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.

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.

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.

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.

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.

Toxicity, bioaccumulation and tissue partitioning of dieldrin by the shrimp, Macrobrachium faustinum de Sassure, in fresh and brackish waters of Jamaica.

The 2-week no observed effect (NOEC) and lowest observed effect (LOEC) concentrations of dieldrin were determined for Macrobrachium faustinum de Sassure in fresh and brackish waters. LOEC1,10,50,95 values in fresh water were 0.001, 0.003, 0.011 and 0.058 microg l(-1), respectively, and in brackish water, 0.00006, 0.00027, 0.00165, and 0.0172 microg l(-1), respectively. The 96-hr LC10, LC50 and LC95 values were 0.029, 0.123 and 0.771 microg l(-1), respectively. It is proposed that NOEC and LOEC be redefined to take into account the percentage of individuals affected, the severity of symptoms and the recovery of poisoned individuals. Two new terms are proposed--Median Observable Effect Concentration (MOEC) for pronounced toxic symptoms in most individuals but mortality in <50%, and Pronounced Observed Effect Concentration (POEC), which inflicts mortality in >50% individuals. Bioaccumulation of dieldrin by M. faustinum from surrounding fresh and brackish waters were rapid and fairly uniform for the first 48 h when the bioconcentration equilibrium (14.4 +/- 0.42 ng g(-1) at 0.001 microg l(-1) and 42.5 +/- 1.72 ng g(-1) at 0.01 phi g l(-1)) was achieved. Relative partitioning of residues (ng g(-1) wet wt.), after 24h exposure to 0.001 microg l(-1) of dieldrin in fresh water, in the different tissues was hepatopancreas > gonads > gills > large claws > muscle and exoskeleton. Shrimp which had accumulated 10.5 +/- 0.52 ng g(-1) dieldrin in fresh and brackish water, eliminated only about 52% of the residues after eight days in uncontaminated water.

Femoral impaction grafting in revision hip arthroplasty with irradiated bone.

We evaluated the results of femoral impaction grafting with the Exeter stem (Stryker Howmedica Osteonics, Newbury, UK) and irradiated bone-graft. We followed 57 hips for an average of 27 months. Endo-Klinik grading showed 8 grade 1, 22 grade 2, and 27 grade 3 hips. Radiographic analysis revealed cortical repair in 34% and graft incorporation in 39% but no evidence of trabecular remodeling. Moderate subsidence (5-10 mm) occurred in 7 patients (12.5%), and massive subsidence (>10 mm) occurred in 4 patients (7%). Complications included 6 dislocations, 3 periprosthetic fractures, and 2 stem revisions. Impaction grafting with the Exeter system produces satisfactory results for most patients, but a few hips perform poorly, and the reasons for this are unclear. We have concerns about irradiated bone-graft because the characteristic changes of graft remodeling are not seen.

Femoral impaction bone grafting with the Elite Plus stem.

This study evaluates the results of impaction grafting of the femoral stem with the Elite Plus system (DePuy, Leeds, UK) in revision hip arthroplasty with irradiated allograft. Nineteen hips in 19 patients (12 men and 7 women), at an average age of 59 years were followed for an average of 33 months. Endo-Klinik grading of bone stock loss was 5 grade 1, 6 grade 2, 8 grade 3 and no grade 4. Radiographic analysis revealed evidence of graft incorporation in 32% but no evidence of trabecular remodelling or cortical repair. Four patients have undergone revision of the femoral stem, one patient died while awaiting revision and one patient is unfit for revision. Most complications occurred in patients classified as Endo-Klinik grade 3. We found that impaction grafting with the Elite Plus system was associated with a high failure rate, especially in those cases with more severe bone stock loss. (Hip International 2002; 1: 11-6).

Background and framework for ILSI's collaborative evaluation program on alternative models for carcinogenicity assessment. International Life Sciences Institute.

