Bone Phenotype Assessed by HRpQCT and Associations with Fracture Risk in the GLOW Study.

The epidemiology and pathogenesis of fractures in postmenopausal women has previously been investigated in the Global Longitudinal study of Osteoporosis in Women (GLOW). To date, however, relationships between bone imaging outcomes and fracture have not been studied in this cohort. We examined relationships between high-resolution peripheral quantitative computed tomography (HRpQCT) parameters and fracture in the UK arm of GLOW, performing a cluster analysis to assess if our findings were similar to observations reported from older participants of the Hertfordshire Cohort Study (HCS), and extended the analysis to include tibial measurements. We recorded fracture events and performed HRpQCT of the distal radius and tibia and dual-energy X-ray absorptiometry (DXA) of the hip in 321 women, mean age 70.6 (SD 5.4) years, identifying four clusters at each site. We saw differing relationships at the radius and tibia. Two radial clusters (3 and 4) had a significantly lower hip areal bone mineral density (p < 0.001) compared to Cluster 1; only individuals in Cluster 4 had a significantly higher risk of fracture (p = 0.005). At the tibia, clusters 1, 3 and 4 had lower hip areal bone mineral density (p < 0.001) compared to Cluster 2; individuals in Cluster 3 had a significantly higher risk of fracture (p = 0.009). In GLOW our findings at the radius were very similar to those previously reported in the HCS, suggesting that combining variables derived from HRpQCT may give useful information regarding fracture risk in populations where this modality is available. Further data relating to tibial HRpQCT-phenotype and fractures are provided in this paper, and would benefit from validation in other studies. Differences observed may reflect age differences in the two cohorts.

Ankle arthrodesis and its relationship to ipsilateral arthritis of the hind- and mid-foot.

It has been suggested that arthrodesis of the ankle leads to osteoarthritis of the joints of the ipsilateral hind- and midfoot. We believe these studies overlooked the presence of osteoarthritic changes in these joints before the arthrodesis. We reviewed the pre-operative radiographs of 70 patients with osteoarthritis of the ankle who underwent 71 ankle arthrodeses (one was bilateral). The talonavicular, calcaneocuboid, subtalar and naviculocuneiform joints were given an osteoarthritis score according to Kellgren and Lawrence. The mean age at operation was 54.9 years and the most common indication was for post-traumatic osteoarthritis (52 cases). A total of 68 patients showed pre-existing arthritis in either the hind- or mid-foot, with the subtalar joint the most commonly affected. Ipsilateral hind- and mid-foot arthritis is almost universally present in patients with arthritis of the ankle requiring arthrodesis. The presence of such changes may not be a consequence of this arthrodesis.

A review of the methods used to define glucocorticoid exposure and risk attribution when investigating the risk of fracture in a rheumatoid arthritis population.

BACKGROUND: Glucocorticoid therapy is used widely in patients with rheumatoid arthritis (RA) with good efficacy but concerns about safety including fractures. Estimates of fracture risk for any given patient are complicated by the dynamic pattern of glucocorticoid use, where patients vary in their dose, duration and timing of glucocorticoid use. OBJECTIVE: To investigate which methods are currently used to attribute fractures to glucocorticoid exposure and investigate whether such methods can consider individual treatment patterns. RESULTS: Thirty-eight studies used five common definitions of risk attribution to glucocorticoid exposure: "current use", "ever use", "daily dose", "cumulative dose" and "time variant". One study attempted to combine multiple definitions where "cumulative dose" was nested within "daily dose", covering the effects of dose and duration but not timing. The majority of results demonstrated an equivocal or increased risk of fracture with increased exposure, although there was wide variation, with odds ratios, hazard ratios and relative risks ranging from 0.16 to 8.16. Within definitions there was also variability in the results with the smallest range for "time variant", 1.07 to 2.8, and the largest for "cumulative dose", ranging from risk estimates of 0.88 to 8.12. CONCLUSION: Many studies have looked into the effect of glucocorticoids on fracture risk in patients with RA. Despite this, there is no clear consensus about the magnitude of risk. This is a consequence of the varied analysis models and their different assumptions. Moreover, no current analysis method allows consideration of dose, duration and timing of glucocorticoid therapy, preventing a clear understanding of fracture risk for patients and their individual treatment patterns.

