Novel Dental Anomaly–associated Mutations in WNT10A Protein Binding Sites

ObjectiveWNT/β-catenin signaling is initiated by binding of a WNT protein to a Frizzled (FZD) receptor and a co-receptor, low-density lipoprotein (LDL) receptor-related protein 5 or 6 (LRP5/6). The objective of this study was to find the genetic variants responsible for dental anomalies found in 4 families.MethodsClinical and radiographic examination and whole exome sequencing were performed on 5 patients affected with dental anomalies and the mutant proteins modeled.ResultsFive patients were heterozygous for the WNT10A variants, including c.877C>T; p.Arg293Cys, c.874A>G; p.Ser292Gly, c.1042C>T; p.Arg348Cys, and c.1039G>T; p.347GluX. The p.Arg293Cys and p.Ser292Gly mutations are located in the WNT10A N-terminal domain region with binding sites for FZD receptor, porcupine, WNTLESS, and extracellular binding proteins, so they are likely to have adverse effects on binding these proteins. The p.Arg348Cys mutation, which is located in the binding site of LRP5/6 co-receptors, is postulated to result in impaired binding to these co-receptors. The nonsense mutation p.347GluX is predicted to result in the truncation of most of the C-terminal domain, which is likely to disrupt the binding of WNT10A to WNTLESS, the membrane protein that binds lipid-acylated WNT proteins to carry them from the endoplasmic reticulum to the cell surface and FZD.ConclusionsFour novel mutations in WNT10A were identified in patients with isolated tooth agenesis. The mutations in the N-terminal domain and the interface between the N- and C-terminal domains of WNT10A in our patients are likely to disrupt its binding with FZD, LRP5/6, and various other proteins involved in WNT10A processing and transport, impair WNT and SHH signaling, and subsequently result in tooth agenesis, microdontia, and root maldevelopment.Key words: WNT10A mutation, Frizzled binding site, Dental anomaly, Hypodontia, Dental malformation, Dental defect     

Diarylheptanoid 1-(4-hydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-one enhances C2C12 myoblast differentiation by targeting membrane estrogen receptors and activates Akt-mTOR and p38 MAPK-NF-κB signaling axes

Journal of Natural Medicines - Diarylheptanoid, 1-(4-hydroxyphenyl)-7-phenyl(6E)-6-hepten-3-one (HPPH), has been reported to enhance myoblast differentiation via estrogen receptor (ER). However,...     

Epidemiologic Analysis of Proximal Deep Vein Thrombosis in Thai Patients: Malignancy,the Predominant Etiologic Factor

From January 1995 to December 2000, 1555 patients (585 males, 970 females, with a mean age of 52.3 years) with acute limb swelling underwent diagnostic duplex venous ultrasonagraphy at the Vascular Surgery Unit, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. Of these 1555 patients, 514 (188 males, 326 females, with a mean age of 53 years) were diagnosed with deep vein thrombosis (DVT). DVT was found mainly in the lower extremities, occurring in 506 of these 514 cases (98.4%). The affected vein in the lower extremity was found more commonly in the left side (359 limbs) than in the right side (184 limbs) (p < 0.001). DVT also occurred in the upper extremities in 8 of the 514 cases (1.6%). In this study, out of 308 patients with DVT in their lower limbs, DVT was associated with malignancy in 123 cases (39.9%), with postoperation in 48 cases (15.6%), and with limb immobilization in 38 cases (12.3%). Malignancy-related DVT was found to be more extensive and virulent and was associated with high morbidity and mortality. Further study should be conducted to investigate the role of anticoagulant drugs for the prevention of DVT in cancer patients. Perhaps the spectrum of DVT as presented in this series is characteristic not only of the Thai population but also of the populations of other Asian countries.     

Fertility and electrolyte composition of the rat cauda epididymal plasma and spermatozoa before and after castration

Attempts have been made to assess the changes in Na⁺ and K⁺ concentrations in the cauda epididymal plasma and spermatozoa, and to correlate these parameters to changes in fertility shortly after castration in the rat. Fertility was markedly decreased 3 days after androgen withdrawal. By contrast, spermatocrit and Na⁺ concentration in spermatozoa were increased on day 2 post-castration. Neither Na⁺ and K⁺ concentrations in the plasma nor K⁺ inside spermatozoa were altered. The results are discussed in terms of a reduction in the epididymal secretion of macromolecules which are responsible for an increase in net Na⁺ influx into sperm cells.     

