Inhibition of cyst growth in PCK and Wpk rat models of polycystic kidney disease with low doses of peroxisome proliferator-activated receptor γ agonists

Background and Objectives The studies were designed to test the efficacy of two peroxisome proliferator-activated receptor γ (PPARγ) agonists in two rodent models of polycystic kidney disease (PKD). Materials and Methods The PCK rat is a slowly progressing cystic model while the Wpk-/- rat is a rapidly progressing model. PCK rats were fed with a pharmacological (0.4 mg/kg body weight [BW]) and a sub-pharmacological (0.04 mg/kg BW) dose of rosiglitazone (week 4–28). Wpk-/- rats were fed with pharmacological (2.0 mg/kg BW) and sub-pharmacologic (0.2 mg/kg BW) doses of pioglitazone from day 5 to 18. At termination, kidney weights of treated versus untreated cystic animals were used to determine efficacy. The current studies were also compared with previous studies containing higher doses of PPARγ agonists. The concentrations used in the animals were calculated with reference to equivalent human doses for both drugs. Results The current studies demonstrate: 1) that low, pharmacologically relevant, doses of the PPARγ agonists effectively inhibit cyst growth; 2) there is a class action of the drugs with both commercially available PPARγ agonists, rosiglitazone, and pioglitazone, inhibiting cyst growth; 3) the drugs showed efficacy in two different preclinical cystic models. In the PCK rat, animals fed with a sub-pharmacological dose of rosiglitazone for 24 weeks had significantly lower kidney weights than untreated animals (3.68 ± 0.13 g vs. 4.17 ± 0. 11 g, respectively, P < 0.01) while treatment with a pharmacologic dose had no significant effect on kidney weight. The rapidly progressing Wpk-/- rats were fed with pharmacological and sub-pharmacologic doses of pioglitazone from day 5 to 18 and the kidneys were compared with non-treated, cystic animals. Kidney weights on the pharmacologic dose were not statistically lower than the untreated animals while rats fed a sub-pharmacologic dose showed a significant decrease compared with untreated animals (3.35 ± 0.15 g vs. 4.55 ± 0.46 g, respectively, P = 0.045). Conclusion Concentrations of PPARγ agonists below the human equivalent diabetic doses are effective in slowing cyst growth in two rodent models of PKD

Adverse mandibular bone effects associated with kidney disease are only partially corrected with bisphosphonate and/or calcium treatment

Bone Biology Laboratory http://www.iupui.edu/~bonelab/ Department of Anatomy and Cell Biology Indiana University School of Medicine Department of Biomedical Engineering IUPUIBackground/Aims: Patients with chronic kidney disease (CKD) have high prevalence of periodontal disease that may predispose to tooth loss and inflammation. The goal of this study was to test the hypotheses that a genetic rat model of progressive CKD would exhibit altered oral bone properties and that treatment with either bisphosphonates or calcium could attenuate these adverse changes. Methods: At 25 weeks of age, rats were treated with zoledronate, calcium gluconate, or their combination for 5 or 10 weeks. Mandible bone properties were assessed using micro-computed tomography to determine bone volume (BV/TV) and cementenamel junction to alveolar crest distance (CEJ-AC). Results: Untreated CKD animals had significantly lower BV/TV at both 30 (-5%) and 35 (-14%) weeks of age and higher CEJ-AC (+27 and 29%) compared to normal animals. CKD animals had significantly higher PTH compared to normal animals yet similar levels of C-reactive protein. Zoledronate-treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with zoledronate, was effective in normalizing BV/TV at both time points. Neither zoledronate nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not zoledronate, significantly reduced serum parathyroid hormone (PTH) while neither treatment affected C-reactive protein. Conclusions: 1) this progressive animal model of chronic kidney disease shows a clear mandibular skeletal phenotype consistent with periodontitis, 2) the periodontitis is not associated with systemic inflammation as measured by C-reactive protein, and 3) reducing PTH has positive effects on the mandible phenotype.This work was supported by NIH grant (AR058005). We would like to thank Dr. Xianming Chen, Mr. Alex Carr and Mr. Drew Brown for their assistance with the biochemical assays, breeding colony and micro CT scanning/analysis, respectively

