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Turan S.,Harvard University | Turan S.,Marmara University | Fernandez-Rebollo E.,Harvard University | Fernandez-Rebollo E.,Hospital Clinic Of Barcelona | And 10 more authors.
Journal of Bone and Mineral Research | Year: 2014

Pseudohypoparathyroidism type-Ia (PHP-Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of α-subunit of the stimulatory G protein (Gαs) activity. Gαs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP-Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP-Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH resistance occurs in a delayed fashion. Analyzing reported cases of PHP-Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH resistance caused by the maternal loss of Gαs, ie, hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gαs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gαs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (3 weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gαs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gαs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gαs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with the latency of PTH resistance in patients with PHP-Ia. © 2014 American Society for Bone and Mineral Research.


Thiele S.,University of Lübeck | de Sanctis L.,University of Turin | Werner R.,University of Lübeck | Grotzinger J.,University of Kiel | And 5 more authors.
Human Mutation | Year: 2011

Pseudohypoparathyroidism type Ia (PHPIa) is caused by GNAS mutations leading to deficiency of the α-subunit of stimulatory G proteins (Gsα) that mediate signal transduction of G protein-coupled receptors via cAMP. PHP type Ic (PHPIc) and PHPIa share clinical features of Albright hereditary osteodystrophy (AHO); however, in vitro activity of solubilized Gsα protein is normal in PHPIc but reduced in PHPIa. We screened 32 patients classified as PHPIc for GNAS mutations and identified three mutations (p.E392K, p.E392X, p.L388R) in four unrelated families. These and one novel mutation associated with PHPIa (p.L388P) were introduced into a pcDNA3.1(-) expression vector encoding Gsα wild-type and expressed in a Gsα-null cell line (GnasE2-/E2-). To investigate receptor-mediated cAMP accumulation, we stimulated the endogenous expressed β2-adrenergic receptor, or the coexpressed PTH or TSH receptors, and measured the synthesized cAMP by RIA. The results were compared to receptor-independent cholera toxin-induced cAMP accumulation. Each of the mutants associated with PHPIc significantly reduced or completely disrupted receptor-mediated activation, but displayed normal receptor-independent activation. In contrast, PHPIa associated p.L388P disrupted both receptor-mediated activation and receptor-independent activation. We present a new subgroup of PHP that is caused by Gsα deficiency and selectively affects receptor coupling functions of Gsα. © 2011 Wiley-Liss, Inc.


Liu Z.,Harvard University | Segawa H.,Harvard University | Segawa H.,Tokushima University | Aydin C.,Harvard University | And 9 more authors.
Endocrinology | Year: 2011

XLαs, a variant of the stimulatory G protein α-subunit (Gsα), can mediate receptor-activated cAMP generation and, thus, mimic the actions of Gsα in transfected cells. However, it remains unknown whether XLαs can act in a similar manner in vivo. We have now generated mice with ectopic transgenic expression of rat XLαs in the renal proximal tubule (rptXLαs mice), where Gsα mediates most actions of PTH. Western blots and quantitative RT-PCR showed that, while Gsα and type-1 PTH receptor levels were unaltered, protein kinase A activity and 25-hydroxyvitamin D 1-α-hydroxylase (Cyp27b1) mRNA levels were significantly higher in renal proximal tubules of rptXLαs mice than wild-type littermates. Immunohistochemical analysis of kidney sections showed that the sodium-phosphate cotransporter type 2a was modestly reduced in brush border membranes of male rptXLαs mice compared to gender-matched controls. Serum calcium, phosphorus, and 1,25 dihydroxyvitamin D were within the normal range, but serum PTH was ∼30% lower in rptXLαs mice than in controls (152 ± 16 vs. 222 ± 41 pg/ml; P < 0.05). After crossing the rptXLαs mice to mice with ablation of maternal Gnas exon 1 (E1m-/+), male offspring carrying both the XLαs transgene and maternal Gnas exon 1 ablation (rptXLαs/E1m-/+) were significantly less hypocalcemic than gender-matched E1m-/+ littermates. Both E1m-/+ and rptXLαs/E1m-/+ offspring had higher serum PTH than wild-type littermates, but the degree of secondary hyperparathyroidism tended to be lower in rptXLαs/E1m-/+ mice. Hence, transgenic XLαs expression in the proximal tubule enhanced Gsα-mediated responses, indicating that XLαs can mimic Gsα in vivo. Copyright © 2011 by The Endocrine Society.


PubMed | Istanbul University and Center for Dental science
Type: Journal Article | Journal: Acta odontologica Scandinavica | Year: 2016

To evaluate the effects of maxillary canine retraction on pulpal blood flow (PBF) in humans as recorded by laser Doppler flowmetry (LDF).Maxillary canines of 24 participants were divided into two groups (n=12 each). Teeth in the study group underwent maxillary canine retraction using mini-implants as anchorage for approximately 4 months, with 100g of force applied via coil springs. Subjects in the control group received no orthodontic treatment. LDF measurements were recorded at baseline (T0); during retraction, at 24hours (T1), 3 days (T2), 7 days (T3) and 1 month (T4); and at the end of retraction (T5) in the study group and at similar time-points in control subjects. Data were analyzed using the Friedman, Wilcoxon signed rank and Mann-Whitney U tests, with the significance level set at 0.05.No significant changes in PBF perfusion units (PU) were observed in the control group over the course of the study. However, PBF in the study group increased significantly from T0 (3.60.2 PU) to T1 (3.70.2 PU, p<0.001) and decreased severely from T1 to T2 (3.30.1, p<0.001). PBF in the study group was still significantly lower at T3 (3.40.1 PU, p<0.001) in comparison to T0; however, at T4 and T5, PBF was found to have returned to pre-retraction levels.The fact that PBF values returned to initial levels within one month of the initiation of retraction despite short-term, hyperaemic, regressive changes demonstrates that the changes observed in PBF during canine retraction are reversible.


