Biomedical subjects

C J Hernandez

Publications and source records attributed to C J Hernandez.

12 recordsLinked to original sources

PubMed2006

A biomechanical perspective on bone quality.

Observations that dual-energy X-ray absorptiometry (DXA) measures of areal bone mineral density cannot completely explain fracture incidence after anti-resorptive treatment have led to renewed interest in bone quality. Bone quality is a vague term but generally refers to the effects of skeletal factors that contribute to bone strength but are not accounted for by measures of bone mass. Because a clinical fracture is ultimately a mechanical event, it follows then that any clinically relevant modification of bone quality must change bone biomechanical performance relative to bone mass. In this perspective, we discuss a framework for assessing the clinically relevant effects of bone quality based on two general concepts: (1) the biomechanical effects of bone quality can be quantified from analysis of the relationship between bone mechanical performance and bone density; and (2) because of its hierarchical nature, biomechanical testing of bone at different physical scales (<1 mm, 1 mm, 1 cm, etc.) can be used to isolate the scale at which the most clinically relevant changes in bone quality occur. As an example, we review data regarding the relationship between the strength and density in excised specimens of trabecular bone and highlight the fact that it is not yet clear how this relationship changes during aging, osteoporosis development, and anti-resorptive treatment. Further study of new and existing data using this framework should provide insight into the role of bone quality in osteoporotic fracture risk.

Aging↗

PubMed2004

Osteocyte density in woven bone.

Woven bone forms rapidly during tissue growth, following injury and in response to certain anabolic stimuli. Functional differences between woven and lamellar bone may be due, in part, to differences in osteocyte density (cells per unit tissue). Woven bone has been estimated to contain four to eight times more osteocytes than lamellar bone, although primary data to support this assertion are limited. Given recent findings implicating osteocytes as regulators of bone remodeling, bone formation and bone volume, such large differences in osteocyte density between woven and lamellar bone may have important consequences. In this study, we compared the density of osteocyte lacunae (lacunae/mm(2) tissue) in rat lamellar bone with that in woven bone formed under several different circumstances. We found that the lacunar density of lamellar cortical bone in the rat (834+/-83 cells/mm2, mean+/-SD) did not differ significantly from that of periosteal woven bone formed via intramembranous osteogenesis, either in response to mechanical loading (921+/-204 cells/mm2) or in the periosteal buttressing region of the fracture callus (1138+/-168 cells/mm2). In contrast, lacunar density of endochondrally derived woven bone in the center (gap) region of fracture callus was nearly 100% greater (1875+/-270 cells/mm2) than in lamellar cortical bone while lacunar density of primary spongiosa of the growth plate was 40% greater (1674+/-228 cells/mm2) than that in lamellar cancellous bone (1189+/-164). These findings demonstrate that lacunar density in woven bone varies depending on skeletal site and developmental history and appears to be elevated in endochondrally derived woven bone adjacent to marrow space. Given the considerable evidence supporting osteocytes as local initiators of bone remodeling, we suggest that woven bone with increased lacunar density may undergo remodeling at an accelerated rate.

Animals↗

PubMed2003

A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis.

Factors that determine a post-menopausal woman's bone mineral density (BMD) include her mass at the time of skeletal maturity (peak BMD), menopause and the rate of loss she experiences as she ages. Understanding the relative influence of each of these factors may help identify important preventive treatments and provide new ways to identify women at risk for osteoporosis. In this analysis we utilize a computer model of the bone remodeling process to predict the relative influences of peak BMD, menopause and age-related bone loss on the development of osteoporosis. The delay in the onset of osteoporosis (defined as BMD <2.5 SD from the young adult mean) caused by modifying peak BMD, age-related bone loss or the age at menopause is quantified. A 10% increase in peak BMD is predicted to delay the development of osteoporosis by 13 years, while a 10% change in the age at menopause or the rate of non-menopausal bone loss is predicted to delay osteoporosis by approximately 2 years, suggesting that peak BMD may be the single most important factor in the development of osteoporosis.

Adult↗

PubMed2003

A theoretical analysis of the changes in basic multicellular unit activity at menopause.

Bone loss at menopause is an important contributor to the development of osteoporosis in women. Although alterations in bone remodeling are the implied process through which bone is lost at menopause, how menopause influences basic multicellular units (BMUs), the teams of cells that perform bone remodeling, is not completely clear. In this analysis we utilize a computer simulation of BMU activity to evaluate the changes that occur at menopause. Transient and maintained changes in both the rate of bone turnover (expressed as the BMU birthrate or origination frequency) and the focal bone balance (differences between the amount of bone formed and resorbed at each remodeling site) are considered. The magnitude of the change in BMU activity is determined parametrically through comparison to lumbar spine bone mineral density data present in the literature. We find that a change in bone turnover that is maintained after menopause, a transient change in focal bone balance at menopause, or a combination of the two is consistent with bone loss patterns seen clinically. Understanding the changes in BMU activity that occur at menopause could lead to improved strategies to treat and prevent postmenopausal osteoporosis.