The willingness of the agencies involved in the regulation of pharmaceuticals to accept data from newly proposed models for carcinogenicity testing (eg, transgenic animals, neonatal rodent models, initiation-promotion models) has stimulated international interest in gaining experience and a greater understanding of the strengths and limitations of the specific models. Over a 4-year period, the International Life Sciences Institute (ILSI) Health and Environmental Science Institute (HESI) has coordinated a large-scale collaborative research program to help to better characterize the responsiveness of several models proposed for use in carcinogenicity assessment. The overall objective of this partnership among industry, government, and academic scientists was to evaluate the ability of these new models to provide useful information for human cancer risk assessment. This research program reflected a commitment of nearly US$35 million by over 50 industrial, govemment, and academic laboratories from the United States, Europe, and Japan. Evaluation of the models required the development of standardized protocols to allow reproducibility and comparability of data obtained across multiple laboratories. Test compounds were selected on the basis of mechanistically meaningful carcinogenic activity or noncarcinogenicity in the rodent bioassay as well as humans. Criteria were established for dose selection, pathology review, quality control, and for evaluation of study outcome. The database from these studies represents an important contribution to the future application of new models for human cancer risk assessment. Beyond the data, the collaborative process by which the models were evaluated may also represent a prototype for assessing new methods in the future.

Inactivation of protein farnesyltransferase by active-site-targeted dicarbonyl compounds.

Upon farnesylation by protein farnesyltransferase (FTase), key proteins become compartmentalized in cells. For example, cell membrane localization is essential for the mitogenic role of mutant Ras protein, which acts as a switch for cancer cell proliferation. We report that alpha-dicarbonyl compounds derived from the isoprenoid skeleton or other hydrophobic groups potently obstruct farnesylation of a Ras model peptide by human recombinant FTase in vitro. A geranyl-derived isoprenoid diketone, 5,9-dimethyl-8-decene-2,3-dione, at 17 microM caused a 62% reduction in FTase activity after 30 minutes. A farnesyl-derived isoprenoid diketone, 5,9,13-trimethyl-8,12-tetradecadiene-2,3-dione, at 93 microM caused a 94% reduction after 30 minutes. Other dicarbonyl compounds found to be effective against FTase in vitro were (+/-)-6-(camphorquinone-10-sulfonamido)-hexanoic acid, 4,4'-biphenyldiglyoxaldehyde, dehydroascorbic acid 6-palmitate, 2-oxododecanal, and phenylglyoxal. Higher concentrations of the alpha-dicarbonyl compound resulted in more rapid and more extensive inactivation. These findings demonstrate that alpha-dicarbonyl compounds targeted to FTase interfere with protein farnesylation in vitro and may lead to derivatives that have utility as chemotherapeutic agents.

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.

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.

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.

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.

Fate and transport of ethoprophos in the Jamaican environment.

The hydrolytic half lives of ethoprophos in distilled, river, brackish and open sea water were 25, 133, 65 and 81 days, respectively. Under laboratory conditions, volatilisation of the residues after 12 h was 1.4-3.6, 2.3-4.5 and 6.5-20.2% from a sandy loam soil with 1, 10 and 20% moisture levels, respectively. Photolysis in soil was significantly faster (P < 0.05) in direct sunlight (T1/2 of 4.7 days) than in the shade (T1/2 of 12.3 days). The microbial degradation of ethoprophos was more than two-fold faster in unsterile soil (T1/2 of 10.9 days) than in sterile soil (T1/2 of 28.8 days). The runoff of ethoprophos from unweeded plantation soil at 23 degrees slope was significantly (P = 0.015) less than at 38 degrees slope; the amounts lost after 9 weeks and 27.5 mm of rainfall were 89.4 and 91.2%, respectively, of the applied amount from the two respective slopes. In the weeded plots, 93.6 and 92.4% of the applied insecticide were lost from 23 degrees and 38 degrees slopes, respectively. Under laboratory conditions, between 67.0 and 85.1% of ethoprophos leached through the soil columns. Under field conditions, after 9 weeks and 25 mm of rainfall, only 2.8 and 2.0% residues were recovered at a depth of 10-15 cm from unweeded and weeded slopes, respectively at 23 degrees slope, and 2.2 and 1.9% from the two respective plots at 38 degrees slope.

Mmu and D2 receptor antisense oligonucleotides injected in nucleus accumbens suppress high alcohol intake in genetic drinking HEP rats.