PubMed | Center for Dental science
Type: Comparative Study | Journal: Journal of endodontics | Year: 2010

The aim of this study was to evaluate the push-out bond strength of iRoot SP (Innovative Bioceramix, Vancouver, Canada) and compare it with that of other widely used root canal sealers.Sixty extracted human maxillary canines were sectioned transversally below the cement-enamel junction to obtain 120 4-mm-thick dentin disks that were randomly divided into four groups (n = 30) for treatment with one of four different root-canal sealers (iRoot SP, AH Plus [Dentsply DeTrey GmbH, Konstanz, Germany], Sealapex [SybronEndo Corporation, Orange, CA], EndoREZ [Ultradent Inc, South Jordan, UT]). Standardized cavities were prepared to simulate root canals, cavities were filled with sealer material, and push-out bond-strength testing was performed using a universal testing machine. Failure modes were assessed quantitatively under a stereomicroscope and morphologically under a scanning electron microscope. Statistical analysis was performed using one-way analysis of variance and the post hoc Tukey test, with the significance level set at 0.05.Bond strengths of iRoot SP and AH Plus were significantly higher than those of Sealapex and EndoREZ. There was no significant difference between the bond strength of iRoot SP and AH Plus (p= 0.274).iRoot SP and AH Plus performed similarly and better than EndoREZ and Sealapex in terms of bond strength.


To assess and compare the water sorption, solubility and apical sealing ability of iRoot SP and three other widely used root canal sealers.Solubility was assessed by immersing standardized samples of calcium silicate- (iRoot SP), calcium hydroxide- (Sealapex), methacrylate resin- (EndoREZ) and epoxy resin- (AH Plus) based sealers in distilled water and measuring weight gain and weight loss at 6 h, 24 h and daily for 14 days. Roots of extracted mandibular premolars (n = 80) were prepared with 0.04-taper nickel-titanium rotary files to a final size 40. Roots were then randomly divided into four experimental groups (n = 18) and two control groups (n = 4), root canal sealers were applied and apical leakage was assessed using the fluid filtration method. Data was analyzed using Kruskal Wallis analysis of variance and Mann-Whitney U-tests, with the level of significance set at p 0.05.EndoREZ exhibited the highest water sorption, followed by iRoot SP, Sealapex and AH Plus. Sealapex exhibited significantly higher solubility than the other sealers, whereas no significant differences in solubility levels were observed between the other three sealers tested. AH Plus exhibited significantly lower microleakage than Sealapex and EndoREZ, whereas no difference in microleakage was found between AH Plus and iRoot SP.In view of the study findings, all tested sealers except Sealapex met the ANSI/ADAs requirements for solubility and no difference was found between AH Plus and iRoot SP in terms of apical sealing ability.


Aydin C.,Center for Dental science | Inan U.,Ondokuz Mayis University | Tunca Y.M.,Center for Dental science
Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology | Year: 2010

Objective: The aim of this study was to evaluate cyclic fatigue resistance of used and new RaCe rotary nickel-titanium instruments. Study design: Forty RaCe (FKG Dentaire, La-Chaux-de-Fonds, Switzerland) instruments of sizes 30/.06, 30/.02, 25/.04, and 25/.02 were selected and divided into 2 groups: group A = 20 new instruments; group B = 20 used instruments. In group B, each instrument was used for shaping 5 curved molar root canals. Cyclic fatigue testing of new and used instruments was performed using a device that allowed the instruments to rotate freely inside a stainless steel artificial canal. Data were analyzed using t test to determine any statistical significance between used and new instruments of the same file size. Results: For all sizes, new instruments were more resistant to failure then the used ones (P < .05). A reduction in lifespan was observed ranging from 18% (30/.06) to 51% (25/.02). Conclusion: The results showed that clinical use significantly reduced cyclic fatigue resistance of RaCe rotary instruments compared with new ones. © 2010 Mosby, Inc. All rights reserved.


Aim. To assess and compare the water sorption, solubility and apical sealing ability of iRoot SP and three other widely used root canal sealers. Materials and methods. Solubility was assessed by immersing standardized samples of calcium silicate- (iRoot SP), calcium hydroxide- (Sealapex), methacrylate resin- (EndoREZ) and epoxy resin- (AH Plus) based sealers in distilled water and measuring weight gain and weight loss at 6 h, 24 h and daily for 14 days. Roots of extracted mandibular premolars (n = 80) were prepared with 0.04-taper nickel-titanium rotary files to a final size 40. Roots were then randomly divided into four experimental groups (n = 18) and two control groups (n = 4), root canal sealers were applied and apical leakage was assessed using the fluid filtration method. Data was analyzed using Kruskal Wallis analysis of variance and Mann-Whitney U-tests, with the level of significance set at p ≤ 0.05. Results. EndoREZ exhibited the highest water sorption, followed by iRoot SP, Sealapex and AH Plus. Sealapex exhibited significantly higher solubility than the other sealers, whereas no significant differences in solubility levels were observed between the other three sealers tested. AH Plus exhibited significantly lower microleakage than Sealapex and EndoREZ, whereas no difference in microleakage was found between AH Plus and iRoot SP. Conclusions. In view of the study findings, all tested sealers except Sealapex met the ANSI/ADA's requirements for solubility and no difference was found between AH Plus and iRoot SP in terms of apical sealing ability. © 2013 Informa Healthcare.

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