Bone Density↗

PubMed2002

Long-term predictions of the therapeutic equivalence of daily and less than daily alendronate dosing.

Less than daily alendronate dosing has been identified as an attractive alternative to daily dosing for patients and physicians. A recent 2-year study found bone mineral density (BMD) changes caused by weekly alendronate dosing therapeutically equivalent to that caused by daily dosing. There are no methods that can be used to predict how long therapeutic equivalence will be maintained after the first 2 years of treatment. In addition, it is unclear if dosing less frequently than weekly also might be therapeutically equivalent to daily dosing. In this study we use a computer simulation to develop predictions of the therapeutic equivalence of daily and less than daily dosing over time periods as long as a decade. The computer simulation uses a cell-based computer model of bone remodeling and a quantitative description of alendronate pharmacokinetics/pharmacodynamics (PK/PD). The analyses suggest that less than daily dosing regimens do not increase BMD as much as daily dosing. However, model predictions suggest that dosing as frequent as weekly still may be therapeutically equivalent to daily dosing over periods as long as 10 years. In addition, the simulations predict dosing less frequently than weekly may be therapeutically equivalent to daily dosing within the first year of treatment but may not be therapeutically equivalent after 10 years. Hypotheses based on these simulations may be useful for determining which dosing regimen may be most attractive for clinical trials.

Alendronate↗

PubMed2001

The influence of bone volume fraction and ash fraction on bone strength and modulus.

Although bone strength and modulus are known to be influenced by both volume fraction and mineral content (ash fraction), the relative influence of these two parameters remains unknown. Single-parameter power law functions are used widely to relate bone volume or ash fraction to bone strength and elastic modulus. In this study we evaluate the potential for predicting bone mechanical properties with two-parameter power law functions of bone volume fraction (BV/TV) and ash fraction (alpha) of the form y = a(BV/TV)(b) alpha(c) (where y is either ultimate strength or elastic modulus). We derived an expression for bone volume fraction as a function of apparent density and ash fraction to perform a new analysis of data presented by Keller in 1994. Exponents b and c for the prediction of bone strength were found to be 1.92 +/- 0.02 and 2.79 +/- 0.09 (mean +/- SE), respectively, with r(2) = 0.97. The value of b was found to be consistent with that found previously, whereas the value of c was lower than values previously reported. For the prediction of elastic modulus we found b and c to be 2.58 +/- 0.02 and 2.74 +/- 0.13, respectively, with r(2) = 0.97. The exponent related to ash fraction was typically larger than that associated with bone volume fraction, suggesting that a change in mineral content will, in general, generate a larger change in bone strength and stiffness than a similar change in bone volume fraction. These findings are important for interpreting the results of antiresorptive drug treatments that can cause changes in both ash and bone volume fraction.

Biomechanical Phenomena↗

PubMed2001

A theoretical analysis of the contributions of remodeling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment.

In patients with osteoporosis, alendronate treatment causes an increase in bone mineral density (BMD) and a decrease in fracture incidence. Alendronate acts by changing the bone remodeling process. Changes in bone remodeling resulting in decreased remodeling space, increased bone balance per remodeling cycle, and increased mineralization (ash mass/bone mass) have all been associated with alendronate treatment. Understanding the relative contributions of these parameters to BMD increases could help predict the utility of long-term (>10 years) or intermittent treatment strategies, as well as treatment strategies in which another pharmaceutical is administered concurrently. We have developed a computer simulation of bone remodeling to compare the contributions of focal bone balance and mineralization on BMD by simulating alendronate treatment using a bone balance method (decreased remodeling space, increased focal bone balance, uniform bone mineralization) and a mineralization method (decreased remodeling space, neutral focal bone balance, varying bone mineralization). Although both methods are able to predict BMD increases caused by alendronate over short periods, our findings suggest that the mineralization method may be more descriptive of long-term alendronate treatment. This implies that mineralization may be a larger contributor to BMD changes caused by alendronate than the focal bone balance. Based on this finding we offer a hypothesis to describe how remodeling space, focal bone balance, and mineralization each contribute to alendronate-induced BMD changes. Future analyses with this method could be used to identify improved dosing regimens and to predict which osteoporosis treatments would best complement each other.

Alendronate↗

PubMed1999

The relationship between basic multicellular unit activation and origination in cancellous bone.

Activation frequency is often used as a measure of basic multicellular unit (BMU) activity in cancellous bone. However, activation frequency expresses the rate of BMU appearance in a histologic slide and not the rate of origination, which is a more physiologic indicator of remodeling activity and is necessary for the development of BMU-level bone remodeling simulations. Using identical assumptions to those for calculating the activation frequency, it is shown that the origination frequency in cancellous bone is equal to the activation frequency divided by the total distance traveled by the BMU and its width.

