Showing papers by "Aarhus University published in 1999"

The efficiency of systematic sampling in stereology--reconsidered.

Abstract: In the present paper, we summarize and further develop recent reseach in the estimation of the variance of sterelogical estimators based on systematic sampling. In particular, it is emphasized that the relevant estimation procedure depends on the sampling density. The validity of the variance estimation is examined in a collection of data sets, obtained by systematic sampling. Practical recommendations are also provided in a separate section.

Comparative Effects of Low and High Doses of the Angiotensin-Converting Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart Failure

Abstract: Background—Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits. Methods and Results—We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction #30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n51596) or high doses (32.5 to 35 mg daily, n51568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (P50.128) but a significant 12% lower risk of death or hospitalization for any reason (P50.002) and 24% fewer hospitalizations for heart failure (P50.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions—These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small. (Circulation. 1999;100:2312-2318.)

Quantum computation with ions in thermal motion

Abstract: We propose an implementation of quantum logic gates via virtual vibrational excitations in an ion-trap quantum computer. Transition paths involving unpopulated vibrational states interfere destructively to eliminate the dependence of rates and revolution frequencies on vibrational quantum numbers. As a consequence, quantum computation becomes feasible with ions whose vibrations are strongly coupled to a thermal reservoir.

Multiparticle Entanglement of Hot Trapped Ions

Abstract: We propose an efficient method to produce multiparticle entangled states of ions in an ion trap for which a wide range of interesting effects and applications have been suggested. Our preparation scheme exploits the collective vibrational motion of the ions, but it works in such a way that this motion need not be fully controlled in the experiment. The ions may, e.g., be in thermal motion and exchange mechanical energy with a surrounding heat bath without detrimental effects on the internal state preparation. Our scheme does not require access to the individual ions in the trap.

A plant regulator controlling development of symbiotic root nodules

Abstract: Symbiotic nitrogen-fixing root nodules on legumes are founded by root cortical cells that de-differentiate and restart cell division to establish nodule primordia. Bacterial microsymbionts invade these primordia through infection threads laid down by the plant and, after endocytosis, membrane-enclosed bacteroids occupy cells in the nitrogen-fixing tissue of functional nodules. The bacteria excrete lipochitin oligosaccharides, triggering a developmental process that is controlled by the plant and can be suppressed. Nodule inception initially relies on cell competence in a narrow infection zone located just behind the growing root tip. Older nodules then regulate the number of nodules on a root system by suppressing the development of nodule primordia. To identify the regulatory components that act early in nodule induction, we characterized a transposon-tagged Lotus japonicus mutant, nin (for nodule inception), arrested at the stage of bacterial recognition. We show that nin is required for the formation of infection threads and the initiation of primordia. NIN protein has regional similarity to transcription factors, and the predicted DNA-binding/dimerization domain identifies and typifies a consensus motif conserved in plant proteins with a function in nitrogen-controlled development.

Cellular and molecular biology of the aquaporin water channels.

Abstract: The high water permeability characteristic of mammalian red cell membranes is now known to be caused by the protein AQP1 This channel freely permits movement of water across the cell membrane, but it is not permeated by other small, uncharged molecules or charged solutes AQP1 is a tetramer with each subunit containing an aqueous pore likened to an hourglass formed by obversely arranged tandem repeats Cryoelectron microscopy of reconstituted AQP1 membrane crystals has revealed the three-dimensional structure at 3-6 A AQP1 is distributed in apical and basolateral membranes of renal proximal tubules and descending thin limbs as well as capillary endothelia Ten mammalian aquaporins have been identified in water-permeable tissues and fall into two groupings Orthodox aquaporins are water-selective and include AQP2, a vasopressin-regulated water channel in renal collecting duct, in addition to AQP0, AQP4, and AQP5 Multifunctional aquaglyceroporins AQP3, AQP7, and AQP9 are permeated by water, glycerol, and some other solutes Aquaporins are being defined in numerous other species including amphibia, insects, plants, and microbials Members of the aquaporin family are implicated in numerous physiological processes as well as the pathophysiology of a wide range of clinical disorders

