Five-year follow-up of Japanese patients with Paget's disease of the bone after treatment with low-dose oral alendronate: a case series

<p>Abstract</p> <p>Introduction</p> <p>Paget's disease of the bone is characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton. Although this disease is rare in Japan, it is common in western and southern Europe, and among British migrants in Australia and New Zealand. Bisphosphonates have been widely used for the treatment of Paget's disease of the bone and are considered to be the treatment of choice. However, there have been few reports on the long-term follow-up examination of patients after their treatment with bisphosphonates.</p> <p>Case presentation</p> <p>We report the treatment with a low dose of oral alendronate (5 mg per day) which was effective in reducing bone turnover and pain over the five-year follow-up period in two Japanese patients, a 66-year-old man and a 68-year-old woman, with Paget's disease of the bone. Furthermore, in one patient, no clinical symptoms, such as bone pain or increases in serum total alkaline phosphatase and urinary N-terminal telopeptide of type I collagen as markers of bone turnover, were observed over the patient's five-year follow-up period.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the first report of a long-term follow-up of patients with Paget's disease of the bone after a six-month treatment with low-dose oral alendronate (5 mg per day).</p

Effect of screening of the electron-phonon interaction on the temperature of Bose-Einstein condensation of intersite bipolarons

Here we consider an interacting electron-phonon system within the framework of extended Holstein-Hubbard model at strong enough electron-phonon interaction limit in which (bi)polarons are the essential quasiparticles of the system. It is assumed that the electron-phonon interaction is screened and its potential has Yukawa-type analytical form. An effect of screening of the electron-phonon interaction on the temperature of Bose-Einstein condensation of the intersite bipolarons is studied for the first time. It is revealed that the temperature of Bose-Einstein condensation of intersite bipolarons is higher in the system with the more screened electron-phonon interaction.Comment: 6 pages, 4 figure

Cross-Protective Peptide Vaccine against Influenza A Viruses Developed in HLA-A*2402 Human Immunity Model

Background: The virus-specific cytotoxic T lymphocyte (CTL) induction is an important target for the development of a broadly protective human influenza vaccine, since most CTL epitopes are found on internal viral proteins and relatively conserved. In this study, the possibility of developing a strain/subtype-independent human influenza vaccine was explored by taking a bioinformatics approach to establish an immunogenic HLA-A24 restricted CTL epitope screening system in HLAtransgenic mice. Methodology/Principal Findings: HLA-A24 restricted CTL epitope peptides derived from internal proteins of the H5N1 highly pathogenic avian influenza A virus were predicted by CTL epitope peptide prediction programs. Of 35 predicted peptides, six peptides exhibited remarkable cytotoxic activity in vivo. More than half of the mice which were subcutaneously vaccinated with the three most immunogenic and highly conserved epitopes among three different influenza A virus subtypes (H1N1, H3N2 and H5N1) survived lethal influenza virus challenge during both effector and memory CTL phases. Furthermore, mice that were intranasally vaccinated with these peptides remained free of clinical signs after lethal virus challenge during the effector phase. Conclusions/Significance: This CTL epitope peptide selection system can be used as an effective tool for the development of a cross-protective human influenza vaccine. Furthermore this vaccine strategy can be applicable to the development o

On absolute continuity of the spectrum of a periodic magnetic Schr\"odinger operator

We consider the Schr\"odinger operator in ${\mathbb R}^n$, $n\geq 3$, with the electric potential $V$ and the magnetic potential $A$ being periodic functions (with a common period lattice) and prove absolute continuity of the spectrum of the operator in question under some conditions which, in particular, are satisfied if $V\in L^{n/2}_{{\mathrm {loc}}}({\mathbb R}^n)$ and $A\in H^q_{{\mathrm {loc}}}({\mathbb R}^n;{\mathbb R}^n)$, $q>(n-1)/2$.Comment: 25 page

Significance of Metastatic Lymph Node Ratio on Stimulated Thyroglobulin Levels in Papillary Thyroid Carcinoma after Prophylactic Unilateral Central Neck Dissection

Background: Prognostic significance of metastatic central lymph node ratio (CLNR) in papillary thyroid carcinoma (PTC) remains unknown. Because postsurgical detectable stimulated thyroglobulin (DsTg) after radioiodine ablation may imply persistent or recurrent disease, we evaluated the association between CLNR and rate of DsTg in patients with PTC who underwent unilateral prophylactic central neck dissection. Methods: To be eligible for analysis, the prophylactic central neck dissection specimen had to contain ≥3 central lymph nodes (CLNs) with ≥1 harboring metastasis. Of 129 specimens, 51 (39.5%) were eligible. CLNR was calculated as follows: (number of metastatic CLNs/number of CLNs retrieved) × 100. They were categorized into group 1 (CLNR 66.67%) (n = 22). Postablation sTg level was measured 6 months after radioiodine ablation. A multivariate analysis was conducted to identify factors for postablation DsTg. Results: Young age, palpable neck swelling, large tumor size, advanced tumor, node, metastasis system (TNM) stage, and large number of metastatic CLNs were significantly associated with high CLNR (Ppublished_or_final_versionSpringer Open Choice, 21 Feb 201

