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C H Turner

Publications and source records attributed to C H Turner.

At least 55 records · Page 3Linked to original sources
PubMed2001

Effects of loading frequency on mechanically induced bone formation.

The anabolic effect of mechanical loading on bone tissue is modulated by loading frequency. The objective of this study was to characterize the new bone formation on the periosteal and endocortical surfaces of the ulnar diaphysis in adult, female rats in response to controlled dynamic loading and to examine the interactions between strain magnitude, loading frequency, and bone formation rate (BFR/BS) for frequencies ranging from 1 to 10 Hz. Cyclic, compressive loading was applied to the ulnas of 60 adult, female rats divided into 12 loading groups. Loading was applied for 360 cycles/day with peak loads ranging from 4.3 to 18N at frequencies of 1, 5, and 10 Hz. After 2 weeks of loading, bone formation on the periosteal and endocortical surfaces of the ulna was quantified using double-label histomorphometry on transverse sections obtained at the middiaphysis. Periosteal bone formation increased in a dose-response manner with peak load at each of the three loading frequencies tested. Loading frequency significantly affected the x intercepts and slopes of the peak strain versus BFR/BS (p < 0.001) and peak strain versus mineralizing surface (MS/BS; p < 0.001) curves. Periosteal osteogenesis was best predicted by a mathematical model that assumed: (1) bone cells are activated by fluid shear stresses and (2) that stiffness of the bone cells and the extracellular matrix near the cells increases at higher loading frequencies because of viscoelasticity. Consequently, mechanotransduction appears to involve a complex interaction between extracellular fluid forces and cellular mechanics.

Animals↗
PubMed2001

Variability in skeletal mass, structure, and biomechanical properties among inbred strains of rats.

The aim of this study was to assess the usefulness of the inbred rat model for studies of genetic influences on skeletal fragility. We characterized bone mass, geometry, and skeletal biomechanics in 11 inbred strains of rats. This study showed that considerable variation exists in bone structure, areal bone mineral density (aBMD), and fragility phenotypes among inbred strains of rats. Interestingly, the variability in skeletal phenotypes in rats was site specific, suggesting that no single gene regulates skeletal fragility at all sites. For instance, the Copenhagen 2331 (COP) strain had the greatest biomechanical properties in the femoral neck but only modest bone strength at the femoral midshaft, compared with other strains. Consequently, COP rats appear to have alleles that specifically enhance femoral neck biomechanical properties and may serve as a model for studying genetic influences on hip strength. The Brown Norway (BN) and Fischer 344 (F344) strains may provide models for vertebral fragility because each has relatively fragile lumbar vertebrae. The F344 rats also had the most fragile femora and, thus, appear to carry alleles that cause overall skeletal fragility. We identified two inbred rat crosses that will facilitate the study of genetic influences on skeletal fragility at clinically relevant skeletal sites: Lewis (LEW) with F344 (primarily for vertebral fragility) and COP with DA (primarily for femoral neck fragility). The results strongly suggest that selected crosses of inbred strains of rats will provide useful models for studying genetic influences on bone strength and structure.

Animals↗
PubMed2001

Skeletal loading in animals.

A number of in vivo skeletal loading models have been developed to test specific hypotheses addressing the key mechanical and biochemical signals involved in bone's adaptive response to loading. Exercise protocols, osteotomy procedures, loading of surgically implanted pins, and force application through the soft tissues are common approaches to alter the mechanical environment of a bone. Although each animal overload model has a number of assets and limitations, models employing extrinsic forces allow greater control of the mechanical environment. Sham controls, for both surgical intervention (when performed) and loading, are required to unequivocally demonstrate that responses to loading are mechanically adaptive. Collectively, extrinsic loading models have fostered a greater understanding of the mechanical signals important for stimulating bone cells, and highlighted the roles of key signaling molecules in the adaptive response.

Journal Article↗
PubMed2000

Three-dimensional modeling of the effects of parathyroid hormone on bone distribution in lumbar vertebrae of ovariectomized cynomolgus macaques.