Cluster analysis of bone microarchitecture from high resolution peripheral quantitative computed tomography demonstrates two separate phenotypes associated with high fracture risk in men and women.

Osteoporosis is a major healthcare problem which is conventionally assessed by dual energy X-ray absorptiometry (DXA). New technologies such as high resolution peripheral quantitative computed tomography (HRpQCT) also predict fracture risk. HRpQCT measures a number of bone characteristics that may inform specific patterns of bone deficits. We used cluster analysis to define different bone phenotypes and their relationships to fracture prevalence and areal bone mineral density (BMD). 177 men and 159 women, in whom fracture history was determined by self-report and vertebral fracture assessment, underwent HRpQCT of the distal radius and femoral neck DXA. Five clusters were derived with two clusters associated with elevated fracture risk. "Cluster 1" contained 26 women (50.0% fractured) and 30 men (50.0% fractured) with a lower mean cortical thickness and cortical volumetric BMD, and in men only, a mean total and trabecular area more than the sex-specific cohort mean. "Cluster 2" contained 20 women (50.0% fractured) and 14 men (35.7% fractured) with a lower mean trabecular density and trabecular number than the sex-specific cohort mean. Logistic regression showed fracture rates in these clusters to be significantly higher than the lowest fracture risk cluster [5] (p<0.05). Mean femoral neck areal BMD was significantly lower than cluster 5 in women in cluster 1 and 2 (p<0.001 for both), and in men, in cluster 2 (p<0.001) but not 1 (p=0.220). In conclusion, this study demonstrates two distinct high risk clusters in both men and women which may differ in etiology and response to treatment. As cluster 1 in men does not have low areal BMD, these men may not be identified as high risk by conventional DXA alone.

Arthroscopic ankle arthrodesis.

We reviewed 116 patients who underwent 118 arthroscopic ankle arthrodeses. The mean age at operation was 57 years, 2 months (20 to 86 years). The indication for operation was post-traumatic osteoarthritis in 67, primary osteoarthritis in 36, inflammatory arthropathy in 13 and avascular necrosis in two. The mean follow-up was 65 months (18 to 144). Nine patients (10 ankles) died before final review and three were lost to follow-up, leaving 104 patients (105 ankles) who were assessed by a standard telephone interview. The preoperative talocrural deformity was between 22 degrees valgus and 28 degrees varus, 94 cases were within 10 degrees varus/valgus. The mean time to union was 12 weeks (6 to 20). Nonunion occurred in nine cases (7.6%). Other complications included 22 cases requiring removal of a screw for prominence, three superficial infections, two deep vein thromboses/pulmonary emboli, one revision of fixation, one stress fracture and one deep infection. Six patients had a subtalar fusion at a mean of 48 months after ankle fusion. There were 48 patients with excellent, 35 with good, 10 with fair and 11 with poor clinical results.

Effects of d-amphetamine on human aggressive behavior.

Male research subjects were administered placebo and three doses of d-amphetamine (5, 10 and 20 mg/70 kg) in a laboratory situation which provided both aggressive and non-aggressive response options. The non-aggressive response was button pressing maintained by presentation of points exchangeable for money at the end of the session. The aggressive response was button pressing on a separate manipulanda which ostensibly subtracted points from a fictitious partner. Aggressive responding was elicited by subtracting points from the research subjects which was attributed to the fictitious partner. d-Amphetamine increased both aggressive and non-aggressive responding, particularly at 5 and 10 mg/70 kg. At the highest dose (20 mg/70 kg), aggressive responding decreased to levels similar to those observed during placebo sessions, while monetary reinforced responding remained elevated.

Effects of acute administration of diazepam and d-amphetamine on aggressive and escape responding of normal male subjects.

Normal males participated in sessions providing two operant response options and were administered either diazepam (study I and II) or d-amphetamine (study II). The acute effects of diazepam on human aggressive responding, which ostensibly subtracted points from another person, were determined in study I. Study II was conducted to determine the extent to which social context and response consequence influenced diazepam (study I) and d-amphetamine (previous research) effects on aggressive responding. In study II, the other response option was escape responding which protected the subject's counter from point losses. Aggressive and escape responding were engendered by subtracting points from the subject's counter, and maintained by initiation of intervals free of point loss. Point subtractions were attributed to the other person (study I) or to a machine (study II). Responding to accumulate points exchangeable for money was available in both studies. Acute diazepam administration decreased aggressive responding in most subjects (study I), slightly increased escape responding (study II), and decreased responding to accumulate points. In study II, d-amphetamine increased both escape responding and responding to accumulate points. The effects of d-amphetamine and diazepam were altered by the instructed source of point loss.

