Dental impact of anti-fibroblast growth factor 23 therapy in X-linked hypophosphatemia.

Elevated fibroblast growth factor 23 (FGF23) in X-linked hypophosphatemia (XLH) results in rickets and phosphate wasting, manifesting by severe bone and dental abnormalities. Burosumab, a FGF23-neutralizing antibody, an alternative to conventional treatment (phosphorus and active vitamin D analogs), showed significant improvement in the long bone phenotype. Here, we examined whether FGF23 antibody (FGF23-mAb) also improved the dentoalveolar features associated with XLH. Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg-1 of FGF23-mAb for 2 months and compared to wild-type (WT) and vehicle (PBS) treated Hyp mice (n = 3-7 mice). Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice, the higher concentration resulting in a rescue similar to WT levels. FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones. Histology revealed improved mineralization of the dentoalveolar tissues, with a decreased amount of osteoid, predentin and cementoid. Better periodontal ligament attachment was also observed, evidenced by restoration of the acellular cementum. These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features. Taken together, our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment, heralding its benefit in clinics for dental abnormalities.

Orthodontic tooth movement alters cementocyte ultrastructure and cellular cementum proteome signature.

Cementum is a mineralized tissue that covers tooth roots and functions in the periodontal attachment complex. Cementocytes, resident cells of cellular cementum, share many characteristics with osteocytes, are mechanoresponsive cells that direct bone remodeling based on changes in loading. We hypothesized that cementocytes play a key role during orthodontic tooth movement (OTM). To test this hypothesis, we used 8-week-old male Wistar rats in a model of OTM for 2, 7, or 14 days (0.5 N), whereas unloaded contralateral teeth served as controls. Tissue and cell responses were analyzed by high-resolution micro-computed tomography, histology, tartrate-resistant acid phosphatase staining for odontoclasts/osteoclasts, and transmission electron microscopy. In addition, laser capture microdissection was used to collect cellular cementum, and extracted proteins were identified by liquid chromatography coupled to tandem mass spectrometry. The OTM model successfully moved first molars mesially more than 250 µm by 14 days introducing apoptosis in a small number of cementocytes and areas of root resorption on mesial and distal aspects. Cementocytes showed increased nuclear size and proportion of euchromatin suggesting cellular activity. Proteomic analysis identified 168 proteins in cellular cementum with 21 proteins found only in OTM sites and 54 proteins only present in control samples. OTM-down-regulated several extracellular matrix proteins, including decorin, biglycan, asporin, and periostin, localized to cementum and PDL by immunostaining. Furthermore, type IV collagen (COL14A1) was the protein most down-regulated (-45-fold) by OTM and immunolocalized to cells at the cementum-dentin junction. Eleven keratins were significantly increased by OTM, and a pan-keratin antibody indicated keratin localization primarily in epithelial remnants of Hertwig's epithelial root sheath. These experiments provide new insights into biological responses of cementocytes and cellular cementum to OTM.

Cementocyte alterations associated with experimentally induced cellular cementum apposition in Hyp mice.

BACKGROUND: Cellular cementum, a mineralized tissue covering apical tooth roots, grows by apposition to maintain the tooth in its occlusal position. We hypothesized that resident cementocytes would show morphological changes in response to cementum apposition, possibly implicating a role in cementum biology. METHODS: Mandibular first molars were induced to super-erupt (EIA) by extraction of maxillary molars, promoting rapid new cementum formation. Tissue and cell responses were analyzed at 6 and/or 21 days post-procedure (dpp). RESULTS: High-resolution micro-computed tomography (micro-CT) and confocal laser scanning microscopy showed increased cellular cementum by 21 dpp. Transmission electron microscopy (TEM) revealed that cementocytes under EIA were 50% larger than control cells, supported by larger pore sizes detected by micro-CT. Cementocytes under EIA displayed ultrastructural changes consistent with increased activity, including increased cytoplasm and nuclear size. We applied EIA to Hyp mutant mice, where cementocytes have perilacunar hypomineralization defects, to test cell and tissue responses in an altered mechanoresponsive milieu. Hyp and WT molars displayed similar super-eruption, with Hyp molars exhibiting 28% increased cellular cementum area versus 22% in WT mice at 21 dpp. Compared to control, Hyp cementocytes featured well-defined, disperse euchromatin and a thick layer of peripherally condensed heterochromatin in nuclei, indicating cellular activity. Immunohistochemistry (IHC) for cementum markers revealed intense dentin matrix protein-1 expression and abnormal osteopontin deposition in Hyp mice. Both WT and Hyp cementocytes expressed gap junction protein, connexin 43. CONCLUSION: This study provides new insights into the EIA model and cementocyte activity in association with new cementum formation.