Biomechanical and quantitative computed tomography (QCT) analyses showed beneficial effects of parathyroid hormone (PTH (1-34)) on lumbar vertebrae from ovariectomized monkeys, even after withdrawal of treatment for 6 months. Adult cynomolgus monkeys were randomized, ovariectomized (except for sham ovariectomy controls), and treated subcutaneously with vehicle (OVX) or 5 micrograms/kg per day PTH (1-34) (PTH5) for 18 months. An additional group was treated subcutaneously with 5 micrograms/kg per day PTH (1-34) (PTH5W) for 12 months and then switched to vehicle for the remaining 6 months. Lumbar vertebrae were excised at necropsy, and L5 were serially scanned by QCT, using 70 x 70 x 500 microns voxels. PTH increased volumetric bone mineral density (BMD, mg/cm3) and bone mineral content (BMC, mg) for both PTH5 and PTH5W compared with OVX and Sham without inducing hypermineralization, without stimulating periosteal expansion, and without significant constriction of the neural canal. BMD values for the voxels were then averaged to create nearly isotropic voxels of 490 x 490 x 500 microns. Serial scans were stacked and a triangular surface mesh generated for each bone, using a 'marching cubes' algorithm. A smoothed version of each surface mesh was used to generate a tetrahedral element for three-dimensional finite element modeling. An isotropic Young's modulus for each tetrahedral element was calculated as a function of the original voxel BMDs. Linear elastic stress analysis was then performed for each finite element model in which a distributed load of 100 newtons (N) was applied to the top surface of the centrum, perpendicular to the bottom surface with the bottom surface constrained in the direction of loading. Analysis of the effective strain showed considerable reduction in vertebral strain for both PTH5 and PTH5W, compared with OVX. Compression testing of the adjacent L3 and L4 confirmed that vertebral strength and stiffness for PTH5 and PTH5W were significantly greater than for OVX. Histogram and QCT analyses showed PTH conversion of low-density bone (trabecular bone) into medium-density bone (more and thicker trabeculae) by stimulating bone apposition. PTH withdrawal induced conversion of medium-density into low-density and high-density bone with the latter higher than in OVX. These data show that even transient PTH treatment improves vertebral architecture and bone quality to reduce the likelihood of fracture, and that transient treatment is better than no PTH treatment at all.

Animals↗
PubMed2000

Does suppression of bone turnover impair mechanical properties by allowing microdamage accumulation?

One plausible purpose of bone turnover is to repair bone microdamage. We hypothesized that suppression of bone turnover impairs bone quality by allowing accumulation of microdamage. We investigated the effect of high-dose etidronate (EHDP) on bone's mechanical properties and microdamage accumulation. Skeletally mature beagles, 1-2 years old at the beginning of the study, were treated with daily injections of vehicle or EHDP at 0.5 mg/kg per day or 5.0 mg/kg per day for 1 year. X-rays were taken at baseline and monthly from 7 to 12 months. Bones were taken upon sacrifice and biomechanical tests, histomorphometry, and microdamage analyses were performed. Fractures of ribs and/or thoracic spinous processes were found in 10 of 11 dogs treated with the higher dose EHDP. Only one fracture of a thoracic spinous process was found in dogs treated with the lower dose EHDP, and no fractures were found in the vehicle controls. Biomechanical tests showed reduced mechanical strength in ribs and lumbar vertebrae, but not in the femoral diaphysis or thoracic spinous process in the higher dose EHDP group. Histomorphometric measurements showed a significant reduction of cancellous bone turnover in both EHDP-treated groups compared with controls. In dogs treated with the higher dose EHDP, activation frequency was reduced to zero in both cortical and cancellous bone. Osteoid volume increased significantly, especially in trabecular bone, resulting in reduced mineralized bone volume in the higher dose EHDP group. Microcrack numerical density (Cr.Dn) increased significantly only in the lumbar vertebral body in the higher dose EHDP group, but not in the rib or thoracic spinous process where fractures occurred. These findings show that suppression of bone turnover using high doses of EHDP is associated with fractures of the ribs and spinous processes in dogs. This is most likely the result of excessive amounts of unmineralized bone produced by the inhibition of mineralization at these high doses, rather than by the accumulation of microdamage.

Animals↗
PubMed2000

Ca(2+) regulates fluid shear-induced cytoskeletal reorganization and gene expression in osteoblasts.