Bone Development↗

PubMed1993

Alloantigen-dependent endothelial phenotype and lymphokine mRNA expression in rejecting murine cardiac allografts.

Recent studies suggest that graft microvascular endothelia may play an important role in the regulation of rejection. Alloantigen-dependent changes in microvascular endothelial phenotype may be associated with differences in infiltrate function in allografts vs. isografts, as reflected in alloantigen-specific CTL accumulation and cytokine production. To correlate cytokine production with differences in microvascular endothelial phenotype during allograft inflammation, we used PCR to identify cytokine mRNAs isolated from pooled cardiac isografts and allografts on days 1, 3, and 5 after transplantation. Graft microvascular endothelia express an inflamed phenotype associated with wound healing and the repair of tissue damage due to mechanical trauma, ischemia, and/or reperfusion injury--i.e., high levels of ICAM-1 expression and MECA-32 mAb reactivity. By day 1 in both isografts and allografts, mRNAs for the cytokines IL1 alpha, IL6, TNF, LT, and TGF beta are upregulated or induced. By the third day in cardiac allografts, an antigen-dependent endothelial phenotype is expressed, characterized by the presence of cell surface VCAM-1. Concomitantly, mRNAs for the lymphokines IL2 and IFN gamma are detected, followed by IL4 mRNA by day 5. The expression of VCAM-1 by allograft endothelia may influence the inflammatory process, by physically recruiting specific T cell subpopulations into the response and/or by delivering additional signals to the infiltrating cells. Eventually, these and other regulatory events occurring at these early times initiate a process that later results in alloreactive tissue destruction.

Animals↗

PubMed1993

Detection of cytokine mRNA in vivo by polymerase chain reaction. Problems and solutions.

The expression of cytokine mRNAs in murine sponge matrix graft infiltrates was studied using the polymerase chain reaction (PCR). In infiltrates of both C57B1/6 > C57B1/6 isografts and DBA/2 > C57B1/6 allografts, a similar pattern of cytokine expression was observed. On days 6, 8, and 10 postimplant, mRNAs encoding IL-4, IL-6, and IFN-gamma were detected. On days 8 and 10, mRNAs encoding IL-1 alpha, TNF, and lymphotoxin/TNF beta were also expressed. Surprisingly, no IL-2 mRNA was observed in isografts or allografts. Two modified PCR techniques were utilized to compare the level of expression of cytokine mRNAs in isografts versus allografts and to detect the expression of IL-2 mRNA in this system. A semiquantitative PCR protocol based on limiting cycles of amplification is described that was used to determine the amount of IL-4 mRNA expressed in isograft and allograft infiltrates relative to beta-actin mRNA. Using this method, no difference was found in the amount of IL-4 mRNA in infiltrates of day 8 isografts and allografts. The validation of this technique by analysis of samples with known relative mRNA levels is presented. A nested PCR protocol is described that provided greatly enhanced sensitivity over standard PCR analysis. Using this technique, IL-2 mRNA was detected in infiltrates from sponge allografts on all days tested, beginning on day 2 postimplant. No IL-2 mRNA was detected in isograft infiltrates or in peripheral blood from allograft-bearing animals. The pattern of cytokine mRNA expression observed in sponge matrix allografts is consistent with the presence of a weak alloreactive response superimposed upon an intense granulomatous process that occurs in both the isografts and allografts. This report demonstrates modified PCR techniques that can be used to resolve experimental problems associated with the analysis of cytokine mRNA expression in vivo.

Animals↗

PubMed1975

[Ganglionic cytoarchitecture of the esophagus in the cat and the rhesus monkey].

The comparative study of neuron distribution in the myenteric and submucous plexuses has granted an appraisal of the various neuron types in the oesophagus ganglia of cat and rhesus monkey. Neurons are classified in Dogiel types I and II, plus an intermediate one, the so-called "type III". From the functional point of view, the hypothesis is established that these types are, respectively: efferent, afferent and associative. A confirmation of this hypothesis requires the endorsement of the results of degeneration experiments and their integration with the roles of the rest of the structures which participate in the oesophagus innervation as a whole.

Animals↗

PubMedDate not supplied

A model of mechanobiologic and metabolic influences on bone adaptation.

Bone adaptation, the process through which bone mass is modified in the body, plays a key role in the development of osteoporosis. Bone adaptation is known to be influenced by both mechanical and metabolic stimuli. Previous studies have concentrated on changes in bone adaptation caused by mechanical stimuli (mechanobiologic influences), yet current treatments for osteoporosis depend significantly on metabolic influences. We develop a theoretical model of bone adaptation that accounts for both mechanobiologic and metabolic influences. We demonstrate the utility of this model using a simulation of the cellular processes of bone adaptation on a representative volume of cancellous bone. Our long-term objective is the development of a more comprehensive computational model that will aid in the study of osteoporosis and other bone diseases.

Adaptation, Physiological↗