The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A

Abstract: Proteolytic cleavage of the six known insulin-like growth factor binding proteins (IGFBPs) is a powerful means of rapid structure and function modification of these important growth-regulatory proteins. Intact IGFBP-4 is a potent inhibitor of IGF action in vitro, and cleavage of IGFBP-4 has been shown to abolish its ability to inhibit IGF stimulatory effects in a variety of systems, suggesting that IGFBP-4 proteolysis acts as a positive regulator of IGF bioavailability. Here we report the isolation of an IGF-dependent IGFBP-4-specific protease from human fibroblast-conditioned media and its identification by mass spectrometry microsequencing as pregnancy-associated plasma protein-A (PAPP-A), a protein of unknown function found in high concentrations in the maternal circulation during pregnancy. Antibodies raised against PAPP-A both inhibited and immunodepleted IGFBP-4 protease activity in human fibroblast-conditioned media. Moreover, PAPP-A purified from pregnancy sera had IGF-dependent IGFBP-4 protease activity. PAPP-A mRNA was expressed by the human fibroblasts and osteoblasts, and PAPP-A protein was secreted into the culture medium. In conclusion, we have identified an IGF-dependent IGFBP protease and at the same time assigned a function to PAPP-A. This represents an unanticipated union of two areas of research that were not linked in any way before this report.

Telomere Fluorescence Measurements in Granulocytes and T Lymphocyte Subsets Point to a High Turnover of Hematopoietic Stem Cells and Memory T Cells in Early Childhood

Abstract: To study telomere length dynamics in hematopoietic cells with age, we analyzed the average length of telomere repeat sequences in diverse populations of nucleated blood cells. More than 500 individuals ranging in age from 0 to 90 yr, including 36 pairs of monozygous and dizygotic twins, were analyzed using quantitative fluorescence in situ hybridization and flow cytometry. Granulocytes and naive T cells showed a parallel biphasic decline in telomere length with age that most likely reflected accumulated cell divisions in the common precursors of both cell types: hematopoietic stem cells. Telomere loss was very rapid in the first year, and continued for more than eight decades at a 30-fold lower rate. Memory T cells also showed an initial rapid decline in telomere length with age. However, in contrast to naive T cells, this decline continued for several years, and in older individuals lymphocytes typically had shorter telomeres than did granulocytes. Our findings point to a dramatic decline in stem cell turnover in early childhood and support the notion that cell divisions in hematopoietic stem cells and T cells result in loss of telomeric DNA.

Miniature synaptic events maintain dendritic spines via AMPA receptor activation.

Abstract: We investigated the influence of synaptically released glutamate on postsynaptic structure by comparing the effects of deafferentation, receptor antagonists and blockers of glutamate release in hippocampal slice cultures. CA1 pyramidal cell spine density and length decreased after transection of Schaffer collaterals and after application of AMPA receptor antagonists or botulinum toxin to unlesioned cultures. Loss of spines induced by lesion or by botulinum toxin was prevented by simultaneous AMPA application. Tetrodotoxin did not affect spine density. Synaptically released glutamate thus exerts a trophic effect on spines by acting at AMPA receptors. We conclude that AMPA receptor activation by spontaneous vesicular glutamate release is sufficient to maintain dendritic spines.

Reliability of a new caries diagnostic system differentiating between active and inactive caries lesions.