Osteoblasts subjected to fluid shear increase the expression of the early response gene, c-fos, and the inducible isoform of cyclooxygenase, COX-2, two proteins linked to the anabolic response of bone to mechanical stimulation, in vivo. These increases in gene expression are dependent on shear-induced actin stress fiber formation. Here, we demonstrate that MC3T3-E1 osteoblast-like cells respond to shear with a rapid increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) that we postulate is important to subsequent cellular responses to shear. To test this hypothesis, MC3T3-E1 cells were grown on glass slides coated with fibronectin and subjected to laminar fluid flow (12 dyn/cm(2)). Before application of shear, cells were treated with two Ca(2+) channel inhibitors or various blockers of intracellular Ca(2+) release for 0. 5-1 h. Although gadolinium, a mechanosensitive channel blocker, significantly reduced the [Ca(2+)](i) response, neither gadolinium nor nifedipine, an L-type channel Ca(2+) channel blocker, were able to block shear-induced stress fiber formation and increase in c-fos and COX-2 in MC3T3-E1 cells. However, 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM, an intracellular Ca(2+) chelator, or thapsigargin, which empties intracellular Ca(2+) stores, completely inhibited stress fiber formation and c-fos/COX-2 production in sheared osteoblasts. Neomycin or U-73122 inhibition of phospholipase C, which mediates D-myo-inositol 1,4,5-trisphosphate (IP(3))-induced intracellular Ca(2+) release, also completely suppressed actin reorganization and c-fos/COX-2 production. Pretreatment of MC3T3-E1 cells with U-73343, the inactive isoform of U-73122, did not inhibit these shear-induced responses. These results suggest that IP(3)-mediated intracellular Ca(2+) release is required for modulating flow-induced responses in MC3T3-E1 cells.

3T3 Cells↗
PubMed2000

Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib.

It has been hypothesized that suppression of bone remodeling allows microdamage to accumulate, leading to increased bone fragility. This study evaluated the effects of reduced bone turnover produced by bisphosphonates on microdamage accumulation and biomechanical properties of cortical bone in the dog rib. Thirty-six female beagles, 1-2 years old, were divided into three groups. The control group (CNT) was treated daily for 12 months with saline vehicle. The remaining two groups were treated daily with risedronate (RIS) at a dose of 0.5 mg/kg per day or alendronate (ALN) at 1.0 mg/kg per day orally. After sacrifice, the right ninth rib was assigned to cortical histomorphometry or microdamage analysis. The left ninth rib was tested to failure in three-point bending. Total cross-sectional bone area was significantly increased in both RIS and ALN compared with CNT, whereas cortical area did not differ significantly among groups. One-year treatment with RIS or ALN significantly suppressed intracortical remodeling (RIS, 53%; ALN, 68%) without impairment of mineralization and significantly increased microdamage accumulation in both RIS (155%) and ALN (322%) compared with CNT. Although bone strength and stiffness were not significantly affected by the treatments, bone toughness declined significantly in ALN (20%). Regression analysis showed a significant nonlinear relationship between suppressed intracortical bone remodeling and microdamage accumulation as well as a significant linear relationship between microdamage accumulation and reduced toughness. This study showed that suppression of bone turnover by high doses of bisphosphonates is associated with microdamage accumulation and reduced some mechanical properties of bone.

Alendronate↗
PubMed2000

Genetic regulation of cortical and trabecular bone strength and microstructure in inbred strains of mice.

The inbred strains of mice C57BL/6J (B6) and C3H/HeJ (C3H) have very different femoral peak bone densities and may serve as models for studying the genetic regulation of bone mass. Our objective was to further define the bone biomechanics and microstructure of these two inbred strains. Microarchitecture of the proximal femur, femoral midshaft, and lumbar vertebrae were evaluated in three dimensions using microcomputed tomography (microCT) with an isotropic voxel size of 17 microm. Mineralization of the distal femur was determined using quantitative back-scatter electron (BSE) imaging. MicroCT images suggested that C3H mice had thicker femoral and vertebral cortices compared with B6. The C3H bone tissue also was more highly mineralized. However, C3H mice had few trabeculae in the vertebral bodies, femoral neck, and greater trochanter. The trabecular number (Tb.N) in the C3H vertebral bodies was about half of that in B6 vertebrae (2.8(-1) +/- 0.1 mm(-1) vs. 5.1(-1) +/- 0.2 mm(-1); p < 0.0001). The thick, more highly mineralized femoral cortex of C3H mice resulted in greater bending strength of the femoral diaphysis (62.1 +/- 1.2N vs. 27.4 +/- 0.5N, p < 0.0001). In contrast, strengths of the lumbar vertebra were not significantly different between inbred strains (p = 0.5), presumably because the thicker cortices were combined with inferior trabecular structure in the vertebrae of C3H mice. These results indicate that C3H mice benefit from alleles that enhance femoral strength but paradoxically are deficient in trabecular bone structure in the lumbar vertebrae.

