A whole genome linkage scan for QTLs underlying peak bone mineral density.

UNLABELLED: We conducted a whole genome linkage scan for quantitative trait loci (QTLs) underlying peak bone mineral density (PBMD). Our efforts identified several potential genomic regions for PBMD and highlighted the importance of epistatic interaction and sex-specific analyses in identifying genetic regions underlying PBMD variation. INTRODUCTION: Peak bone mineral density (PBMD) is an important clinical risk predictor of osteoporosis and explains a large part of bone mineral density (BMD) variation. METHODS: To detect susceptive quantitative trait loci (QTLs) for PBMD variation including consideration of epistatic and sex-specific effects, we conducted a whole genome linkage scan (WGLS) for PBMD using 2,200 Caucasians from 207 pedigrees, aged 20-50 years. All the individuals were genotyped with 410 microsatellite markers. In addition to WGLS in the total combined sample of males and females, we conducted epistatic interaction analyses, and sex-specific subgroup linkage analyses. RESULTS: We identified several potential genomic regions that met the criteria for suggestive linkage. The most impressing region is 12p12 for hip PBMD (LOD = 2.79) in the total sample. Epistatic interaction analyses found a significant epistatic interaction between 12p12 and 22q13 (p = 0.0021) for hip PBMD. Additionally, we detected suggestive linkage evidence at 15q26 (LOD = 2.93), 2p13 (LOD = 2.64), and Xq27 (LOD = 2.64). Sex-specific analyses suggested the presence of sex-specific QTLs for PBMD variation. CONCLUSIONS: Our efforts identified several potential regions for PBMD and highlighted the importance of epistatic interaction and sex-specific analyses in identifying genetic regions underlying PBMD variation.

Biomechanical comparison of fixation methods in transverse patella fractures.

OBJECTIVE: To compare monofilament wire versus braided cable for stabilizing transverse patella fractures using the modified AO tension band technique. DESIGN: A randomized blocked (paired) study comparing two fixation methods. Statistical analysis was performed using a nested repeated measures analysis, followed by Bonferroni post hoc testing. METHODS: Seven paired embalmed knees (mean age 71.8 years, SD 14.6 years) were dissected, and transverse fractures were simulated. The knees were reduced and randomly fixed by either two parallel 0.062-inch Kirschner wires with a 1.0-millimeter-diameter 316L stainless steel monofilament wire tension loop or two Kirschner wires with a 1.0-millimeter-diameter 316L stainless steel braided cable tension loop. Knees were tested by applying a cyclic load through the suprapatellar tendon between twenty and 300 newtons for thirty cycles. RESULTS: The maximum fracture displacement increased with each cycle of loading for both the braided cable and monofilament wire tension loop configurations (p = 0.0001). The average peak displacement at the thirtieth cycle was 2.25 millimeters for monofilament wire and 0.73 millimeters for the cable. When comparing both methods for all cycles, the braided cable allowed less fracture displacement than did the monofilament wire (p = 0.002), and the rate of increase per cycle of maximum fracture displacement was less for the cable than for the wire (p = 0.0001). CONCLUSIONS: In transverse, noncomminuted patella fractures, fixation with two Kirschner wires and a 1.0-millimeter braided cable tension loop was superior to the monofilament wire tension loop. Most importantly, the braided cable afforded more predictable results during cyclic loading.

Bone remodelling adjacent to intramedullary stems: an optimal structures approach.

The internal parameters in bone remodelling theories often are not clearly related to the bony structure which results from the simulations in which they are implemented. For a restricted class of bone remodelling theories, we have previously found a connection between overall structural optimization and the parameters within a continuum-level remodelling rule. In this study, we assess whether a simplified analytical formula based on structural optimization can predict the behaviour of a large-scale finite element bone remodelling simulation. The analytical formula predicts when bone will remain around an intramedullary implant. The predictions of the formula are borne out in the numerical results. This leads to a physical interpretation of one of the two parameters in the remodelling rule used. The results also show some characteristics which are clinically relevant. This study extends earlier results due to Huiskes for internal remodelling around intramedullary implants by using a different, numerically stable remodelling algorithm based on optimization. The study also shows a direct practical application of the optimizing remodelling theory the authors have developed previously.

Distal chevron osteotomy with lateral release for treatment of hallux valgus deformity.