Convenient preparation of O-linked polymer-bound N-substituted hydroxylamines, intermediates for synthesis of N-substituted hydroxamic acids.

[reaction: see text] An efficient procedure for preparation of O-linked polymer-bound N-substituted hydroxylamines by reduction of resin-bound oximes with borane.pyridine complex in the presence of dichloroacetic acid is reported. Other reducing systems commonly used for imine or oxime reduction were ineffective, including borane.pyridine in the presence of acetic acid. Oximes derived from a variety of aromatic and aliphatic aldehydes and ketones were successfully reduced. The N-substituted products were acylated and cleaved from resin to afford N-substituted hydroxamic acids.

Lessons learned in applying the U.S. EPA proposed cancer guidelines to specific compounds.

An expert panel was convened to evaluate the U.S. Environmental Protection Agency's "Proposed Guidelines for Carcinogen Risk Assessment" through their application to data sets for chloroform (CHCl3) and dichloroacetic acid (DCA). The panel also commented on perceived strengths and limitations encountered in applying the guidelines to these specific compounds. This latter aspect of the panel's activities is the focus of this perspective. The panel was very enthusiastic about the evolution of these proposed guidelines, which represent a major step forward from earlier EPA guidance on cancer-risk assessment. These new guidelines provide the latitude to consider diverse scientific data and allow considerable flexibility in dose-response assessments, depending on the chemical's mode of action. They serve as a very useful template for incorporating state-of-the-art science into carcinogen risk assessments. In addition, the new guidelines promote harmonization of methodologies for cancer- and noncancer-risk assessments. While new guidance on the qualitative decisions ensuing from the determination of mode of action is relatively straightforward, the description of the quantitative implementation of various risk-assessment options requires additional development. Specific areas needing clarification include: (1) the decision criteria for judging the adequacy of the weight of evidence for any particular mode of action; (2) the role of mode of action in guiding development of toxicokinetic, biologically based or case-specific models; (3) the manner in which mode of action and other technical considerations provide guidance on margin-of-exposure calculations; (4) the relative roles of the risk manager versus the risk assessor in evaluating the margin of exposure; and (5 ) the influence of mode of action in harmonizing cancer and noncancer risk assessment methodologies. These points are elaborated as recommendations for improvements to any revisions. In general, the incorporation of examples of quantitative assessments for specific chemicals would strengthen the guidelines. Clearly, any revisions should retain the emphasis present in these draft guidelines on flexibility in the use of scientific information with individual compounds, while simultaneously improving the description of the processes by which these mode-of-action data are organized and interpreted.

Effects of vehicle supplementation on total estradiol absorption from a transdermal estradiol delivery system.

OBJECTIVE: To evaluate the effects of vehicle supplementation on serum estradiol (E2) delivery pharmacokinetics from the Ciba-Geigy (Summit, NJ) 0.1-mg Estraderm Patch. DESIGN: Postmenopausal women were randomized to a 28-day crossover treatment protocol separated by a 14-day wash out period. SETTING: Normal human volunteers were studied in an academic research environment. PATIENTS, PARTICIPANTS: The subject pool included eight healthy postmenopausal women between 32 and 60 years of age. INTERVENTIONS: In treatment A, a 0.1-mg Estraderm Patch was worn for 7 days; in treatment B, and identical patch was worn into which 0.6 mL of ethanol was injected on day 3 of use. MAIN OUTCOME MEASURES: Serum E2 levels were measured in both groups. RESULTS: Although E2 absorption showed characteristic interpatient variability, addition of ethanol significantly extended the mean time for serum E2 levels to return to baseline, without increasing peak absorption. The mean extension was 50 hours. CONCLUSION: The addition of ethanol to the Estraderm Patch increased the duration of elevated serum E2 levels measured in menopausal women, thus potentially increasing the effective life span of the transdermal therapeutic system.

The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone.