Animals↗
PubMed2000

Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZ-parathyroid hormone 893.

Daily administration of parathyroid hormone (PTH) and PTH-related protein (PTHrP) peptides has been shown to increase bone mass and strength in animals and, for PTH, to increase bone mass in humans. Long-term direct comparison of multiple members of the PTH/PTHrP family in vivo has not been reported. We therefore selected three PTH/PTHrP molecules for direct comparison in vivo in an adult rat model of postmenopausal osteoporosis: PTH(1-34), PTHrP(1-36), and the PTH analog, SDZ-PTH 893 ¿Leu8, Asp10, Lys11, Ala16, Gln18, Thr33, Ala34 human PTH 1-34 [hPTH(1-34)]¿. A 6-month study was performed in which adult (6-month-old) vehicle-treated ovariectomized (OVX) and sham OVX rats were compared with OVX rats receiving 40 micrograms/kg per day of either PTH(1-34), PTHrP(1-36), or PTH-SDZ-893. Bone mass, as assessed by ash weight and densitometry, bone histomorphometry, biomechanical properties at trabecular and cortical sites, and indices of bone formation markedly increased in all three PTH/PTHrP peptide-treated groups as compared with controls. In general, this improvement followed a rank order of SDZ-PTH-893 > PTH > PTHrP. The adverse effect profile also was greatest with SDZ-PTH-893; these rats developed moderate hypercalcemia, marked renal calcium accumulation, and displayed a 13% mortality. These studies show that PTH(1-34), PTHrP(1-36), and PTH-SDZ-893 significantly and progressively increase bone mass and bone strength in this rat model of postmenopausal osteoporosis. The adverse effect profile correlates in general terms with efficacy. All three peptides show promise as skeletal anabolic agents. Further studies in humans will be required to define optimal efficacy-to-adverse effect ratios and relative efficacy for each peptide in human osteoporosis.

Animals↗
PubMed2000

Partitioning a daily mechanical stimulus into discrete loading bouts improves the osteogenic response to loading.

A single 3-minute bout of mechanical loading increases bone formation in the rat tibia. We hypothesized that more frequent, shorter loading bouts would elicit a greater osteogenic response than a single 3-minute bout. The right tibias of 36 adult female Sprague-Dawley rats were subjected to 360 bending cycles per day of a 54 N force delivered in 1, 2, 4, or 6 bouts on each of the 3 loading days. Rats in the 6-bouts/day group received 60 bending cycles per bout (60 x 6); rats in the 4-bouts/day group received 90 bending cycles per bout (90 x 4); the 2- and 1-bouts/day groups received 180 and 360 bending cycles per bout, respectively (180 x 2 and 360 x 1). A nonloaded, age-matched control group (0 x 0) and two sham-bending groups (60 x 6 and 360 x 1) also were included. Fluorochrome labeling revealed a 10-fold increase in endocortical lamellar bone formation rate (BFR/bone surface [BS]) in the right tibia versus the left (nonloaded) side in the 60 x 6 bending group. Endocortical BFR/BS in the right tibia of the 4-, 2-, and 1-bout bending groups exhibited 8-, 4-, and 4-fold increases, respectively, over the control side. Relative (right minus left) values for endocortical BFR/BS, mineralizing surface (MS/BS), and mineral apposition rate (MAR) were 65-94% greater in the 90 x 4 and 60 x 6 bending groups compared to the 360 x 1 bending group. Sham-bending tibias exhibited relative endocortical bone formation values similar to those collected from the control (0 x 0) group. The data show that 360 daily loading cycles applied at intervals of 60 x 6 or 90 x 4 represent a more osteogenic stimulus than 360 cycles applied all at once, and that mechanical loading is more osteogenic when divided into discrete loading bouts. Presumably, bone cells become increasingly "deaf" to the mechanical stimulus as loading cycles persist uninterrupted, and by allowing a rest period between loading bouts, the osteogenic effectiveness of subsequent cycles can be increased.