Thermodynamic characteristics of the classical n-vector magnetic model in three dimensions

The method of calculating the free energy and thermodynamic characteristics of the classical n-vector three-dimensional (3D) magnetic model at the microscopic level without any adjustable parameters is proposed. Mathematical description is perfomed using the collective variables (CV) method in the framework of the $\rho^4$ model approximation. The exponentially decreasing function of the distance between the particles situated at the N sites of a simple cubic lattice is used as the interaction potential. Explicit and rigorous analytical expressions for entropy,internal energy, specific heat near the phase transition point as functions of the temperature are obtained. The dependence of the amplitudes of the thermodynamic characteristics of the system for $T>T_c$ and $T<T_c$ on the microscopic parameters of the interaction potential are studied for the cases $n=1,2,3$ and $n\to\infty$. The obtained results provide the basis for accurate analysis of the critical behaviour in three dimensions including the nonuniversal characteristics of the system.Comment: 25 pages, 5 figure

High resolution analysis of DNA copy-number aberrations of chromosomes 8, 13, and 20 in gastric cancers

DNA copy-number gains of chromosomes 8q, 13q, and 20q are frequently observed in gastric cancers. Moreover gain of chromosome 20q has been associated with lymph node metastasis. The aim of this study was to correlate DNA copy-number changes of individual genes on chromosomes 8q, 13q, and 20q in gastric adenocarcinomas to clinicopathological data. DNA isolated from 63 formalin-fixed and paraffin-embedded gastric adenocarcinoma tissue samples was analyzed by whole-genome microarray comparative genomic hybridization and by multiplex ligation-dependent probe amplification (MLPA), targeting 58 individual genes on chromosomes 8, 13, and 20. Using array comparative genomic hybridization, gains on 8q, 13q, and 20q were observed in 49 (77.8%), 25 (39.7%), and 49 (77.8%) gastric adenocarcinomas, respectively. Gain of chromosome 20q was significantly correlated with lymph node metastases (p = 0.05) and histological type (p = 0.02). MLPA revealed several genes to be frequently gained in DNA copy number. The oncogene c-myc on 8q was gained in 73% of the cancers, while FOXO1A and ATP7B on 13q were both gained in 28.6% of the cases. Multiple genes on chromosome 20q showed gains in more than 60% of the cancers. DNA copy-number gains of TNFRSF6B (20q13.3) and ZNF217 (20q13.2) were significantly associated with lymph node metastasis (p = 0.02) and histological type (p = 0.02), respectively. In summary, gains of chromosomes 8q, 13q, and 20q in gastric adenocarcinomas harbor DNA copy-number gains of known and putative oncogenes. ZNF217 and TNFRSF6B are associated with important clinicopathological variables, including lymph node status

Deletion of Porcn in Mice Leads to Multiple Developmental Defects and Models Human Focal Dermal Hypoplasia (Goltz Syndrome)

Focal Dermal Hypoplasia (FDH) is a genetic disorder characterized by developmental defects in skin, skeleton and ectodermal appendages. FDH is caused by dominant loss-of-function mutations in X-linked PORCN. PORCN orthologues in Drosophila and mice encode endoplasmic reticulum proteins required for secretion and function of Wnt proteins. Wnt proteins play important roles in embryo development, tissue homeostasis and stem cell maintenance. Since features of FDH overlap with those seen in mouse Wnt pathway mutants, FDH likely results from defective Wnt signaling but molecular mechanisms by which inactivation of PORCN affects Wnt signaling and manifestations of FDH remain to be elucidated.We introduced intronic loxP sites and a neomycin gene in the mouse Porcn locus for conditional inactivation. Porcn-ex3-7flox mice have no apparent developmental defects, but chimeric mice retaining the neomycin gene (Porcn-ex3-7Neo-flox) have limb, skin, and urogenital abnormalities. Conditional Porcn inactivation by EIIa-driven or Hprt-driven Cre recombinase results in increased early embryonic lethality. Mesenchyme-specific Prx-Cre-driven inactivation of Porcn produces FDH-like limb defects, while ectodermal Krt14-Cre-driven inactivation produces thin skin, alopecia, and abnormal dentition. Furthermore, cell-based assays confirm that human PORCN mutations reduce WNT3A secretion.These data indicate that Porcn inactivation in the mouse produces a model for human FDH and that phenotypic features result from defective WNT signaling in ectodermal- and mesenchymal-derived structures

Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia

<p>Abstract</p> <p>Background</p> <p>Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E₂and PGD₂.</p> <p>Findings</p> <p>We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE₂and PGD₂without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE₂and PGD₂. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE₂and PGD₂levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE₂in non-stimulated microglia.</p> <p>Conclusion</p> <p>Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p