A new approach for assessing early osteoarthritis in the rat.

Several animal models have been developed to investigate osteoarthritis and potential disease-modifying therapeutics. However, early disease data from these models are limited by the resolution of current imaging modalities. In this in-vitro study, an optical coherence tomography (OCT) system with an axial resolution of 15 micro m was used to track sequential changes in osteoarthritic rat knees. Osteoarthritis was induced via transection of the medial collateral ligament and an artificial full thickness meniscal tear. Imaging occurred at one, two, and three weeks after surgery. OCT successfully detected early signs of osteoarthritic change, including alteration of the cartilage surface and disruption of the bone-cartilage interface. This study demonstrates that OCT, along with the induction of mechanical injury, provides an excellent model for monitoring the sequential changes of osteoarthritis.

Abnormal bone architecture and biomechanical properties with near-lifetime treatment of rats with PTH.

Skeletal effects are described for near-lifetime treatment of young, female rats with recombinant human PTH (1-34) (PTH). Rats (5-8 wk of age) were administered 0, 5, 30, or 75 microg/kg x d sc PTH for up to 2 yr, as part of an oncogenicity evaluation, which is required by regulatory agencies for potential chronic therapies. Proliferative lesions were observed in the skeleton as described in Vahle et al. (1 ); in this paper, we describe the quantitative bone data for this study. In the appendicular skeleton, PTH stimulated trabecular and endocortical mineral apposition to the near exclusion of marrow spaces at 5 microg/kg, with some periosteal apposition at 30 microg/kg, followed by considerable periosteal apposition and altered geometry at 75 microg/kg. Increased bone mass was observed for all treatment groups that substantially exceeded normal levels attained by vehicle controls and exceeded skeletal efficacy reported previously for similar doses in shorter-term studies. Dose-dependent increases in osteocalcin levels and a linear increase in wet weight of femora were observed for the entire treatment duration, suggesting nearly continuous PTH stimulation of osteoblasts and skeletal growth throughout life. Histology showed many osteocytes and prominent osteoblasts, but a conspicuous absence of osteoclasts. Morphometry showed a lack of distinction between trabecular and cortical bone. Biomechanics of vehicle controls showed that optimal mechanical integrity for the normal skeleton is observed at about 11 months of age. PTH greatly strengthened and stiffened vertebra and femora; however, the midshaft showed reduced toughness and increased brittleness with treatment, which was not the case for vertebra. Related studies of 6 and 9 months duration showed that the optimal duration for PTH skeletal efficacy was about 6 months in rats, based on toughness, strength, ultimate displacement, and architecture, especially for cortical bone. Therefore, treatment duration is an under appreciated aspect of PTH pharmacology; and PTH skeletal effects are a complex function of dose and duration. Comparative analyses showed that short-term treatment (6 months or less) is more advantageous than near-lifetime treatment, because PTH stimulates skeletal growth throughout life, resulting in abnormal architecture and untoward biomechanical properties in rats.

Skeletal efficacy with parathyroid hormone in rats was not entirely beneficial with long-term treatment.

We report the consequences of prolonged treatment with recombinant human parathyroid hormone (1-34) (PTH) in male and ovariectomized female rats with mature skeletons. Intact male and osteopenic, ovariectomized, female F-344 rats were evaluated after 1 year of treatment with 0, 8, or 40 microg/kg/day s.c. PTH. Males and females were about 6 months of age at study initiation; females were ovariectomized (Ovx) for 5 weeks before initiation of PTH treatment. PTH did not affect the survival of either intact males or ovariectomized females. Qualitative histopathology showed expected changes associated with aging in kidneys and proximal tibiae, with no treatment-related anomalies after 1 year of PTH administration. PTH slightly increased the femoral length of ovariectomized females but not that of males. No significant differences in femoral length were observed between sham and Ovx controls. Proximal femora of the males and ovariectomized females given the high dose of 40 microg/kg showed 211 and 186% greater trabecular bone area, 118 and 94% greater cortical thickness, 170 and 189% greater trabecular number, and 321 and 404% greater connectivity (node-to-node struts) compared with respective vehicle controls. Increased trabecular and endocortical surface apposition coincided with a 78 and 70% loss of marrow space for males and females treated with PTH, respectively. Biomechanical strength (ultimate load) of the femoral neck increased by 73 and 76%, respectively, in males and ovariectomized females. Cortical bone analyses of the femoral midshaft showed 105 and 72% increases in bone mineral content, 67 and 55% increases in bone mineral density, and 22 and 10% increases in cross-sectional area for males and ovariectomized females, respectively, with altered shape of femora. Biomechanical analyses of the midshaft showed substantial increases in strength and stiffness but a reduction in ultimate strain, which was likely due to the altered geometry of the midshaft for PTH groups. Aging effects on strength of vertebra and femoral midshaft were reversed by PTH treatment. In summary, the 1-year treatment duration, which represents about 50% of lifetime, did not affect survival and was not associated with any treatment-related anomalies in the kidney or skeleton. PTH reversed the aging process in bones but not kidneys and substantially increased bone mass and strength to well beyond normally attained levels. However, compared with short-term studies reported previously, there seemed to be no advantages to extending PTH treatment to 12 months in rat bones.