Animals↗
PubMed1999

Elastic anisotropy and collagen orientation of osteonal bone are dependent on the mechanical strain distribution.

There is evidence that the collagen microarchitecture of bone is influenced by mechanical stresses or strains. We hypothesized that peak functional strains correlate with the elastic anisotropy and collagen orientation of bone tissue and that the bone anisotropy might be changed by altering the strain patterns in canine radii for 12 months. We tested these hypotheses in studies using nine adult foxhounds. The baseline group (n = 3) had three rosette strain gauges placed around the midshaft of the radius, and strain distributions were measured during walking. The osteotomy group (n = 3) had 2 cm of the ulna surgically removed, and the sham group (n = 3) received a sham osteotomy. The osteotomy and sham groups were allowed free movement in cages with runs for 12 months, after which strain distributions were measured on the radii during walking. Bone-tissue anisotropy and collagen architecture were measured in radii from which the in vivo longitudinal strain patterns had been measured. The collagen birefringence patterns were measured with use of a circularly polarized light technique, and the elastic anisotropy of the bone, mineral, and collagen matrix was evaluated with a novel acoustic microscopy technique. Peak longitudinal strains in the radius correlated with the normalized longitudinal structure index (a polarized light measure of collagen birefringence) and the tissue anisotropy ratio. The average anisotropy ratio was 1.28+/-0.01 in the posterior (compressive) cortex and 1.43+/-0.01 in the anterior (tensile) cortex (these values are significantly different at p < 0.0001). The ulnar osteotomy changed the strain pattern on the radius, causing increased tensile strains in the medial cortex by more than 5-fold that were associated with a significant increase in the anisotropy ratio in the bone tissue. The longitudinal structure index was strongly correlated (r = 0.62, p < 0.005) with the anisotropy ratio of demineralized bone but was not correlated with that of deproteinized bone; this indicates that it reflects collagen fibril orientation in the bone matrix. These results indicate that mechanical strains affect both collagen and mineral microarchitecture in bone tissue, i.e., tensile strains are associated with increased tissue anisotropy and compressive strains, with decreased anisotropy.

Animals↗
PubMed1999

The effect of fluoride treatment on bone mineral in rabbits.

Fluoride therapy has been used clinically for many years, but its use remains controversial and many basic questions remain unanswered. Accordingly, this study returns to an animal model to study the effects of high doses of fluoride on bone mineral in rabbits. Twelve rabbits, aged 3(1/2) months at the start of the study, received drinking water fluoridated at 100 ppm while their 12 control counterparts drank distilled water. All rabbits were sacrificed after 6 months. Fluoride was readily incorporated into femoral cortical bone (7473 +/- 966 ppm F versus 1228 +/- 57 ppm in controls; P < 0.00005). Fluoride therapy led to increased mineralization, as measured by density fractionation (P < 0.0005 for the distributions). The bone mineral itself was altered, with a significant increase in the width of crystals (66.2 +/- 2.0 A versus 61.2 +/- 0.9 A; P < 0.01). The microhardness of both cortical and cancellous bone in the femoral head of fluoride-treated rabbits was greater than that in the controls (P < 0.05). The phosphate, calcium, and carbonate contents in the bone was the same in both groups. Finally, fluoride administration did not affect the architecture or connectivity of cancellous bone in the femoral head. Previously published data [1] indicated that the mechanical properties of bone were adversely affected; this suggests that the effect of high doses of fluoride on the strength and stiffness of bone may be mediated by its effect on bone mineral.

Age Factors↗
PubMed1999

Toward a mathematical description of bone biology: the principle of cellular accommodation.