Abstract: Current scoring systems for dental caries do not consider the dynamic nature of the disease. The aims of the present study were to describe a new set of clinical caries diagnostic criteria which differentiate between active and inactive caries lesions at both the cavitated and non-cavitated levels and to evaluate the reliability of this criteria system in a population with high caries experience. Ten diagnostic codes were defined: 0 = sound; 1 = active (intact); 2 = active (surface discontinuity); 3 = active (cavity); 4 = inactive (intact); 5 = inactive (surface discontinuity); 6 = inactive (cavity); 7 = filling; 8 = filling with active caries; 9 = filling with inactive caries. Distinction between active and inactive caries lesions was made on the basis of a combination of visual and tactile criteria. The inter- and intra-examiner reliability was assessed through repeated examinations of 50 children by 2 recorders over a period of 3 years. The percentage agreement of caries diagnoses varied between 94.2 and 96.2%. The kappa values ranged between 0.74 and 0.85 for intra-examiner examinations and between 0.78 and 0.80 for inter-examiner examinations; 81.6% of all misclassifications involved non-cavitated caries lesions. Disagreement between sound surfaces and non-cavitated active or non-cavitated inactive lesions (31.3 and 31.2%, respectively) was more common than disagreement between non-cavitated active and non-cavitated inactive lesions (10. 6%). The probability of reconfirming a sound, non-cavitated active or non-cavitated inactive caries lesion - given that the surface was diagnosed as either sound, non-cavitated active or non-cavitated inactive at the first examination - was 98.0, 68.7 and 72.5%, respectively. The results show that the use of a new set of clinical caries diagnostic criteria based on activity assessment can be performed with a high reliability, even when non-cavitated diagnoses are included in the criteria system.

Rapid gating and anion permeability of an intracellular aquaporin

Abstract: Aquaporin (AQP) water-channel proteins are freely permeated by water but not by ions or charged solutes. Although mammalian aquaporins were believed to be located in plasma membranes, rat AQP6 is restricted to intracellular vesicles in renal epithelia. Here we show that AQP6 is functionally distinct from other known aquaporins. When expressed in Xenopus laevis oocytes, AQP6 exhibits low basal water permeability; however, when treated with the known water channel inhibitor, Hg2+, the water permeability of AQP6 oocytes rapidly rises up to tenfold and is accompanied by ion conductance. AQP6 colocalizes with H+-ATPase in intracellular vesicles of acid-secreting alpha-intercalated cells in renal collecting duct. At pH less than 5.5, anion conductance is rapidly and reversibly activated in AQP6 oocytes. Site-directed mutation of lysine to glutamate at position 72 in the cytoplasmic mouth of the pore changes the cation/anion selectivity, but leaves low pH activation intact. Our results demonstrate unusual biophysical properties of an aquaporin, and indicate that anion-channel function may now be explored in a protein with known structure.

Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Müller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains

Abstract: Postembedding immunogold labeling was used to examine the subcellular distribution of the inwardly rectifying K+ channel Kir4.1 in rat retinal Muller cells and to compare this with the distribution of the water channel aquaporin-4 (AQP4). The quantitative analysis suggested that both molecules are enriched in those plasma membrane domains that face the vitreous body and blood vessels. In addition, Kir4. 1, but not AQP4, was concentrated in the basal approximately 300-400 nm of the Muller cell microvilli. These data indicate that AQP4 may mediate the water flux known to be associated with K+ siphoning in the retina. By its highly differentiated distribution of AQP4, the Muller cell may be able to direct the water flux to select extracellular compartments while protecting others (the subretinal space) from inappropriate volume changes. The identification of specialized membrane domains with high Kir4.1 expression provides a morphological correlate for the heterogeneous K+ conductance along the Muller cell surface.

The Distribution of Exchange Rate Volatility

Abstract: Using high-frequency data on Deutschemark and Yen returns against the dollar, we construct model-free estimates of daily exchange rate volatility and correlation, covering an entire decade. In addition to being model-free, our estimates are also approximately free of measurement error under general conditions, which we delineate. Hence, for all practical purposes, we can treat the exchange rate volatilities and correlations as observed rather than latent. We do so, and we characterize their joint distribution, both unconditionally and conditionally. Noteworthy results include a simple normality-inducing volatility transformation, high contemporaneous correlation across volatilities, high correlation between correlation and volatilities, pronounced and highly persistent temporal variation in both volatilities and correlation, clear evidence of long-memory dynamics in both volatilities and correlation, and remarkably precise scaling laws under temporal aggregation.