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.

Tomographic imaging of the angular-dependent coherent-scatter cross section.

A new special-purpose computed tomographic (CT) imaging system is described which produces images based on measurements of the low-angle (0-10 degrees) x-ray diffraction properties of an object. Low-angle scatter in the diagnostic x-ray energy range is dominated by coherent scatter, and the system uses first-generation CT geometry to acquire a diffraction pattern for each pencil beam. The patterns are used to reconstruct a series of images which represent the coherent-scatter intensity at a series of scatter angles. To demonstrate the potential of coherent-scatter CT (CSCT), the scanner has been built and used to image a phantom consisting of a water-filled Lucite cylinder containing rods of polyethylene, Lucite, polycarbonate, and nylon. In this paper, the system is described and a sequence of CSCT images of this phantom is shown. Coherent-scatter cross sections of these materials are generated for each pixel from this sequence of images and compared with cross sections measured separately. The resulting excellent agreement shows that the angular-dependent coherent-scatter cross section can be accurately imaged in a tomographic slice through an object. These cross sections give material-specific information about the object. The long-term goal of this research is to make measurements of bone-mineral content for every pixel in a tomographic slice.

Angular-dependent coherent scatter measured with a diagnostic x-ray image intensifier-based imaging system.

Low-angle scatter of x rays at diagnostic energies is primarily coherent. This coherence gives rise to interference effects resulting in x-ray diffraction patterns that are characteristic of the scattering material. A method is described of imaging these low-angle (0 degree-10 degrees) x-ray diffraction properties of tissue specimens using a diagnostic x-ray beam and image intensifier-based system. The coherent-scatter cross sections of several materials measured this way are presented. It is shown theoretically that the measurements made with this system can be expressed as the mono-energetic cross section "blurred" by the x-ray spectrum using a linear superposition integral. Experimental results using aluminum powder confirm this. Using a 70 kVp x-ray beam filtered with gadolinium to reduce the spectral width, materials such as water, Lucite, and hydroxyapatite all have significantly different diffraction patterns. The cross sections determined from this analysis from the basis of a unique method of characterizing and identifying tissue samples according to their atomic structure rather than x-ray attenuation properties.

Clinical experience with patient-controlled and staff-administered intermittent bolus epidural analgesia in labour.

A prospective, randomized study was performed to detail clinical experience with both patient-controlled epidural analgesia (PCEA) and midwife-administered intermittent bolus (IB) epidural analgesia during labour, under the conditions pertaining in a busy obstetric delivery unit. Both methods used 0.125% bupivacaine plus fentanyl, and similar rescue supplementation, although management decisions related to epidural analgesia were made principally by attending midwives. One hundred and ninety-eight women were recruited and data analysed from 167 (PCEA n = 82, IB n = 85). The groups were demographically similar. Median hourly pain scores, ratings of analgesia and satisfaction did not differ. Maximum pain scores were significantly higher in those receiving IB epidural analgesia (P < 0.05). The PCEA group had a significantly higher rate of supplementation and bupivacaine use (P < 0.01), and a longer duration of the second stage of labour (P < 0.03). The relative risk of instrumental delivery with PCEA versus the IB method was 1.57 (CI 1.07-2.38). Experience within our unit with PCEA is contrasted with that of IB epidural analgesia, the method most commonly used; and with that of controlled trials comparing these two methods.