Mathematical theories for bone biology or more specifically, bone mass regulation, should be viewed with considerable interest because they provide powerful tools for prediction of bone mass changes in response to mechanical or humeral stimuli. Frost [1] put forward one such theory when he postulated that bone mass is a controlled mechanical feedback system called the "mechanostat." He suggested that certain hormones and biochemical agents act on bone biology by changing the thresholds (or minimum effective strains) of the mechanostat. Critical examination of the mechanostat theory indicates that it does not conform well with certain experimental observations. In the present paper, a new theory is presented that addresses some of the flaws in the mechanostat. The new theory is based upon the assumption that bone cells react strongly to transients in their environment, but eventually "accommodate" to steady state signals. This cellular accommodation, represented by a relaxation function, forms the basis for mathematical rate equations that describe bone mass changes in response to external stimuli. Importantly, the cellular accommodation theory can have the property of "path dependence," meaning that final bone mass will be dependent upon the temporal sequence of preceding mechanical loading/hormonal events. Bone tissue demonstrates path dependence in its responses to mechanical loading and anabolic agents. Theoretically, it is possible to exploit the nonlinear character of path dependence to maximize the osteogenic effect of various therapeutic regimens. An experimental approach to test this possibility is described.

Adaptation, Physiological↗
PubMed1999

The elastic properties of trabecular and cortical bone tissues are similar: results from two microscopic measurement techniques.

Acoustic microscopy (30-60 microm resolution) and nanoindentation (1-5 microm resolution) are techniques that can be used to evaluate the elastic properties of human bone at a microstructural level. The goals of the current study were (1) to measure and compare the Young's moduli of trabecular and cortical bone tissues from a common human donor, and (2) to compare the Young's moduli of bone tissue measured using acoustic microscopy to those measured using nanoindentation. The Young's modulus of cortical bone in the longitudinal direction was about 40% greater than (p<0.01) the Young's modulus in the transverse direction. The Young's modulus of trabecular bone tissue was slightly higher than the transverse Young's modulus of cortical bone, but substantially lower than the longitudinal Young's modulus of cortical bone. These findings were consistent for both measurement methods and suggest that elasticity of trabecular tissue is within the range of that of cortical bone tissue. The calculation of Young's modulus using nanoindentation assumes that the material is elastically isotropic. The current results, i.e., the average anisotropy ratio (E(L)/E(T)) for cortical bone determined by nanoindentation was similar to that determined by the acoustic microscope, suggest that this assumption does not limit nanoindentation as a technique for measurement of Young's modulus in anisotropic bone.

Aged↗
PubMed1999

Development of a fluorescent light technique for evaluating microdamage in bone subjected to fatigue loading.

A new method using fluorescent light microscopy has been developed to visualize and evaluate bone microdamage. We report the findings of two different experiments with a common aim of comparing the fluorescent light technique to the brightfield method for quantifying microdamage in bone. In Experiment 1, 36 canine femurs were tested in four-point cyclic bending until they had lost between 5 and 43% of their stiffness. The loaded portion of the bone was stained en bloc with basic fuchsin for the presence of damage. Standard point counting techniques were used to calculate fractional damaged area (Dm.Ar = Cr.Ar/B.Ar, mm2/mm2) under brightfield and fluorescent microscopy. In Experiment 2, bone microdamage adjacent to endosseous implants, subjected to fatigue loading (150,000 cycles, 2 Hz and 37 degrees C) ex vivo was examined. The bone around the implant was either allowed to heal (adapted specimen) for 12 weeks after placement in dog mid-femoral diaphyses prior to testing or was loaded immediately to simulate non-healed bone surrounding endosseous implants (non-adapted). Crack numerical density (Cr.Dn = Cr.N/B.Ar, #/mm2), crack surface density (Cr.S.Dn = Tt.Cr.Le/B.Ar, mm/mm2) and fractional damaged area were calculated separately by both techniques in the adapted and non-adapted specimens. In both Experiments 1 and 2, significantly more microdamage was detected by the fluorescent technique than by the brightfield method. Also, there was a trend towards higher intraobserver repeatability when using the fluorescent method. These results suggest that the brightfield technique underestimates microdamage accumulation and that the fluorescent technique better represents the actual amounts of microdamage present. The results demonstrate that the fluorescent method provides an accurate and precise approach for bone microdamage evaluation, and that it improves the prediction of stiffness loss from damage accumulation.

Animals↗