OBJECTIVES: To examine the effects of food ingestion and administered dose on the absorption of oral micronized P (Utrogestan; Besins-Iscovesco, Paris, France) and to compare the bioavailability of intramuscular versus oral routes of administration. DESIGN: Prospective, randomized, open label crossover protocol with 7 days between dosages. SETTING: Academic institution. PARTICIPANTS: Fifteen normal postmenopausal women. INTERVENTIONS: All subjects participated in three separate protocols: [1] micronized P (200 mg) or placebo under fasting or nonfasting conditions once daily for 5 days; [2] micronized P (100, 200, or 300 mg) once daily under fasting conditions for 5 days; and [3] micronized P (200 mg) or intramuscular P (50 mg in oil) administered once daily for 2 days. MAIN OUTCOME MEASURES: Serum P concentrations were measured in all groups. RESULTS: Concomitant food ingestion increased the area under the serum P concentration versus time curve (AUC0 to 24) and the maximum serum P concentration (Cmax) without affecting time to maximum serum concentration (Tmax) (P < 0.05). Micronized P absorption and elimination were first-order processes and exhibited dose-independent pharmacokinetics between 100 and 300 mg. After intramuscular P, Cmax was higher and Tmax occurred later compared with the oral P preparation. Oral P had lower relative bioavailability (8.6%) than intramuscular P. CONCLUSIONS: Absorption of micronized P was enhanced twofold in the presence of food. Both absorption and elimination were dose-independent, dose proportionality being confirmed. Bioavailability of the oral P was approximately 10% compared with intramuscular P.

Elastography--the movement begins.

The advent of real-time ultrasound in the 1970s, together with a growing interest in tissue characterization, led to a number of investigators using the nature of tissue motion to distinguish healthy from diseased tissue. Our group at the (then) Ultrasonics Institute demonstrated the use of phase methods for detecting very small tissue motions, using natural stimuli. The method could also be applied in the lag (autocorrelation) domain to directly measure the amount of deformation to high accuracy. This method was also applied to measuring the amount of dilatation of blood vessels using both conventional and intravascular ultrasound. A basic limitation of these techniques was the poor spatial resolution, and quasistatic methods soon replaced this method of measuring tissue deformation. However, a new way of assessing the health of tissues had been established.

Unscheduled DNA synthesis tests. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The utility of unscheduled DNA synthesis (UDS) testing for screening potentially hazardous chemicals was evaluated using the published papers and technical reports available to the UDS Work Group. A total of 244 documents were reviewed. Based on criteria defined in advance for evaluation of the results, 169 were rejected. From the 75 documents accepted, results were reviewed for 136 chemicals tested using autoradiographic approaches and for 147 chemicals tested using liquid scintillation counting (LSC) procedures; 38 chemicals were tested by both approaches to measure UDS. Since there were no documents available that provided detailed recommendations of UDS screening protocols or criteria for evaluating the results, the UDS Work Group presents suggested protocols and evaluation criteria suitable for measuring and evaluating UDS by autoradiography in primary rat hepatocytes and diploid human fibroblasts and by the LSC approach in diploid human fibroblasts. UDS detection is an appropriate system for inclusion in carcinogenicity and mutagenicity testing programs, because it measures the repair of DNA damage induced by many classes of chemicals over the entire mammalian genome. However, for this system to be utilized effectively, appropriate metabolic activation systems for autoradiographic measurements of UDS in human diploid fibroblasts must be developed, the nature of hepatocyte-to-hepatocyte variability in UDS responses must be determined, and the three suggested protocols must be thoroughly evaluated by using them to test a large number of coded chemicals of known in vivo mutagenicity and carcinogenicity.

An approach to digital signal processing for ultrasonics research.

The increasingly sophisticated techniques for the extraction of information from ultrasonic data entail a corresponding increase in complexity of the software used. An interactive signal and image processing package, called TWODIMSY, has been developed at the Ultrasonics Institute to allow non-programmers an entry to digital signal processing, and to simplify the task of staff involved in programming. We present an outline of the design considerations which shaped TWODIMSY, and a brief history of its ancestors. A detailed description of the package is given, including the type of computational facilities provided and the approach taken to solve the problems of data storage, operator interface and documentation.

Measurement of velocity of propagation from ultrasonic pulse-echo data.