From 1986 to 1990, 42 feet in 30 patients had a combined chevron osteotomy and lateral release to correct their painful bunion deformity. Seventeen patients, 23 feet, were available for follow-up. The purpose of this study was to evaluate the outcome of this procedure and to determine the incidence of avascular necrosis. The patients were examined by an independent examiner, radiographs obtained, and questionnaires filled out. Avascular necrosis was determined using plain films read by a musculoskeletal radiologist who did not know the outcomes. The average age was 45 years at the time of the procedure. Average follow-up was 50 months. The preoperative intermetatarsal angle averaged 13 degrees and the hallux valgus angle averaged 31 degrees. At study follow-up, the intermetatarsal angle averaged 8 degrees and the hallux valgus angle averaged 17.5 degrees. The results were graded by the Mayo Clinic Forefoot Scoring System (75-point scale) and a subjective scoring system. Average postoperative Mayo Clinic score was 67. Fifteen feet were subjectively rated as excellent, six as good, and two as fair. Complications occurred in four feet. Hallux varus occurred in two feet, extension contracture in one foot, and an infection in one foot. None of the feet developed definite radiographic evidence of avascular necrosis. Distal chevron osteotomy combined with a lateral release for corrective bunion surgery has come under scrutiny, because of the risk of avascular necrosis of the first metatarsal head. However, our study showed no evidence of avascular necrosis on radiographs. In addition, 91% of patients had good to excellent results at an average 50-month follow-up.

Bone remodeling and structural optimization.

Bone remodeling has been viewed both as a process which adapts bone tissue to the mechanical environment at each point in the structure, and as a process which optimally adjusts the tissue distribution within bones to bear the loads placed on them. We have developed a connection between these two views of bone remodeling, in a restricted sense. We start with a remodeling rate equation based on strain energy density. We then define an indicator function which is a weighted sum of total strain energy and a measure of bone mass, and we show that finding bone density distributions in which the remodeling rate equation predicts no changes with time is the same as finding density distributions in which the indicator function is insensitive to small changes in density. The set point in the remodeling rate equation corresponds to a parameter in the indicator function which determines the relative importance of bone mass and strain energy in the optimization indicator function. We have not assessed whether the density distributions which make the density rate of change zero are actually local or global minima for the indicator function in this study, but a related study shows that there is a single unique minimum for the indicator function developed here, implying that a unique solution exists for the bone remodeling rate equations considered in this study.

A comparative study of hepatic HMG CoA reductase activity and LDL receptor relative mass in suckling and adult guinea pigs.

The reason why plasma cholesterol levels increase soon after birth is unknown but may be related to change rates of cholesterol synthesis and/or expression of LDL receptors. Plasma cholesterol levels, along with hepatic HMG CoA reductase activity, the rate-limiting enzyme of cholesterol synthesis, and hepatic LDL receptor relative mass were measured in suckling (1, 4 and 8 days of age) and adult guinea pigs. Plasma cholesterol was measured by an enzymatic assay, HMG CoA reductase activity was determined using a radiolabelled substrate and LDL receptor-relative mass was measured by ligand blotting with gold-labelled rabbit beta VLDL. Among the young animals, HMG CoA reductase activity and plasma cholesterol levels increased between 1 and 4 days of age. The LDL receptor mass did not change in the first 8 days after birth, but was 2-fold higher in adult than suckling animals. Hepatic HMG CoA reductase activity was also higher in the adult animals. Increased hepatic HMG CoA reductase and low LDL receptor mass may contribute to the elevation in plasma LDL cholesterol levels in the 4-day-old guinea pig.

Bone strain sensation via transmembrane potential changes in surface osteoblasts: loading rate and microstructural implications.

A model is developed in which osteoblasts can sense the strains applied to a small region of bone through electrical coupling between adjacent cells. The stress-generated potentials within bone are assumed to occur through streaming potentials, and the coupled network of osteocytes is assumed to act in a manner similar to the classical cable model for nerve cells. In a one-dimensional model, the linear poroelastic equations for motion of the fluid are solved analytically for sinusoidally varying imposed strains, and the streaming potentials are predicted from the fluid flow. The changes in the osteocyte and osteoblast transmembrane potential are given by an analytical solution to the governing equations, and the dependence of the transmembrane potential changes (TPC) on position, loading rate, manner of loading (compression versus bending), and on the degree of cellular coupling is discussed. The model correctly predicts the rate dependence of remodelling established by other investigators. The influence of the electrical parameters within the model indicate that further study of the cellular coupling in bone can yield important new information on bone remodelling.

Output beam intensity noise induced by fiber perturbations in a fiber-linked laser.

The effects of acoustic perturbations on an optical fiber intended to link a laser to an optical cavity have been studied. Acoustic noise above the level of -45 dBre(l µbar) in the frequency band of 500-1500 Hz has a measurable effect on intensity fluctuations at the fiber's output.

Effects of developmental changes and early nutrition on cholesterol metabolism in infancy: a review.

