Physics of Nuclei: Key Role of an Emergent Symmetry.

We show through first-principles nuclear structure calculations that the special nature of the strong nuclear force determines highly regular patterns heretofore unrecognized in nuclei that can be tied to an emergent approximate symmetry. This symmetry is ubiquitous and mathematically tracks with a symplectic symmetry group. This, in turn, has important implications for understanding the physics of nuclei: we find that nuclei are made of only a few equilibrium shapes, deformed or not, with associated vibrations and rotations. It also opens the path for ab initio large-scale modeling of open-shell intermediate-mass nuclei without the need for renormalized interactions and effective charges.

Biphasic effect of calcitonin on tartrate-resistant acid phosphatase activity in isolated rat osteoclasts.

Tartrate-resistant acid phosphatase (TRAP) has been implicated as being involved in osteoclastic bone resorption, and calcitonin (CT) is known to inhibit the resorptive process. This study investigates the kinetics of CT action on TRAP activity in isolated rat osteoclasts using both biochemical and quantitative cytochemical methods. The latter technique has been developed to detect very small changes in intracellular TRAP activity at the single-cell level. The biochemical study showed that 10(-9) M salmon CT (sCT) decreased TRAP activity in medium throughout the experimental period; TRAP activity in the cells was increased during the first 2 h but subsequently declined and was decreased to a significant level at 6 h. TRAP activity in sCT-treated osteoclasts measured by the cytochemical method showed significant increases within the first hour. This response was dose dependent between 10(-16) and 10(-11) M sCT with EC50 at 8 X 10(-14) M. After 1 h, the initial increase in intracellular TRAP activity in CT-treated osteoclasts was followed by a decline to below control levels, reaching statistical significance at 9 h. Treatment with forskolin (10(-5) M) showed a similar trend, suggesting that this response is mediated by cyclic AMP-regulated phosphorylation events. From these results, we conclude that CT has two actions on TRAP in isolated rat osteoclasts: the first to inhibit its release, the second to inhibit its synthesis and/or increase its degradation.

A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts.

PTH-related protein (PTHrP) interacts, via its amino-terminal 34 residues, with PTH receptors on osteoblasts to stimulate osteoclastic bone resorption indirectly. We now report that mature hPTHrP-(1-141) (EC50, approximately 10(-11) M) and a carboxyl-terminal fragment, PTHrP-(107-139) (EC50, approximately 10(-15) M), are potent inhibitors of resorption in an isolated rat osteoclast bone resorption assay, whereas hPTHrP-(1-108) and hPTHrP-(1-34) are inactive in this respect. PTHrP-(107-139) also inhibits resorption in a rat long bone organ culture system and reduces osteoclast spreading. PTHrP-(107-139) does not act on osteoclasts via a cAMP signal transduction mechanism, but its effects may be mediated by protein kinase-C. This previously unrecognized action of PTHrP, to inhibit osteoclastic bone resorption directly, indicates that PTHrP may be a precursor of multiple biologically active peptides with differing physiological functions.

Effects of a fluorinated bisphosphonate on bone remodeling in vivo.

A new fluorinated bisphosphonate, difluoromethylene bisphosphonate (F2MBP), was studied for its effects on physiologic bone remodeling in the actively growing rat tibia. Young male Sprague-Dawley rats were given daily subcutaneous injections of either saline (control) or 30 mg/kg per day of F2MBP, dichloromethylene bisphosphonate (Cl2MBP), or 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) for 30 days. Microradiographs of the epiphysealmetaphyseal region of tibiae from animals treated with either F2MBP or Cl2MBP demonstrated increased radiodensity but, unlike those treated with HEBP, without an increase in the width of the epiphyseal growth plate. Quantitative analyses of these microradiographs showed that there was an increase of calcified tissue in the metaphyseal region in all diphosphonate groups when compared with controls. However, the HEBP-treated animals exhibited significantly less increase than either F2MBP-treated or Cl2MBP-treated rats. In addition, the total area of calcified tissue in the diaphyseal transverse sections was greater in the F2MBP-treated animals than in controls. Elemental calcium, phosphorus, and fluorine, as detected by the electron probe, also increased in the metaphyseal region of the F2MBP-treated animals, but no significant differences in the calcium: phosphorous ratio were found among the control, F2MBP, and Cl2MBP treatment groups, indicating no alterations in the chemical composition of bone. The greater amount of fluorine in the tibiae of F2MBP-treated animals reflected the presence of the F2MBP molecule. Thus, this study has demonstrated that this new fluorinated bisphosphonate, like Cl2MBP, inhibits physiologic bone remodeling without disturbing mineralization. Furthermore, the presence of fluorine in F2MBP allows the precise localization of the incorporation of the bisphosphonate within the bone.

Uptake of a fluorinated bisphosphonate by cultured bones.