Relationship between oversizing of self-expanding stents and late loss index in carotid stenting

Stenting of the internal carotid artery is facilitated by stenting across the carotid bifurcation and sizing the diameter of a self-expanding stent to the large common carotid segment. This usually results in marked oversizing of the self-expanding stent in the internal carotid segment. This study was done to determine the relationship between stent oversizing and late luminal loss index after stenting of the internal carotid artery. Between September 1995 and March 1997, there were 165 patients (189 vessels) who underwent successful carotid stenting with self-expanding stents. Fifty-nine patients (63 vessels) had six-month follow-up carotid angiograms and on-line quantitative angiographic analysis. The mean reference diameter of the internal carotid arteries was 4.93 ± 1.31 mm. Nominal stent size was 5 mm in 4 patients, 6 mm in 6 patients, 8 mm in 106 patients, 10 mm in 77 patients, and 12 mm in 1 patient. The average stent/patient was 1.03 ± 0.16. There were three patients who had more than 50% diameter renarrowing at follow-up. The mean late loss index was 0.25 ± 0.41. By linear regression analysis, there was no clear linear relationship between stent oversizing and late loss index after stenting (correlation coefficient = -0.21, P = 0.09). When analysis of variance with linear contrast was used to analyze six groups of different stent/artery ratios (from 1.4 to ≥ 2), late loss indexes are significantly lower in the groups of high stent/artery ratio than the groups of low stent/artery ratio (P = 0.01). The process of oversizing of self-expanding stents deployed in the internal carotid artery does not appear to be associated with late restenosis and high stent/artery ratio seems to be associated with low late loss index. Cathet. Cardiovasc. Diagn. 45:139–143, 1998. © 1998 Wiley-Liss, Inc.     

A rapidly fatal case of Panton-valentine leukocidin positive Staphylococcus aureus necrotizing pneumonia in an HIV-infected patient

This article reports a rare case of necrotizing pneumonia caused by Panton-Valentine leukocidin (PVL) positive Staphylococcus aureus in an HIV-infected patient presenting with severe back pain and rash. The back pain progressed to excruciating abdominal pain which was misleading, resulting in an investigation on intraabdominal conditions. He developed massive hemoptysis and died within 2 days of the first clinical symptoms. Recognizing the emergence of PVL-producing S. aureus is important in both immunocompetent and immunocompromised patients. This organism was transmitted from his wife.     

Pedal bypass with deep venous arterialization: the therapeutic option in critical limb ischemia and unreconstructable distal arteries

Heavily calcified and severely stenotic distal arteries defined as unreconstructable, precludes the possibility of revascularization, resulting in major amputation in patients with critical limb ischemia. However, providing blood supply to the ischemic foot through the venous system instead of the arterial system may improve the circulation adequately for the healing process in the vascular compromised distal tissue. This study aimed to assess the safety and efficacy of pedal bypass with deep venous arterialization, one of the possible procedures to improve the circulation through the venous system in critically ischemic limbs and unreconstructable distal arteries. Twenty-six patients with critical limb ischemia and an unreconstructable distal artery of the lower extremities were included for the surgical procedure. Arterial bypass with distal anastomosis at the paramalleolar deep vein was carried out through a composite graft combined with adequate destruction of valve competency in the distal vein. The primary endpoint was complete healing of ischemic ulcer with amelioration of rest pain within six months. The secondary endpoints were the outcomes of survival, limb salvage and primary graft patency rate at six-month intervals to 24 months. Nineteen patients (73.1%) had complete healing of ischemic ulcer and disappearance of rest pain within six months. Six patients (23.1%) underwent major amputation. Perioperative mortality was 3.8%. After 24 months of follow-up study, the survival rate was 87.5%, whereas the limb salvage and graft patency rates were 76.02 and 49.17%, respectively. Pedal bypass with deep venous arterialization may be another therapeutic option to enhance the healing of ischemic ulcer and limb salvageability in patients with critical limb ischemia and unreconstructable distal artery.     

Nitric oxide signalling is involved in diarylheptanoid‐induced increases in femoral arterial blood flow in ovariectomized rats

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Activity and subcellular trafficking of the sodium-coupled choline transporter CHT is regulated acutely by peroxynitrite

Excess formation of nitric oxide and superoxide by-products (peroxynitrite, reactive oxygen, and reactive nitrogen species) attenuates cholinergic transmission potentially having a role in Alzheimer disease pathogenesis. In this study, we investigated mechanisms by which acute exposure to peroxynitrite impairs function of the sodium-dependent hemicholinium-3 (HC-3)-sensitive choline transporter (CHT) that provides substrate for acetylcholine synthesis. The peroxynitrite generator 3-morpholinosydnonimine (SIN-1) acutely inhibited choline uptake in cells stably expressing FLAG-tagged rat CHT in a dose- and time-dependent manner, with an IC(50) = 0.9 +/- 0.14 mM and t((1/2)) = 4 min. SIN-1 significantly reduced V(max) of choline uptake without altering the K(m). This correlated with a SIN-1-induced decrease in cell surface CHT protein, observed as lowered levels of HC-3 binding and biotinylated CHT at the plasma membrane. It is noteworthy that short-term exposure of cells to SIN-1 accelerated the rate of internalization of CHT from the plasma membrane, but it did not alter return of CHT back to the cell surface. SIN-1 did not disrupt cell membrane integrity or cause cell death. Thus, the inhibitory effect of SIN-1 on choline uptake activity and HC-3 binding was related to enhanced internalization of CHT proteins from the plasma membrane to subcellular organelles.