A spatial-frequency dependent quantum accounting diagram and detective quantum efficiency model of signal and noise propagation in cascaded imaging systems.

The detective quantum efficiency (DQE) is a system parameter that can be used to accurately describe image noise transfer characteristics through many imaging systems. A simpler approach used by some investigators, particularly when evaluating new ideas and system designs, is to describe the system as a series of cascaded stages. Each stage may correspond to either an increase in the number of quanta (e.g., conversion from x-ray to optical quanta in a radiographic screen), or a loss (a detection or coupling probability). The number of secondary quanta at each stage per incident primary quantum is given by the product of all preceding gains, and can be displayed graphically for convenient interpretation. The stage with the fewest quanta is called the "quantum sink," limiting the pixel signal-to-noise ratio to less than the square root of the number of quanta per pixel. This conventional zero-spatial-frequency "quantum accounting diagram" (QAD), however, neglects the spatial spreading of secondary quanta and can seriously underestimate image noise. It is shown that this problem is avoided with the introduction of a spatial-frequency dependent QAD, expressed as the product of the gains and squared modulation-transfer functions (MTF) of each stage. A generalized expression is developed for the DQE of a cascaded imaging system that is dependent only on the gain, gain Poisson excess (related to the variance), and MTF, of each stage. A direct relationship is then shown to exist between the DQE and values in the QAD. The QAD of a hypothetical system consisting of a charge-coupled device camera and a scintillating screen is evaluated as an illustrative example. The conventional zero-frequency analysis suggests two quantum sinks occur with approximately equal importance: one in the number of x rays, and one in the number of optical quanta. The spatial-frequency dependent analysis, however, shows the optical quantum sink becomes severe and dominates at nonzero frequencies. The necessary increase in gain or optical numerical aperture required to prevent the optical quantum sink for spatial frequencies of interest is determined from the QAD analysis. The visual impact of this nonzero spatial-frequency quantum sink is shown in images generated using a Monte Carlo simulation of the cascading process.

Postoperative epidural fentanyl infusion--is the addition of 0.1% bupivacaine of benefit?

A randomised, double-blind controlled clinical trial was conducted in 90 women scheduled for major abdominal gynaecological oncology surgery to determine the effect of adding 0.1% plain bupivacaine to a thoracic epidural fentanyl infusion. Following combined epidural and general anaesthesia, patients were randomised to receive epidural fentanyl 10 micrograms/ml, with (group FB) or without (group F) bupivacaine. After an initial 50 micrograms bolus of fentanyl, infusion rate was adjusted according to need between 2 and 10 ml/hr for 48 hours. The two groups (n = 40) were similar with regard to age, weight and preoperative status. Analgesia both at rest and with movement were significantly better in group FB (P < 0.0001) during the first 24 hours postoperatively, the greatest difference occurring in the 4 to 16 hour period. There was no significant difference between groups from 24 to 48 hours postoperatively. Fentanyl utilisation was significantly lower in group FB (median 41 versus 53 micrograms/hr, P < 0.001), although clinically the fentanyl dose-sparing effect of bupivacaine was small and did not reduce opioid-induced side-effects. There was no significant difference between groups with respect to side-effects or lower limb weakness, although fewer patients in group FB could be mobilised on the morning of the first postoperative day (P < 0.01). Nevertheless, all study patients were ambulant by the same afternoon. We concluded that, in this patient population, the addition of 0.1% bupivacaine to a thoracic epidural fentanyl infusion was beneficial in the early postoperative period.

Effects of extradural anaesthesia on umbilical and uteroplacental arterial flow velocity waveforms.

Flow velocity waveforms were recorded from the umbilical artery and uteroplacental arterial circulations of 15 women undergoing elective Caesarean section under extradural anaesthesia. The systolic: diastolic ratios of the flow velocity waveform were determined before and after extradural block. Extradural block did not alter fetal or maternal heart rates; however, umbilical artery systolic:diastolic ratio decreased from a mean (SD) of 2.4 (0.42) to 2.26 (0.38) (P = 0.049). There were no significant changes in the uteroplacental systolic:diastolic ratios. These results were compared with those from a control group in which no statistically significant changes in maternal and fetal systolic:diastolic ratios or heart rates were observed. The application of a pulse correction factor to standardize the data to fixed maternal and fetal heart rates had little effect on the significance of the findings. Extradural block in normal pregnant women during late gestation was associated with a small reduction in umbilical artery systolic:diastolic ratios, suggesting a decrease in downstream fetoplacental vascular resistance.