A method is proposed for determining velocity of propagation of ultrasound in tissue by processing the pulse-echo data obtained from a compound scan. Individual sectors from different transducer positions are reconstructed and a suitable area common to the two sectors is selected. Cross-correlation of the region of interest is used to detect an apparent shift in the image due to refractive effects. The refractive effects are analysed by a ray-tracing procedure to determine an effective velocity within the tissue. The system has been tested using the U.I. Octoson as input device and both model targets with known velocity of propagation and in vivo liver tissue. The accuracy in the model experiment was +/- 5 ms-1 while the repeatability of measurements in tissue was +/- 15 ms-1. techniques for extending the method to multiple region systems are suggested.

Quantitative sonography.

The review presents a perspective on ultrasonic techniques which place numerical values on properties of tissue or physiological function. Two distinct approaches to tissue characterisation are identified and the various techniques employed are reviewed. The range of Doppler techniques currently in use or under development are described. The potential roles of the various techniques are discussed, using clinical results from the Ultrasonics Institute as a basis. Attenuation measurements show a considerable spread in results, but sound speed appears to correlate closely with the degree of fibrosis in liver and spleen. Other methods have been found useful in specialised areas. The use of pulsed Doppler with a resolution cell sufficiently large to encompass the entire vessel, in conjunction with B-mode imaging to determine geometry, permits volumetric flow measurements to be made in deep vessels and reveals previously inaccessible physiological data. The use of analysis techniques to provide quantitative information in the physiological state or function of tissue promises to add a new dimension to diagnostic ultrasound.

Pulse-echo ultrasound speed measurements: progress and prospects.

The data on the relationship of sound speed to tissue condition, and the development of methods for measurement of sound speed in vivo, are outlined. The methods developed by the authors are discussed. These include methods which use the spatial shift in images of targets viewed from different directions, time-of-flight measurements along incrementally tracked beams and echo tracking during transaxial compression of tissue. The reported sound-speed values are discussed, discrepancies noted and suggestions made on the potential clinical applications of in vivo sound-speed estimation.

A sonographic technique to reduce beam distortion by curved interfaces.

Ultrasonic beams are distorted during propagation between two media with different velocities if the traversed interface is curved within the ultrasonic beamwidth. The distorting effects of various interfaces on a beam generated by a multi-element transducer are analyzed and a technique to reduce these by controlling the time delays to the individual elements is presented.

Iliopsoas hematoma with femoral neuropathy presenting a diagnostic dilemma after spinal decompression.

STUDY DESIGN: Case report of an iliopsoas hematoma with femoral neuropathy appearing 8 weeks after a posterior spinal decompression procedure. OBJECTIVES: To describe a potential complication and differential diagnosis for nerve root symptoms following spinal decompression. SUMMARY OF BACKGROUND DATA: Iliopsoas hematoma is usually a complication of anticoagulation, hemophilia, or trauma. It has not been described previously as a complication of posterior spinal decompression. Femoral neuropathy results from compression within the iliopsoas compartment. METHODS: A 53-year-old woman reported pain in the right side of her groin and an increasing fixed flexion deformity of the right hip 8 weeks after a posterior, midline, spinal decompression. A femoral neuropathy later developed. Magnetic resonance imaging and computed tomography were performed. RESULTS: Imaging studies demonstrated a diffusely enlarged iliopsoas. Exploration revealed a large hematoma, which was evacuated. The compartment was fully decompressed with resolution of the nerve root symptoms within 48 hours. CONCLUSIONS: Iliopsoas pathology is a rare cause of nerve root symptoms and presented diagnostic difficulties after an apparently successful spinal decompression.

Arthroscopic treatment of osteochondral lesions of the talus.

We reviewed, retrospectively, 65 patients who had undergone arthroscopic treatment for osteochondral lesions of the talus. The 46 men and 19 women with a mean age at operation of 34.25 years, were followed up for a mean of 3.5 years. The medial aspect was affected in 45 patients and the lateral aspect in 20. All the lateral lesions and 35 (75%) of the medial lesions were traumatic in origin. Medial lesions presented later than lateral lesions (3 v 1.5 years) and had a much greater incidence of cystic change (46% v 8%). At follow-up, 34 patients had achieved a good result, and 17 and 14 fair and poor results, respectively. Of the 14 poor results, 13 involved medial lesions. Cystic lesions had a poor outcome in 53% of patients. Excision and curettage led to better results than excision and drilling of the base. Further arthroscopic surgery for patients with a poor result was disappointing. There was no association between outcome and the patient's age.