The uptake of bisphosphonates into bone was studied using 19-day-old fetal rat bones cultured with a new fluorinated bisphosphonate, difluoromethylidene bisphosphonate (F2MBP). F2MBP uptake was assessed by determining the weight percent of fluoride using electron probe microanalysis. By 30 min the weight percent of fluoride was significantly greater in the F2MBP-treated bones than in controls and continually increased throughout the duration of the experiment to reach a fluoride concentration 6-fold greater than controls after 120 h of incubation. When the peripheral cortical bone was analyzed separately from the interior trabecular bone in the F2MBP-treated bones, the fluoride concentration in the periphery increased until 24 h and then remained somewhat constant, while the interior, which is more actively remodeling, showed a continual increase. The uptake of F2MBP during the 1 to 6 h time intervals demonstrated no differences between vital and devitalized bone and, thus, is not cell-mediated. Because analysis of free fluoride in F2MBP media incubated with bones showed that the concentration of fluoride was less than 1% of the total amount of fluoride, the fluoride detected by the probe was most likely that of the intact molecule and not free fluoride. The rapid uptake of the F2MBP molecule was supported by assessing the effects of short-term F2MBP treatment on subsequent bone resorption, as determined by the release of 45Ca from prelabeled bones. Bones treated with F2MBP for only 5 min exhibited reductions in the percentage of 45Ca released during the remainder of the 120 h incubation period similar to that when F2MBP was continuously in the medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophoretic separation of tissue-specific serum alkaline phosphatases.

Previous electrophoretic methods for the separation of tissue-specific serum alkaline phosphatases have either been unable to separate the liver and bone enzymes or have been too involved for routine clinical use. A relatively simple electrophoretic method is described which separates placental, liver, bone, and intestinal alkaline phosphatases in serum. The clinical applications of such a method appear to be mainly in the differential diagnosis of liver and bone disease, especially in complicated hypercalcaemic states where tumour metastases can affect both bone and liver, in children, and possibly in cirrhosis of the liver.No differences in electrophoretic mobility could be seen between zymograms of different diseases affecting the same organ. Patients presenting with hepatic cirrhosis all showed a marked serum intestinal alkaline phosphatase zone as well as a liver zone on electrophoresis. An intestinal zone was not present with other types of hepatobiliary disease.The heterogeneity of total serum alkaline phosphatase activity in normal subjects is demonstrated, alkaline phosphatases of liver and bone, and sometimes of intestine being present in normal serum. Results obtained in women in the last trimester of pregnancy and in old people are also discussed.

Diagnostic strategy to monitor diabetic nephropathy.

Although much evidence supports the theory that microalbuminuria is predictive of the development of clinical diabetic nephropathy, other experimental data fail to support this conclusion. It remains unclear whether random urine samples offer as much clinical information as timed overnight or 24 hour samples. Clinical decisions as to treatment based on improved glycemic control or enhanced antihypertensive treatment should be structured to the urinary albumin concentration. Tubular dysfunction is common in diabetes, but is clinical relevance remains unclear.

Production of matrix-degrading enzymes and inhibition of osteoclast-like cell differentiation by fibroblast-like cells from the periodontal ligament of human primary teeth.

Clinically, the most apparent difference between the primary and permanent dentitions is the physiologic loss of the primary tooth by root resorption. Root resorption is associated with loss of integrity of the periodontal ligament (PDL), followed by recruitment of resorptive cells that remove root structure. We therefore cultured primary dentition PDL fibroblasts (PPDL cells) to investigate in vitro their production of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs), and the effects of soluble factors produced by these cells on osteoclast-like cell differentiation. These studies demonstrate that PPDL cells in vitro have a heterogeneous morphology, and they constitutively synthesize 92-kDa gelatinase, 72-kDa gelatinase, and 53/57-kDa procollagenase as well as TIMP-1, -2, and a third inhibitor of matrix metalloproteinase, as determined by substrate gel zymography and immunoblot analysis. Compared with PDL cells from the permanent dentition, PPDL cells generally produced a greater amount of collagenase but similar amounts of the gelatinases and inhibitors. PPDL cells were treated with pro-inflammatory cytokines to determine their effect on the expression of matrix-degrading enzymes and inhibitors. Interleukin-1alpha and tumor necrosis factor-alpha enhanced the constitutive expression of proteinases but not that of inhibitors in PPDL cells. Conditioned media from PPDL cell lines inhibited the differentiation of osteoclast-like cells in mouse bone marrow cultures. These findings indicate that PPDL cells may modulate the cascade of root resorption both by their regulated production of proteinases and inhibitors and by synthesis of unknown soluble factor(s) that may regulate osteoclast development.

Measurement of urinary retinol binding protein by immunonephelometry.

A method is described for the determination of retinol binding protein (RBP) by immunonephelometry. The assay is sensitive to 5 microg/l and has acceptable imprecision. The method correlates with an established ELISA assay. A provisional normal range is proposed for daytime random urine samples. The increased excretion of RBP in adult subject with type 1 diabetes mellitus is demonstrated.

An evaluation of blood creatinine measurement by creatinase on the NOVA M7 blood gas analyzer.

This study compared a creatininase method for the analysis at the bedside of creatinine (CR) in whole blood on a NOVA Biomedical M7 analyser, with rate-Jaffe and creatininase-based laboratory methods. Correlation and precision data were obtained and the effect of increased bilirubin concentration was assessed.