Spin Squeezed Atoms: A Macroscopic Entangled Ensemble Created by Light

Abstract: We report on the experimental observation of a spin squeezed ensemble of ${10}^{7}$ cold atoms. This macroscopic ensemble is generated via quantum state transfer from nonclassical light to atoms.

Stereologic methods and their application in kidney research

Abstract: . Stereologic methods are used to obtain quantitative information about three-dimensional structures based on observations from section planes or—to a limited degree—projections. Stereologic methods, which are used in biologic research and especially in the research of normal and pathologic kidneys, will be discussed in this review. Special emphasis will be placed on modern stereologic methods, free of assumptions of the structure, size, and shape, etc. , so-called UFAPP (unbiased for all practical purposes) stereologic methods. The basic foundation of all stereology, sampling, will be reviewed in relation to most of the methods discussed. Estimation of error variances and some of the basic problems in stereology will be reviewed briefly. Finally, a few comments will be made about the future directions for stereology in kidney research.

Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals.

Abstract: The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites, estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17beta++-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7 cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17beta-Estradiol, 17alpha-ethynyl estradiol, and diethylstilbestrol induced a strong estrogenic response in all test systems. Colchicine caused cytotoxicity only. Bisphenol A induced an estrogenic response in all assays. The results obtained for the remaining test compounds--tamoxifen, ICI 182.780, testosterone, bisphenol A dimethacrylate, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol dodecylethoxylate, butylbenzylphthalate, dibutylphthalate, methoxychlor, o,p'-DDT, p,p'-DDE, endosulfan, chlomequat chloride, and ethanol--varied among the assays. The results demonstrate that careful standardization is necessary to obtain a reasonable degree of reproducibility. Also, similar methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods.

Megalin Knockout Mice as an Animal Model of Low Molecular Weight Proteinuria

Abstract: Megalin is an endocytic receptor expressed on the luminal surface of the renal proximal tubules. The receptor is believed to play an important role in the tubular uptake of macromolecules filtered through the glomerulus. To elucidate the role of megalin in vivo and to identify its endogenous ligands, we analyzed the proximal tubular function in mice genetically deficient for the receptor. We demonstrate that megalin-deficient mice exhibit a tubular resorption deficiency and excrete low molecular weight plasma proteins in the urine (low molecular weight proteinuria). Proteins excreted include small plasma proteins that carry lipophilic compounds including vitamin D-binding protein, retinol-binding protein, α 1 -microglobulin and odorant-binding protein. Megalin binds these proteins and mediates their cellular uptake. Urinary loss of carrier proteins in megalin-deficient mice results in concomitant loss of lipophilic vitamins bound to the carriers. Similar to megalin knockout mice, patients with low molecular weight proteinuria as in Fanconi syndrome are also shown to excrete vitamin/carrier complexes. Thus, these results identify a crucial role of the proximal tubule in retrieval of filtered vitamin/carrier complexes and the central role played by megalin in this process.