Finite Nuclei in a Relativistic Mean-Field Model with Derivative Couplings

We study finite nuclei, at the mean-field level, using the Zimanyi-Moskowski model and one of its variations (the ZM3 model). We calculate energy levels and ground-state properties in nuclei where the mean-field approach is reliable. The role played by the spin-orbit potential in sorting out mean-field model descriptions is emphasized.Comment: 17 pages, 9 figures, 30 kbytes. Uses EPSF.TEX. To appear in Zeit. f. Phys. A (Hadrons and Nuclei

A comparison of calcium to zoledronic acid for improvement of cortical bone in an animal model of CKD

Bone Biology Laboratory http://www.iupui.edu/~bonelab/ Department of Anatomy and Cell Biology Indiana University School of MedicinePatients with chronic kidney disease (CKD) have increased risk of fractures, yet the optimal treatment is unknown. In secondary analyses of large randomized trials, bisphosphonates have been shown to improve bone mineral density and reduce fractures. However, bisphosphonates are currently not recommended in patients with advanced kidney disease due to concern about over-suppressing bone remodeling, which may increase the risk of developing arterial calcification. In the present study we used a naturally occurring rat model of CKD with secondary hyperparathyroidism, the Cy/+ rat, and compared the efficacy of treatment with zoledronic acid, calcium given in water to simulate a phosphate binder, and the combination of calcium and zoledronic acid. Animals were treated beginning at 25 weeks of age (approximately 30% of normal renal function) and followed for ten weeks. The results demonstrate that both zoledronic acid and calcium improved bone volume by microCT and both equally suppressed mineral apposition rate, bone formation rate, and mineralizing surface of trabecular bone. In contrast, only calcium treatment with or without zoledronic acid improved cortical porosity and cortical biomechanical properties (ultimate load and stiffness) and lowered parathyroid hormone (PTH). However, only calcium treatment led to the adverse effects of increased arterial calcification and fibroblast growth factor 23 (FGF23). These results suggest zoledronic acid may improve trabecular bone volume in CKD in the presence of secondary hyperparathyroidism, but does not benefit extraskeletal calcification or cortical biomechanical properties. Calcium effectively reduces PTH and benefits both cortical and trabecular bone yet increases the degree of extra skeletal calcification.This work was supported by the NIH NIAMS R01 5R01AR058005 (SMM) and S10-RR023710 (microCT equipment grant). We thank Drew Brown for tissue dissections, CT scanning and analysis

Anti-Sclerostin Antibody Treatment in a Rat Model of Progressive Renal Osteodystrophy

Chronic Kidney Disease (CKD) is associated with abnormalities in bone quantity and quality leading to increased fractures. Recent studies suggest abnormalities of Wnt signaling in animal models of CKD and elevated sclerostin levels in patients with CKD. The goal of this study was to evaluate the effectiveness of anti-sclerostin antibody treatment in an animal model of progressive CKD with low and high parathyroid hormone (PTH) levels. Cy/+ male rats (CKD) were treated without or with calcium in the drinking water at 25 weeks of age to stratify the animals into high PTH and low PTH groups, respectively, by 30 weeks. Animals were then treated with anti-sclerostin antibody at 100 mg/kg IV weekly for 5 doses, a single 20 ug/kg subcutaneous dose of zoledronic acid, or no treatment and sacrificed at 35 weeks. As a positive control, the efficacy of anti-sclerostin antibody treatment was also evaluated in normal littermates. The results demonstrated that the CKD animals with high PTH had lower calcium, higher phosphorus, and lower FGF23 compared to the CKD animals with low PTH. Treatment with anti-sclerostin Ab had no effect on any of the biochemistries, while zoledronic acid lowered dkk-1 levels. The anti-sclerostin antibody increased trabecular BV/TV., trabecular mineralization surface, in animals with low, but not high, PTH. Neither anti-sclerostin antibody nor zoledronic acid improved biomechanical properties in the animals. Cortical porosity was severe in high PTH animals and unaffected by either treatment. In contrast, in normal animals treated with anti-sclerostin antibody, there was an improvement in bone volume, cortical geometry, and biomechanical properties. In summary, this is the first study to test the efficacy of anti-sclerostin Ab treatment on animals with advanced CKD. We found efficacy in improving bone properties only when the PTH levels were low.NIH AR 058005 and Novartis

Multivariate analysis of the influence of peri-implant clinical parameters and local factors on radiographic bone loss in the posterior maxilla: a retrospective study on 277 dental implants