Plasma cholesterol levels usually range between 50 and 100 mg/dl at birth, with the cholesterol approximately equally distributed between low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Plasma cholesterol increases rapidly over the first days after birth, predominantly due to an increase in cholesterol with LDL, irrespective of whether the infant is breast fed or fed with infant formulas. With continued feeding, plasma cholesterol becomes progressively, and significantly, higher in infants who are breast fed compared to those fed low-cholesterol, polyunsaturated fatty acid-rich infant formula. Studies in the developing young of other species have suggested that up-regulation of cholesterol synthesis, or turnover and excretion, at stages when these pathways are acquiring functional maturity may have lasting effects on cholesterol metabolism. The information available, however, indicates the diet-related differences in plasma cholesterol of the more mature human newborn are temporal in nature and probably not of significance to adult cardiovascular disease. Infants born early in the third trimester of gestation, however, are at risk for marked elevations in plasma cholesterol, with stimulation of endogenous cholesterol biosynthesis, as a result of the intravenous nutrition required to sustain life. Whether this has long-term consequences for this group of infants is unknown. There is presently no reason to advocate diet modification to alter the plasma cholesterol of normal infants under the age of 2 years.

An analytical and numerical study of the stability of bone remodelling theories: dependence on microstructural stimulus.

The origin of unstable bone remodelling simulations using strain-energy-based remodelling rules was studied mathematically in order to assess whether the unstable behavior was due to the mathematical rules proposed to characterize the processes, or to the numerical approximations used to exercise the mathematical predictions. A condition which is necessary for the stability of a strain-energy-based remodelling theory was derived analytically using the calculus of variation. The analytical result was derived using a simple elastic model which consists of a long beam loaded by an axial force and a bending moment. This loading situation mimics the coupling between local density and global density distributions seen in vivo. A condition necessary for a stable remodelling scheme is arrived at, but the conditions necessary to guarantee a stable remodelling scheme are not. In this remodelling scheme, the elastic modulus is proportional to volumetric density raised to an exponent n, and the microstructural stimulus is taken as the strain energy density divided by volumetric density raised to an exponent m. In order for a remodelling scheme to be stable in this loading situation, m must be greater than n. Finite-difference time-stepping is used to verify the predictions of the analytical study. These numerical studies appear to confirm the analytical studies. Physiologic interpretation of the behavior found with n greater than m indicates that this type of unstable behavior is unlikely to be observed in vivo. Since numerical approximations are not made in deriving this stability condition, we conclude that the mathematical rules proposed to characterize bone remodelling based on strain energy density should meet this condition to be relevant to physiologic bone remodelling.

Plasma cholesterol and lathosterol levels in term infants in the early neonatal period.

Plasma cholesterol concentrations increase after birth. Whether this is due to increased cholesterol synthesis has not been reported. Additionally, it is not known if formulas, which lack cholesterol, result in higher rates of cholesterol synthesis than feeding breast milk. To address this, plasma lathosterol (quantitated by gas chromatography), a potential indicator of cholesterol synthesis, was measured in term infants at birth (cord) and 4 d of age fed either formula or breast milk (n = 6 each), normal adults (n = 6) at the expected nadir and peak of the diurnal rhythm (1700 h and 0830 h), and cholestyramine-treated hypercholesterolemic adults (n = 6). Plasma cholesterol and apo B increased, and apo AI (measured by immunoprecipitation) did not change over the first 4 d of life. The increase in plasma cholesterol was greater in the formula-fed infants compared with breast-fed infants. The plasma lathosterol concentrations (mumol/L) and the lathosterol:cholesterol ratios (10(2) x mmol lathosterol/mol cholesterol) decreased from birth to 4 d of age by 12 and 36%, respectively, in the breast-fed infants and by 20 and 46%, respectively, in formula-fed infants. The infant plasma lathosterol concentrations, however, were not different from normal adult levels [1700 h: 5.50 +/- 1.52 (SD); 0830 h: 6.18 +/- 1.80], but were lower than those of cholestyramine-treated adults (20.48 +/- 13.41). Sterol ratios of infants were higher than those of normal adults (1700 h: 112.5 +/- 26.0; 0830 h: 129.4 +/- 42.2), but not different from those of cholestyramine-treated adults (322.9 +/- 168.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Elevation of plasma lathosterol, as an indicator of increased cholesterol synthesis, in preterm (23-32 weeks gestation) infants given Intralipid.

