin is a versatile component of focal adhesions in eukaryotic cells. Here we describe a novel binding partner of zyxin, which we have named LIM-nebulette. LIM-nebulette is an alternative splice variant of the sarcomeric protein nebulette, which, in contrast to nebulette, is expressed in non-muscle cells. It displays a modular structure with an N-terminal LIM domain, three nebulin-like repeats, and a C-terminal SH3 domain and shows high similarity to another cytoskeletal protein, Lasp-1 (LIM and SH3 protein-1). Co-precipitation studies and results obtained with the two-hybrid system demonstrate that LIM-nebulette and Lasp-1 interact specifically with zyxin. Moreover, the SH3 domain from LIM-nebulette is both necessary and sufficient for zyxin binding. The SH3 domains from Lasp-1 and nebulin can also interact with zyxin, but the SH3 domains from more distantly related proteins such as vinexin and sorting nexin 9 do not. On the other hand, the binding site in zyxin is situated at the extreme N terminus as shown by site-directed mutagenesis. LIM-nebulette and Lasp-1 use the same linear binding motif. This motif shows some similarity to a class II binding site but does not contain the classical PXXP sequence. LIM-nebulette reveals a subcellular distribution at focal adhesions similar to Lasp-1. Thus, LIM-nebulette, Lasp-1, and zyxin may play an important role in the organization of focal adhesions.

Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery--a randomized controlled trial

OBJECTIVE: Cardiac surgery is frequently followed by postoperative delirium, which is associated with increased 1-year mortality, late cognitive deficits, and higher costs. Currently, there are no recommendations for pharmacologic prevention of postoperative delirium. Impaired cholinergic transmission is believed to play an important role in the development of delirium. We tested the hypothesis that prophylactic short-term administration of oral rivastigmine, a cholinesterase inhibitor, reduces the incidence of delirium in elderly patients during the first 6 days after elective cardiac surgery. DESIGN:: Double-blind, randomized, placebo-controlled trial. SETTING: One Swiss University Hospital. PATIENTS: One hundred twenty patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTION: Patients were randomly assigned to receive either placebo or 3 doses of 1.5 mg of oral rivastigmine per day starting the evening before surgery and continuing until the evening of the sixth postoperative day. MEASUREMENTS AND MAIN RESULTS: The primary predefined outcome was delirium diagnosed with the Confusion Assessment Method within 6 days postoperatively. Secondary outcome measures were the results of daily Mini-Mental State Examinations and clock drawing tests, and the use of a rescue treatment consisting of haloperidol and/or lorazepam in patients with delirium. Delirium developed in 17 of 57 (30%) and 18 of 56 (32%) patients in the placebo and rivastigmine groups, respectively (p = 0.8). There was no treatment effect on the time course of Mini-Mental State Examinations and clock drawing tests (p = 0.4 and p = 0.8, respectively). There was no significant difference in the number of patients receiving haloperidol (18 of 57 and 17 of 56, p = 0.9) or lorazepam (38 of 57 and 35 of 56, p = 0.6) in the placebo and rivastigmine groups, respectively. CONCLUSION: This negative or, because of methodologic issues, possibly failed trial does not support short-term prophylactic administration of oral rivastigmine to prevent postoperative delirium in elderly patients undergoing elective cardiac surgery with cardiopulmonary bypass.

Benign prostatic obstruction and parkinson's disease--should transurethral resection of the prostate be avoided?

PURPOSE: According to the literature transurethral resection of the prostate in patients with Parkinson's disease has an increased risk of postoperative urinary incontinence. However, this conclusion might have been reached because some patients with multiple system atrophy incorrectly diagnosed as Parkinson's disease were included in these reports. Therefore, we investigated the outcome of transurethral prostate resection in patients with a secure neurological diagnosis of Parkinson's disease. MATERIALS AND METHODS: A total of 23 patients with Parkinson's disease who underwent transurethral prostate resection for benign prostatic obstruction were evaluated retrospectively. Subsequent neurological developments in patients were followed, ensuring that those with multiple system atrophy had not been included in analysis. RESULTS: At transurethral prostate resection median patient age was 73 years, median duration of Parkinson's disease before the resection was 3 years, and median Hoehn and Yahr scale was 2. Of the 14 patients with a preoperative indwelling urinary catheter transurethral prostate resection restored voiding in 9 (64%) and only 5 (36%) required catheterization postoperatively. Of the 10 patients with preoperative urge urinary incontinence, continence was restored in 5 and improved in 3 following transurethral prostate resection. There were no cases of de novo urinary incontinence after transurethral prostate resection. At a median postoperative followup of 3 years transurethral prostate resection was successful in 16 of the 23 patients (70%). CONCLUSIONS: Transurethral prostate resection for benign prostatic obstruction in patients with Parkinson's disease may be successful in up to 70% and the risk of de novo urinary incontinence seems minimal. Thus, Parkinson's disease should no longer be considered a contraindication for transurethral prostate resection provided that preoperative investigations including urodynamic assessment indicate prostatic bladder outlet obstruction.

Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1

Leukocyte transmigration is mediated by endothelial cell (EC) junctional molecules, but the associated mechanisms remain unclear. Here we investigate how intercellular adhesion molecule-2 (ICAM-2), junctional adhesion molecule-A (JAM-A), and platelet endothelial cell adhesion molecule (PECAM-1) mediate neutrophil transmigration in a stimulus-dependent manner (eg, as induced by interleukin-1beta [IL-1beta] but not tumor necrosis factor-alpha [TNF-alpha]), and demonstrate their ability to act in sequence. Using a cell-transfer technique, transmigration responses of wild-type and TNF-alpha p55/p75 receptor-deficient leukocytes (TNFR(-/-)) through mouse cremasteric venules were quantified by fluorescence intravital microscopy. Whereas wild-type leukocytes showed a normal transmigration response to TNF-alpha in ICAM-2(-/-), JAM-A(-/-), and PECAM-1(-/-) recipient mice, TNFR(-/-) leukocytes exhibited a reduced transmigration response. Hence, when the ability of TNF-alpha to directly stimulate neutrophils is blocked, TNF-alpha-induced neutrophil transmigration is rendered dependent on ICAM-2, JAM-A, and PECAM-1, suggesting that the stimulus-dependent role of these molecules is governed by the target cell being activated. Furthermore, analysis of the site of arrest of neutrophils in inflamed tissues from ICAM-2(-/-), JAM-A(-/-), and PECAM-1(-/-) mice demonstrated that these molecules act sequentially to mediate transmigration. Collectively, the findings provide novel insights into the mechanisms of action of key molecules implicated in leukocyte transmigration.