Make-up as an adjunct and aid to the practice of dermatology.

Make-up for the medically referred client is an illusory product that is applied and removed on a daily basis. It is not intended to promote or maintain skin health; its sole purpose and function is to alter or normalize the patient's physical or reflective image. It is applied for psychologic reasons only--to normalize the appearance by diminishing or disguising facial disfigurements and some of the visible signs of aging. It assists the patient in becoming more socially acceptable and allows the creation of a well-groomed look that lets him or her re-enter the mainstream of life. The person who has a facial disfigurement--no matter how large or how small, whether it is caused by disease, trauma, an acquired skin discoloration, or a birth anomaly--can use paramedical make-up products and techniques as the "grand illusion" to camouflage or conceal the visible effect of the discoloration. Make-up applied by the qualified and properly trained medical make-up specialist can be a valuable adjunct to the dermatologist's overall practice. It assists the physician's patients in obtaining their goal of disguising their facial disfigurement or aesthetically improving their appearance, and at the same time it has a positive effect on their self-image. All physicians and responsible medical personnel who are concerned with their patients' complete healing and mental well-being should use a properly trained medical make-up specialist as an adjunct to their practice.

Epidural opioids in obstetrics--a review.

Epidural opioids have been used in obstetrics since 1980. Various opioids are reviewed in relation to their pharmacology, their efficacy in labour, during caesarean section and for postoperative analgesia, their side-effects and safety. In this patient population it appears safe to administer epidural opioids on the general ward provided that strict monitoring standards are maintained. Practical considerations of nursing management are discussed.

A double-blind comparison of epidural bupivacaine and bupivacaine-fentanyl for caesarean section.

The effect of adding fentanyl 100 mcg to bupivacaine 0.5% plain to establish epidural anaesthesia for elective caesarean section was investigated in a randomised, double-blind study of sixty healthy women. The quality of intraoperative analgesia as assessed by both patients and anaesthetists was significantly improved with fentanyl. The onset and duration of sensory anaesthesia, degree and duration of motor block, and other characteristics of epidural anaesthesia were unaltered. No adverse maternal side-effects (except mild pruritus) were noted and neonatal outcome was unaffected. The pharmacokinetics of epidural fentanyl administration were investigated by plasma fentanyl assays from maternal and cord blood taken at delivery. Epidural bupivacaine-fentanyl combination is a valuable therapeutic approach to the conduct of epidural anaesthesia for caesarean section in healthy women and foetuses. Further neonatal evaluation of the premature or compromised foetus is suggested before the universal application of this technique.

Effect of general anaesthesia on transient lower oesophageal sphincter relaxations in the dog.

This report investigates the hypothesis that gastro-oesophageal flow is modulated by central nervous activity. The hypothesis was examined using the canine model in which gastro-oesophageal flow was stimulated by gastric insufflation of air at 80 ml/min and central nervous depression was produced with the anaesthetic agents thiopentone, nitrous oxide and halothane. Duplicate paired studies were performed in four dogs, either unsedated or anaesthetized. Gastro-oesophageal flow was assessed manometrically by a sleeve catheter assembly and by pH electrode. Gastric compliance was assessed by inflation of a thin-walled, plastic bag. Transient lower oesophageal sphincter relaxation, the dominant mechanism of retrograde trans-sphincter flow in unsedated animals, was abolished by general anaesthesia. Retrograde flow of gas across the lower oesophageal sphincter in anaesthetized animals eventually occurred, but only after massive gastric distension and elevation of gastric pressure to lower oesophageal sphincter pressure. The effects observed could not be explained by a direct action of anaesthetic on the lower oesophageal sphincter or on the gastric wall. It is proposed that general anaesthesia results in blockade of the neural pathway responsible for transient lower oesophageal sphincter relaxation by withdrawal of facilitative higher centre activity. The findings have implications for the use of sedation in experimental studies on factors which control gastro-oesophageal reflux, and clinical application to the risk of tracheal aspiration during general anaesthesia.