Hypercholesterolemia is common in preterm infants administered 10% Intralipid perhaps because of excess phospholipid in plasma causing efflux of cholesterol from tissues. The purpose of this study was to determine if cholesterol synthesis (as measured by plasma lathosterol) is increased in preterm infants (23-32 wk gestation) during infusion of up to 4 g 10% Intralipid/kg body wt/d. Two groups of infants were studied. Intralipid intake was compared to: 1) plasma cholesterol in blood sampled over the first 100 d of life (preliminary study, n = 22) and 2) plasma cholesterol, lathosterol, and apo AI and B in blood taken at birth (cord), d 3-4 of life, and at least three additional times over the next 25 d (lathosterol study, n = 22). Lathosterol was quantitated by gas liquid chromatography and apo AI and B by immunoprecipitation. In the preliminary study, plasma cholesterol levels rose (to 4.06-10.70 mM) with Intralipid administration. Infants who received less than 2 g Intralipid/kg body wt/d were not hypercholesterolemic. In the lathosterol study, plasma cholesterol increased (1.86-2.24 mM, p = 0.06) and apo AI and B did not change, but lathosterol and the cholesterol:lathosterol ratio decreased (5.24-2.88 microM, p = 0.01, and 284-124 10(2) x mmol lathosterol:mol cholesterol, p = 0.007, respectively) from birth to d 3-4 (n = 11 paired samples). Infants followed longitudinally had increased cholesterol and lathosterol (4- to 7-fold) with increasing Intralipid administration, which decreased after discontinuation of infusion. Apo AI and B decreased upon Intralipid infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Optical motion sensor for resonant-bar gravitational wave antennas.

An experiment is described in which an optical method was used to measure fluctuations in the separation between two mirrors of a Fabry-Perot sensor cavity. Noise measurements were made to determine the sensitivity of this device to vibration amplitudes in the frequency range 1.1-2.1 kHz, which is of interestfor resonant-bar gravitational wave antennas. The rms spectral noise density for length fluctuations inthis range was 3.7 x 10(15-) m/Hz((1/2)) and can be related to electronic noise of the circuitry plus vibrationalnoise from the environment. The cavity finesse was relatively low at 117, and the power dissipated in the mirrors was estimated to be 1.9 muW. On a multimode gravitational wave detector, the sensor cavity would be formed by one reference mirror and by one mirror mounted on the last resonator. For a 1200-kg bar, 1.2-g last resonator system operating at 1600 Hz, the sensor described here would exhibit a noise temperature of 18 muK; the resolution in h in the case of negligible thermal noise from the mechanical system would be 3.7 x 10(-18)/Hz((1/2)). Improvements in the sensitivity in a quiet antenna-like environment should be possible with higher finesse mirrors.

Frequency noise induced by fiber perturbations in a fiber-linked stabilized laser.

The effects of acoustic perturbations on an optical fiber that links a stabilized laser to its reference cavity are studied. An extrapolation indicates that 69 dB of acoustic noise impinging on a 1-m segment of the 10-m fiber contribute frequency noise at the level of 1 Hz/(Hz) ((1/2)) in the 1100- 21 00-Hz band.

High-finesse measurements at low temperatures.

High-reflectivity supermirrors were used to produce a Fabry-Perot cavity that operated at cryogenic temperatures. The best finesse below 80 K was found to be 19,000 and remained constant down to 4.2 K.

Experimental intra-articular calcaneal fractures: anatomic basis for a new classification.

Experimental calcaneus fractures were produce by axially loading 18 specimens. Anatomic dissections were performed and documented. Two constant primary fracture lines were identified, dividing the calcaneus in the coronal and sagittal planes. A constant anterolateral fragment was identified, as were three patterns of calcaneocuboid joint fracture involvement. Based on the pathoanatomy and surgical anatomy of the calcaneus, a medial and lateral column classification is proposed. The medial column includes the superomedial fragment. The lateral column includes the calcaneocuboid joint, lateral wall and posterior facet. This concept can help identify fracture displacements and correlate them with a treatment plan.

Carnitine and carnitine esters in rat bile and human duodenal fluid.

The recent discovery of carnitine and its esters in rat bile has led to much speculation about its role. The objectives of these studies were to investigate the origin of carnitine esters in rat bile and to study the presence of carnitine in human bile-rich duodenal fluid. Bile was collected from chow-fed (n = 11), fasted (72 h, n = 6), and fasted plus 2-tetradecylglycidic acid administered (72 h, n = 5) male adult rats under sodium pentobarbital anaesthesia. Carnitine and carnitine ester content was measured in the bile and compared with serum and liver carnitine. Bile from fed rats was found to contain 80% acylcarnitine, one-third of this as long chain carnitine esters. Fasting caused no change in the secretion rate of acylcarnitine into the bile, although long chain carnitine ester secretion almost doubled. Conversely, 2-tetradecylglycidic acid treatment caused a decrease in long chain carnitine ester secretion into bile. Duodenal fluid was collected from patients with suspected cholelithiasis (n = 10) before and after pancreozymin-cholecystokinin injection. Although carnitine concentration was variable, it was consistently 80% esterified. These data associate bile carnitine with hepatic carnitine metabolism and establish the presence of carnitine and carnitine esters in the human intestinal lumen.