Physiology and Pathophysiology of Renal Aquaporins

Abstract: The discovery of aquaporin membrane water channels by Agre and coworkers answered a long-standing biophysical question of how water specifically crosses biologic membranes, and provided insight, at the molecular level, into the fundamental physiology of water balance and the pathophysiology of water balance disorders. Of nine aquaporin isoforms, at least six are known to be present in the kidney at distinct sites along the nephron and collecting duct. Aquaporin-1 (AQP1) is extremely abundant in the proximal tubule and descending thin limb, where it appears to provide the chief route for proximal nephron water reabsorption. AQP2 is abundant in the collecting duct principal cells and is the chief target for vasopressin to regulate collecting duct water reabsorption. Acute regulation involves vasopressin-regulated trafficking of AQP2 between an intracellular reservoir and the apical plasma membrane. In addition, AQP2 is involved in chronic/adaptational regulation of body water balance achieved through regulation of AQP2 expression. Importantly, multiple studies have now identified a critical role of AQP2 in several inherited and acquired water balance disorders. This concerns inherited forms of nephrogenic diabetes insipidus and several, much more common acquired types of nephrogenic diabetes insipidus where AQP2 expression and/or targeting are affected. Conversely, AQP2 expression and targeting appear to be increased in some conditions with water retention such as pregnancy and congestive heart failure. AQP3 and AQP4 are basolateral water channels located in the kidney collecting duct, and AQP6 and AQP7 appear to be expressed at lower abundance at several sites including the proximal tubule. This review focuses mainly on the role of AQP2 in water balance regulation and in the pathophysiology of water balance disorders.

RNA secondary structure prediction using stochastic context-free grammars and evolutionary history.

Abstract: Motivation: Many computerized methods for RNA secondary structure prediction have been developed. Few of these methods, however, employ an evolutionary model, thus relevant information is often left out from the structure determination. This paper introduces a method which incorporates evolutionary history into RNA secondary structure prediction. The method reported here is based on stochastic context-free grammars (SCFGs) to give a prior probability distribution of structures. Results: The phylogenetic tree relating the sequences can be found by maximum likelihood (ML) estimation from the model introduced here. The tree is shown to reveal information about the structure, due to mutation patterns. The inclusion of a prior distribution of RNA structures ensures good structure predictions even for a small number of related sequences. Prediction is carried out using maximum a posteriori estimation (MAP) estimation in a Bayesian approach. For small sequence sets, the method performs very well compared to current automated methods. Contact: bk@imf.au.dk.

Fivefold symmetric homonuclear dipolar recoupling in rotating solids: Application to double quantum spectroscopy

Abstract: spinning frequencies. We observe dramatic oscillations of the recoupled signal with a period ;v r/2p indicating that the 1 H reservoir is behaving partially inhomogeneously. This kind of double quantum recoupling is explored in multiple spin systems and we derive analytical forms for polarization transfer and double quantum excitation relevant for uniformly labeled systems. Finally, the wide applicability of the fivefold sequence is demonstrated with INADEQUATE type spectra of uniformly 13 C labeled sucrose and L-alanine. © 1999 American Institute of Physics. @S0021-9606~99!01615-3#

Proving in zero-knowledge that a number is the product of two safe primes

Abstract: We present the first efficient statistical zero-knowledge protocols to prove statements such as: - A committed number is a prime. - A committed (or revealed) number is the product of two safe primes, i.e., primes p and q such that (p - 1)=2 and (q - 1)=2 are prime. - A given integer has large multiplicative order modulo a composite number that consists of two safe prime factors. The main building blocks of our protocols are statistical zero-knowledge proofs of knowledge that are of independent interest. We show how to prove the correct computation of a modular addition, a modular multiplication, and a modular exponentiation, where all values including the modulus are committed to but not publicly known. Apart from the validity of the equations, no other information about the modulus (e.g., a generator whose order equals the modulus) or any other operand is exposed. Our techniques can be generalized to prove that any multivariate modular polynomial equation is satisfied, where only commitments to the variables of the polynomial and to the modulus need to be known. This improves previous results, where the modulus is publicly known. We show how these building blocks allow to prove statements such as those listed earlier.