The effect of air-particle abrasion and a zirconia primer application on resin cement bonding strength to zirconia.

BACKGROUND: This study aimed to evaluate the influence of surface treatments on the bond strength between a zirconia-based ceramic and two resin cements. METHODS: Eighty blocks (5.25×3.74×4.5 mm) of a zirconia-based ceramic were divided into eight groups (N.=10) according to the factors "surface treatment" (air-particle abrasion with Al2O3 or Al2O3/SiO2 and zirconia primer) and "cement" (conventional resin cement and self-adhesive resin cement). After the surface treatments, cylinders of each resin cement (Ø=3.5 mm, height: 3 mm) were built up on the zirconia surface and photo-activated (40 s). The samples were stored in water for 30 days at 37 °C, followed by shear bond strength test in a universal testing machine (1 mm/min). Data were analyzed by ANOVA and Tukey test (α=0.05). RESULTS: Regarding the surface treatments, all strategies were statistically different from each other. The Cojet achieved the higher bond strength values, followed by Signum Zirconia Bond. The resin cements were also statistically different from each other, since the U200 achieved higher bond strength values. The interaction between the factors was also significant. Most of the failures were adhesive and mixed. CONCLUSIONS: Regardless of the cement used, the air-particle abrasion with alumina coated by silica particles improved bond strength.

[Magnetic resonance imaging of medial meniscus tears with displaced fragment in the meniscal recesses]. / Diagnostic IRM des lambeaux méniscaux médiaux déplacés le long du ligament tibial collatéral.

PURPOSE OF THE STUDY: Displaced meniscus tears generally result from bucket handle tears with subsequent migration of the meniscal fragment into the intercondylar notch. More rarely, the fragment may move into the meniscal recesses. In this situation, the displaced fragment may be difficult to individualize arthroscopically, so preoperative imaging is crucial. Several studies have demonstrated the reliability of magnetic resonance imaging (MRI) for the diagnosis of meniscus injury with fragment displacement in the intercondylar notch. There have been few studies devoted to fragment displacement into the collateral capsuloligamentary structures. The purpose of this study was to describe MRI findings of medial meniscus tears with displaced fragment in the meniscal recesses. MATERIAL AND METHODS: This prospective study was conducted over a 22-month period (May 2003 - February 2005). During this period, we selected 39 patients whose knee MRI displayed a meniscal fragment within the medial collateral recesses. These 39 patients accounted for 15% of knees with MRI-diagnosed meniscal tears (n=272) and 2% of the knee MRI examinations performed during the study period (n=2239). One the MRI series, we studied fragment migration and morphological anomalies of the injured meniscus. For 16 knees, MRI findings could be compared with arthroscopy findings. RESULTS: For 25 knees (65%), the meniscal fragment had migrated downward along the medial tibial plateau and generally (64%) medially to the collateral tibial ligament. For 14 knees (35%) the meniscal fragment had migrated upward, along the medial femoral condyle in 93%, anteriorly to the medial collateral tibial ligament. For 95%, the MRI demonstrated rupture along the free border of the posterior segment and/or the mid segment of the medial meniscus or a decreased height of the posterior segment of the medial meniscus. For 14 of 16 cases, arthroscopy confirmed the meniscal tear and the localization of the displaced fragment. For two knees, arthroscopy confirmed the presence of the meniscal tear but could not identify the displaced meniscal fragment. DISCUSSION: Meniscal tears with fragment displacement into the meniscal recesses has been associated with displacement of a horizontal fissuration which flap tears described arthroscopically by DJ Dandy. Other authors consider these tear flaps as oblique fissurations. In our study, it was sometimes difficult to determine the exact site and orientation of the initial meniscal tear so it is quite likely that meniscal tears with a displaced fragment in the meniscal recesses could correspond to complex predominantly horizontal or oblique meniscal fissurations. The common feature is the presence of an unstable meniscal flap susceptible to migrate. Our findings are in agreement with the literature. Regarding the two cases where the MRI findings could not be confirmed arthroscopically, the MRI visualized a characteristic image of a meniscal fragment displaced downwardly, lying between the medial tibial plateau and the collateral tibial ligament. Arthroscopy visualized the meniscal tear but failed to visualize the displaced fragment. This might be because mobile meniscal fragments return into the joint interspace when the meniscus is manipulated arthroscopically. Small meniscal fragments might also be inaccessible arthroscopically.