Numerous pharmacological and other studies have implicated both Mmu and dopamine receptor subtypes in alcohol consumption. In the genetic drinking rat as well as those chemically induced to drink, evidence has accrued that the abnormal intake of alcohol is underpined by these receptors in the brain. The purpose of this investigation was to demonstrate unequivocally that a biological impairment by antisense oligodeoxynucleotide (ODN) targeted specifically to these two receptor subtypes would disrupt ongoing alcohol drinking. In this project, a new strain of female and male high-ethanol preferring (HEP) rats was used that had free access to preferred concentrations of alcohol over water in a two choice paradigm. A guide cannula for a microinjection needle was first implanted bilaterally above the nucleus accumbens (NAC) of each rat. Following recovery, a dose of either 250 or 500 ng of the Mmu ODN or 500 ng D2ODN was microinjected into the NAC of the rat in a volume of 0.8-1.0 microl. A standard temporal sequence was used in which microinjections were given four times at successive 12-h intervals over a 2-day interval. The control mismatch ODNs corresponding to both the Mmu or D2 receptor antisense were microinjected identically at homologous sites in the NAC. Following the experiments, the brain of each rat was removed and sectioned in the coronal plane for histological analysis so that each microinjection site was identified. The results showed that the Mmu receptor antisense caused a significant dose dependent fall in free access alcohol drinking within 12 to 24 h following the initial microinjection. This decline often persisted for 1 to 2 days in terms of both g/kg intake and proportion of alcohol to water consumed. Similarly, the D2 receptor ODN likewise induced an intense and significant decline in both g/kg and proportion measures of alcohol intake. Since the corresponding mismatch ODN for both Mmu and D2 receptors exerted no effect on either of these measures of alcohol consumption, the specificity of molecular action of the respective antisense molecules on drinking behavior of the HEP rats was confirmed. Thus, these results provide the first unequivocal evidence that the genes for D2 and Mmu receptors are fundamentally involved in abnormal alcohol drinking in the genetically predisposed individual. Finally, important new anatomical evidence is introduced for the critical role of the NAC in the genetic basis of aberrant drinking of alcohol.

Tetrahydropapaveroline injected in the ventral tegmental area shifts dopamine efflux differentially in the shell and core of nucleus accumbens in high-ethanol-preferring (HEP) rats.

Since the 1970s tetrahydropapaveroline (THP) and other tetrahydroisoquinoline alkaloids have been implicated in the etiology of alcoholism. When injected into the cerebral ventricle or at specific sites in the mesolimbic system such as the ventral tegmental area (VTA), THP evokes spontaneous and intense intake of alcohol in the nondrinking animal. Further, THP evokes the extracellular efflux of dopamine in the nucleus accumbens (NAC), which comprises, in part, the postulated alcohol drinking "circuit" of neurons. The purpose of this study was to characterize the action of a THP reactive structure, the VTA, on the activity of dopamine and its metabolism in the NAC. In the anesthetized high-ethanol-preferring (HEP) rat, artificial CSF was perfused for 10 min at a rate of 10 microl per min specifically in either the core or shell of the NAC. A microbore push-pull cannula system was selected over a microdialysis probe because of its superior recovery of neurotransmitters and tip exposure of less than 1.0 mm. After a series of 5-min perfusions, a single microinjection of 5.0 microg/microl of THP was made in the ipsilateral VTA while the NAC was perfused simultaneously. Sequential samples of the NAC perfusate were assayed by an HPLC coulometric system to quantitate the concentrations of dopamine and its metabolites, DOPAC and HVA, as well as the 5-HT metabolite, 5-HIAA. The results showed that THP injected in the VTA caused a significant increase by 94 +/- 23% in the efflux of dopamine from the core of the NAC. Conversely, the THP injected identically in the VTA suppressed the efflux of dopamine within the shell of the NAC by 51 +/- 10%. The levels of DOPAC, HVA and 5-HIAA within the core and shell of the NAC generally paralleled the increase and decrease in efflux, respectively, of dopamine. CSF control injections in the VTA as well as injections outside of the VTA failed to alter dopamine or metabolite activity in the NAC. These results demonstrate that the presence of THP in the VTA alters directly the function of the pathway of mesolimbic neurons generally and the dopaminergic system specifically. That such a perturbation could account for the induction of alcohol preference is proposed in relation to a reinforcing mechanism involving opioidergic and dopaminergic elements.