Hereditary haemorrhagic telangiectasia: a population‐based study of prevalence and mortality in Danish patients

Abstract: . Introduction. Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by telangiectatic lesions. The disease manifestations are variable and include epistaxis, gastrointestinal bleeding, pulmonary arteriovenous malformations and cerebral arteriovenous malformations. Early death due to these complications has been described. Design. We report a study on the prevalence and mortality of HHT in a Danish population based on two cross-sectional surveys in combination with a long-term follow-up study. Settings and subjects. Prevalent cases of HHT as of 1 January 1974 in the County of Fyn, Denmark, were identified. In 1995–97 a follow-up study of mortality was performed of the initial patient sample, and a new point prevalence rate of HHT as of 1 January 1995 was calculated. All live patients and their families were invited to attend a detailed clinical examination. Results. The prevalence of HHT in the County of Fyn was 13.8 per 100 000 on 1 January 1974 and 15.6 per 100 000 on 1 January 1995. In the HHT group as a whole, we found a slightly increased mortality; however, amongst the HHT patients younger than 60 years at inclusion the mortality of HHT patients was twice the expected. The excess mortality could be fully explained by severe HHT symptoms. Conclusion. This study suggests that HHT is more prevalent than previously believed. In young patients the disease is associated with an excess mortality which is fully attributable to HHT. Future research should aim at the identification of HHT patients at particular risk of developing severe complications.

A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor.

Abstract: Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development less compared with their contribution to disorders such as insulin-dependent diabetes mellitus. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene(s) is responsible for the genetic predisposition. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 4102 peptide; and the human CD4 coreceptor. The amino acid sequence of the MBP 84-102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells.

THz Spectroscopy of Liquid H 2 O and D 2 O

Abstract: We have measured and analyzed the dielectric (01--2 THz) response of liquid ${\mathrm{H}}_{2}\mathrm{O}$ and ${\mathrm{D}}_{2}\mathrm{O}$ from 270 to 368 K The response has been modeled using a Debye model with a fast and a slow decay time By shifting the temperature scale for the slow decay time of ${\mathrm{D}}_{2}\mathrm{O}$ by 72 K we find identical behavior for ${\mathrm{D}}_{2}\mathrm{O}$ and ${\mathrm{H}}_{2}\mathrm{O}$ The temperature dependence and isotope shift of the intermolecular structural relaxation characterized by the slow decay time can be modeled with a singular point at 228 K for ${\mathrm{H}}_{2}\mathrm{O}$ and 235 K for ${\mathrm{D}}_{2}\mathrm{O}$

Intermittent Parathyroid Hormone (1–34) Treatment Increases Callus Formation and Mechanical Strength of Healing Rat Fractures

Abstract: The influence of intermittent parathyroid hormone (PTH(1-34)) administration on callus formation and mechanical strength of tibial fractures in rats was investigated after 20 and 40 days of healing. A dose of 60 microg of PTH(1-34)/kg/day and 200 microg of PTH(1-34)/kg/day, respectively, was administered during the entire periods of healing, and control animals with fractures were given vehicle. The dose of 200 microg of PTH(1-34)/kg/day increased the ultimate load and the external callus volume of the fractures by 75% and 99%, respectively, after 20 days of healing and by 175% and 72%, respectively, after 40 days of healing. The dose of 60 microg of PTH(1-34)/kg/day did not influence either ultimate load or external callus volume of the fractures after 20 days of healing, but the ultimate load was increased by 132% and the external callus volume was increased by 42% after 40 days of healing. During the healing period, the callus bone mineral content (BMC) increased in all groups. After 40 days of healing, the callus BMC was increased by 108% in the 200 microg of PTH(1-34)/kg/day group and by 76% in the 60 microg of PTH(1-34)/kg/day group. Both doses of PTH(1-34) steadily augmented the contralateral intact tibia BMC (20 days and 40 days: 60 microg of PTH (1-34)/kg/day 9% and 19%, respectively; 200 microg of PTH (1-34)/kg/day 12% and 27%, respectively) and bone mineral density (20 days and 40 days: 60 microg of PTH(1-34)/kg/day 11% and 12%, respectively; 200 microg of PTH(1-34)/kg/day 11% and 15%, respectively).