Pharmacokinetics of lamotrigine (Lamictal) in plasma and saliva.

The kinetics of lamotrigine (LTG) disposition in plasma and saliva was evaluated in patients undergoing long-term antiepileptic drug therapy. Blood and saliva samples were collected simultaneously at intervals during the study and the concentration of LTG was measured by HPLC. Concentrations of LTG in saliva were proportional to plasma LTG concentrations, with a significant (p) correlation of r = 0.95 + 0.18. The saliva concentration-time curves of LTG were parallel to those derived for plasma LTG. The kinetics of LTG absorption, elimination and mean residence time were identical in both saliva and plasma estimations. The saliva/plasma ratio, determined from the terminal phase of individual patient LTG concentration vs time curves, was used to predict plasma LTG concentrations from saliva determinations. The binding of LTG to plasma proteins remained constant in patients treated with sodium valproate and/or enzyme-inducing drugs. Thus, LTG determination in saliva represents a noninvasive alternative for therapeutic drug monitoring and may also be employed for studying LTG pharmacokinetics.

Changes of lithium elimination in acute polyuric renal failure caused by cisplatin and mercuric chloride.

Changes in lithium elimination were studied under the condition of experimentally induced polyuric acute renal failure by cisplatin (6 mg/kg body wt) or HgCl2 (3 mg/kg body wt). The histologically proven lesions of tubuli were associated with the decrease of plasma clearance of lithium (C(Li)) and polyfructosan-S (CP(FS). The decrease of these clearance values was not proportional and the ratio C(Li)/CP(FS) (indicating renal fractional excretion of Li+) increased significantly (p less than 0.01). The increase of C(Li)/CP(FS) was related to the increase of renal fractional sodium excretion (FENa) (p less than 0.01). The results suggest that the impairment of tubular cells by cisplatin or HgCl2 caused the decrease of tubular reabsorption of Li+ and Na+. From the pharmacokinetic point of view, these experiments suggest that changes in tubular transport of drugs should be taken into account in their dosing adjustment in patients with acute polyuric tubular lesion.

Contribution of clinical pharmacology to a rational use of cardiac glycosides in Czechoslovakia.

In Czechoslovakia, drug utilization studies showed that oral forms of digoxin and lanatoside C are traditionally the most prescribed cardiac glycosides. Our study of the relative bioavailability of the oral form of lanatoside C revealed that the drug has a low and irregular bioavailability making use of this frequently prescribed drug non-rational. The above data definitely contributed to a sharp decrease in the use of the oral form of lanatoside C in our country, which is in agreement with consumption trends in other European countries. However, the use of only drug forms with a good bioavailability is one aspect of new approaches applied in pharmacotherapy with cardiac glycosides resulting in gradual decrease of their consumption as a pharmacological group. Clinical pharmacological evaluation of individual drug forms and postgraduate education in clinical pharmacology of cardiac glycosides contribute significantly--apart from other regulatory measures--to a more rational use of cardiac glycosides in Czechoslovakia.

[What the data on utilization of antiepileptic agents reveals]. / Co nám mohou prozradit údaje o spotrebe antiepileptik.

Using the method of expressing the consumption of anti-epileptic drugs by the number of defined daily doses per 1000 population per day (DDD/1000/d), data covering the three-year period from September 1984 to August 1987 in districts of the Czech Socialist Republic are presented in tables. The mean and liminal values are given for anti-epileptics as a whole and mean values of the phenytoin consumption in region, incl. liminal values of the percentage ratio of Sanepil (phenytoin 80 mg, phenobarbital 18.5 mg) in districts of different regions of the CSR. On the enclosed map for the first annual period districts where this ratio was 25%, 50%, 75% or more (only in the South Moravian region) are hatched. In the subsequent tables are districts with greater changes of this indicator than +5% and -10% in the course of the three years of the investigation. The greatest drop was recorded in the district where there was a new leading neurologist who came from the area of another medical school to the South Moravian region. The authors discuss the influence of the medical school and present results of an enquiry by means of questionnaires among neurologists regarding the place of medical studies of neurologists in the region and views on the advantage of Sanepil, as compared with pure phenytoin.

Pharmacokinetics of once-daily theophylline dose following the morning versus evening administration.