Objectives: The aim of the present study was to investigate whether peri-implant clinical parameters (modified plaque index (mPI), bleeding and/or suppuration on probing (B/SOP)) and local factors (type of prostheses, screw emergence, platform diameter, and abutment angulation) might contribute to the development of additional bone loss and peri-implantitis around dental implants. Materials and methods: Two hundred seventy-seven external hex connection implants placed in the posterior maxilla of 124 patients were retrospectively evaluated. They were divided into two groups: physiologic bone loss < 2 mm (PBL) or additional bone loss ≥ 2 mm (ABL). GEE logistic regression was applied to evaluate the influence of type of prostheses (implant-supported single crown (ISSC), fixed partial denture (ISFPD), and full denture (ISFD)) and clinical parameters (mPI and S/BOP) on bone loss. Results: Among the 277 implants, 159 (57.4%) presented PBL and 118 (42.6%) presented ABL. Within the ABL group, 20.6% implants were diagnosed with peri-implantitis. mPI significantly correlated with the type of prosthesis and the highest value of mPI (index = 3) was observed in ISFD (23.8%). Moreover, peri-implantitis was more frequently associated with ISFD (32.79%) than ISSC and ISFDP (13.79% and 13.48, respectively) Conclusions: ISFD in the posterior maxilla presented high rates of ABL and showed a higher prevalence of peri-implantitis. None of the local factors seemed to contribute to the development of these conditions. Further investigations are needed to prospectively support the results of the present study. Clinical relevance: Patients rehabilitated with ISFD should be carefully monitored and have more frequent maintenance visits to prevent or control peri-implant bone loss

Derivative-Coupling Models and the Nuclear-Matter Equation of State

The equation of state of saturated nuclear matter is derived using two different derivative-coupling Lagrangians. We show that both descriptions are equivalent and can be obtained from the sigma-omega model through an appropriate rescaling of the coupling constants. We introduce generalized forms of this rescaling to study the correlations amongst observables in infinite nuclear matter, in particular, the compressibility and the effective nucleon mass.Comment: 16 pages, 6 figures, 36 kbytes. To appear in Zeit. f. Phys. A (Hadrons and Nuclei

QCD Sum Rules for Σ\Sigma Hyperons in Nuclear Matter

Within finite-density QCD sum-rule approach we investigate the self-energies of $\Sigma$ hyperons propagating in nuclear matter from a correlator of $\Sigma$ interpolating fields evaluated in the nuclear matter ground state. We find that the Lorentz vector self-energy of the $\Sigma$ is similar to the nucleon vector self-energy. The magnitude of Lorentz scalar self-energy of the $\Sigma$ is also close to the corresponding value for nucleon; however, this prediction is sensitive to the strangeness content of the nucleon and to the assumed density dependence of certain four-quark condensate. The scalar and vector self-energies tend to cancel, but not completely. The implications for the couplings of $\Sigma$ to the scalar and vector mesons in nuclear matter and for the $\Sigma$ spin-orbit force in a finite nucleus are discussed.Comment: 20 pages in revtex, 6 figures available under request as ps files, UMD preprint #94--11

Role of heavy-meson exchange in pion production near threshold

Recent calculations of $s$-wave pion production have severely underestimated the accurately known $pp\rightarrow pp\pi^0$\ total cross section near threshold. In these calculations, only the single-nucleon axial-charge operator is considered. We have calculated, in addition to the one-body term, the two-body contributions to this reaction that arise from the exchange of mesons. We find that the inclusion of the scalar $\sigma$-meson exchange current (and lesser contributions from other mesons) increases the cross section by about a factor of five, and leads to excellent agreement with the data. The results are neither very sensitive to changes in the distorting potential that generates the $NN$ wave function, nor to different choices for the meson-nucleon form factors. We argue that $pp\rightarrow pp\pi^0$\ data provide direct experimental evidence for meson-exchange contributions to the axial current.Comment: 28 Pages, IU-NTC #93-0

Search for solar axions with mass around 1 eV using coherent conversion of axions into photons

A search for solar axions has been performed using an axion helioscope which is equipped with a 2.3m-long 4T superconducting magnet, a gas container to hold dispersion-matching gas, PIN-photodiode X-ray detectors, and a telescope mount mechanism to track the sun. A mass region around m_a = 1eV was newly explored. From the absence of any evidence, analysis sets a limit on axion-photon coupling constant to be g < 5.6-13.4x10^{-10} GeV^{-1} for the axion mass of 0.84<m_a<1.00eV at 95% confidence level. It is the first result to search for the axion in the g-m_a parameter region of the preferred axion models with a magnetic helioscope.Comment: 13 pages, 6 figures, to be published in PL