The pharmacokinetics of theophylline (Uniphyllin) in blood and saliva was compared after morning and evening administration of a once-daily dose in a randomized cross-over study. Ten bronchial asthma patients received multiple doses of 800 mg theophylline at 8 a.m. and 8 p.m. under controlled food conditions. The precision of the serum concentration prediction from salivary measurements in individual patients was sufficient to obtain identical pharmacokinetic parameters and parallel concentration-time curves. There were no significant differences in the values of mean residence time and area under the concentration-time curves after morning and evening dosing, either in the kinetics of elimination and in the volume of distribution. The fluctuation of concentrations during the dosing intervals was 100% after morning doses and 80% after evening doses. No consistent interference with food was found. Circadian variation in the kinetics of drug disposition after once-daily theophylline administration did not occur. In order to achieve higher therapeutical levels at night and in the morning, the evening dosing seems to be preferable.

[The effect of particle size on the pharmacokinetics of piroxicam]. / Vliv velikosti cástic na farmakokinetiku piroxicamu.

Two preparations of Piroxicam cps. (10 mg) VUFB Prague, prepared from crystalline and micronized substance, were compared. The release of the active ingredient into the solution in the medium of artificial gastric juice in vitro was examined. The results show that Piroxicam prepared from micronized substance corresponds to the preparation Felden cps. On the other hand, the release of the active ingredient from the preparation prepared from crystalline substance is lower. The pharmacokinetic parameters of Piroxicam from micronized substance are practically consonant to similar parameters of the preparation Felden cps. In Piroxicam prepared from crystalline substance there was a decrease in the rapidity of absorption, which, however, was not statistically significant in the group of volunteers under study. Other pharmacokinetic parameters were practically the same as in the other preparations described.

[Utilization of cardiac glycosides in Czechoslovakia--does it correspond to need?]. / Spotreba srdecních glykozidu v CSSR--odpovídá potrebe?

The data are given on the consumption of cardiac glycosides (CD) in the CSSR over the past 18 years (1970-1987). Consumption expressed in terms of defined daily doses (DDD) permitted to construct time series of the consumption of this group of pharmacotherapeutic agents as a whole as well as individual CG and to compare the data thus obtained with similar data from abroad. The results indicate that the consumption of CG as a whole culminated in Czechoslovakia in 1983 (27.6 DDD per a population of 1000 per day = 27.6 DDD/1000/d) and that there has been a slow decline ever since. Compared with foreign data, Czechoslovakia's quantitative consumption of CG is roughly between countries noted for traditionally high consumption (GDR 84.8 DDD/1000/d) and those with low consumption (Scandinavian countries with the exception of Sweden, about 10 DDD/1000/d). Unlike Czechoslovakia, however, all other countries with well established CG consumption have been exhibiting a relatively steep and lasting decline in CG consumption since the late 1970s. This reduction reflects modern trends of CG pharmacotherapy, especially stricted consideration of the uses as distinct from the risks of CG administration, as well as some of the recent efforts to terminate long-term CG treatment particularly in vaguely indicated cases. As for individual CG consumption, Czechoslovakia, similarly as other countries, has been favouring more rational prescription of oral digoxin at the expense of the oral form of lanatoside C, while parenteral digoxin has for all practical purposes become a substitute for strophantin.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of penetration-enhancing ability of laurocapram, N-methyl-2-pyrrolidone and dodecyl-L-pyroglutamate.

The study reports on penetration enhancers used to improve drug absorption through the skin. All experiments were carried out in permeation cells in vitro. Insulin (2.5 mg/ml) and Brilliant Blue (50.0 mg/ml) served as model drugs. They were formulated into a 40% solution of propylene glycol with increasing concentrations of N-methyl-2-pyrrolidone (NMP) (0.0 to 20.0%), dodecylazacycloheptan-2-one (laurocapram) and a new compound dodecyl-L-pyroglutamate (DLP; 0.0 to 0.5%). The maximum amount of insulin permeated within 24 h was almost 200 microU/ml in the case of 0.1% laurocapram, while in the case of 0.1% DLP it was approximately half of that. The optimum concentration of NMP was 12.0%. Experiments performed with Brilliant Blue showed no significant difference among formulations containing either 6.0, 12.0 or 20.0% of NMP. When NMP was omitted, flux, permeability as well as the maximum concentration estimated after 26 h reached 50% of the values obtained with NMP. The lag time was twice as long in this case in comparison with the formulations containing NMP.