Hip geometric parameters are associated with radiographic and clinical hip osteoarthritis: Findings from a cross-sectional study in UK Biobank.

OBJECTIVE: To examine the extent to which geometric parameters derived from dual-energy x-ray absorptiometry (DXA) scans in the UK Biobank study are related to hip osteoarthritis (HOA) independently of sex, age and body size. DESIGN: Femoral neck width (FNW), diameter of the femoral head (DFH) and hip axis length (HAL) were derived automatically from left hip DXA scans in UK Biobank using outline points placed around the hip by a machine-learning program. Correlations were calculated between geometric parameters, age, height, and weight. Logistic regression was used to examine the relationship of geometric parameters with radiographic HOA, hospital diagnosed HOA (HESOA), and Cox proportional hazards model to evaluate the relationship with total hip replacement (THR). Analyses were adjusted for sex, age, height, weight, and geometric parameters. RESULTS: The study consisted of 40,312 participants. In age and sex-adjusted analyses, FNW, HAL and DFH were related to increased risk of radiographic HOA. In a model adjusted for age, sex, height, weight and other geometric parameters, both FNW and HAL retained independent relationships with radiographic HOA [FNW: odds ratios 2.38 (2.18-2.59), HAL: 1.25 (1.15-1.36)], while DFH was now protective [0.55 (0.50-0.61)]. Only FNW was independently related to HESOA [2.20 (1.80-2.68)] and THR [hazard ratios 2.51 (1.89-3.32)]. CONCLUSION: Greater FNW and HAL were independently related to an increased risk of radiographic HOA, whereas greater DFH appeared to be protective. Greater FNW was independently associated with HESOA and THR. These results suggest that DXA-derived geometric parameters, particularly FNW, could help determine HOA and THR risk.

Cam morphology but neither acetabular dysplasia nor pincer morphology is associated with osteophytosis throughout the hip: findings from a cross-sectional study in UK Biobank.

OBJECTIVES: To examine whether acetabular dysplasia (AD), cam and/or pincer morphology are associated with radiographic hip osteoarthritis (rHOA) and hip pain in UK Biobank (UKB) and, if so, what distribution of osteophytes is observed. DESIGN: Participants from UKB with a left hip dual-energy X-ray absorptiometry (DXA) scan had alpha angle (AA), lateral centre-edge angle (LCEA) and joint space narrowing (JSN) derived automatically. Cam and pincer morphology, and AD were defined using AA and LCEA. Osteophytes were measured manually and rHOA grades were calculated from JSN and osteophyte measures. Logistic regression was used to examine the relationships between these hip morphologies and rHOA, osteophytes, JSN, and hip pain. RESULTS: 6,807 individuals were selected (mean age: 62.7; 3382/3425 males/females). Cam morphology was more prevalent in males than females (15.4% and 1.8% respectively). In males, cam morphology was associated with rHOA [OR 3.20 (95% CI 2.41-4.25)], JSN [1.53 (1.24-1.88)], and acetabular [1.87 (1.48-2.36)], superior [1.94 (1.45-2.57)] and inferior [4.75 (3.44-6.57)] femoral osteophytes, and hip pain [1.48 (1.05-2.09)]. Broadly similar associations were seen in females, but with weaker statistical evidence. Neither pincer morphology nor AD showed any associations with rHOA or hip pain. CONCLUSIONS: Cam morphology was predominantly seen in males in whom it was associated with rHOA and hip pain. In males and females, cam morphology was associated with inferior femoral head osteophytes more strongly than those at the superior femoral head and acetabulum. Further studies are justified to characterise the biomechanical disturbances associated with cam morphology, underlying the observed osteophyte distribution.

Predictors of total hip replacement in community based older adults: a cohort study.

OBJECTIVE: The purpose of this study is to describe predictors of total hip replacement (THR) in community dwelling older adults. A better understanding of predictors of THR can aid in triaging patients and researching preventative strategies. DESIGN: At baseline, participants had assessment of radiographic OA and cam morphology (from pelvic radiographs), shape mode scores and hip bone mineral density (BMD; from dual energy X-ray absorptiometry (DXA)). After 2.6 and 5 years, participants reported hip pain using WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), and had hip structural changes assessed using magnetic resonance imaging (MRI). Risk of THR was analysed using mixed-effect Poisson regression. RESULTS: Incidence of THR for OA over 14 years was 4.6% (37/801). As expected, WOMAC hip pain and hip radiographic OA both predicted risk of THR. Additionally, shape mode 2 score (decreasing acetabular coverage) (RR 1.83/SD; 95% CI 1.1-3.04), shape mode 4 score (non-spherical femoral head) (RR 0.59/SD; 95% CI 0.36-0.96), cam morphology (α > 60°) (RR 2.2/SD; 95% CI 1.33-3.36), neck of femur BMD (RR 2.09/SD, 95% CI 1.48-2.94) and bone marrow lesions (BMLs) increased risk of THR (RR 7.10/unit; 95% CI 1.09-46.29). CONCLUSION: In addition to hip pain and radiographic hip OA, measures of hip shape, cam morphology, BMD and BMLs independently predict risk of THR. This supports the role of hip bone geometry and structure in the pathogenesis of end stage hip OA and has identified factors that can be used to improve prediction models for THR.

Subregional statistical shape modelling identifies lesser trochanter size as a possible risk factor for radiographic hip osteoarthritis, a cross-sectional analysis from the Osteoporotic Fractures in Men Study.

OBJECTIVE: Statistical shape modelling (SSM) of hip dual-energy X-ray absorptiometry (DXA) scans has identified relationships between hip shape and radiographic hip OA (rHOA). We aimed to further elucidate shape characteristics related to rHOA by focusing on subregions identified from whole-hip shape models. METHOD: SSM was applied to hip DXAs obtained in the Osteoporotic Fractures in Men Study. Whole-hip shape modes (HSMs) associated with rHOA were combined to form a composite at-risk-shape. Subsequently, subregional HSMs (cam-type and lesser trochanter modes) were built, and associations with rHOA were examined by logistic regression. Subregional HSMs were further characterised, by examining associations with 3D-HSMs derived from concurrent hip CT scans. RESULTS: 4,098 participants were identified with hip DXAs and radiographs. Composite shapes from whole-hip HSMs revealed that lesser trochanter size and cam-type femoral head are related to rHOA. From sub-regional models, lesser trochanter mode (LTM)1 [OR 0.74; 95%CI 0.63.0.87] and cam-type mode (CTM)3 [OR 1.27; 1.13.1.42] were associated with rHOA, associations being similar to those for whole hip HSMs. 515 MrOS participants had hip DXAs and 3D-HSMs derived from hip CT scans. LTM1 was associated with 3D-HSMs that also represented a larger lesser trochanter [3D-HSM7 (beta (ß)-0.23;-0.33,-0.14) and 3D-HSM9 (ß0.36; 0.27.0.45)], and CTM3 with 3D-HSMs describing cam morphology [3D-HSM3 (ß-0.16;-0.25,-0.07) and 3D-HSM6 (ß 0.19; 0.10.0.28)]. CONCLUSION: Subregional SSM of hip DXA scans suggested larger lesser trochanter and cam morphology underlie associations between overall hip shape and rHOA. 3D hip modelling suggests our subregional SSMs represent true anatomical variations in hip shape, warranting further investigation.

Osteoarthritis as an organ disease: from the cradle to the grave.

Considered for decades as a cartilage disease, recent studies of osteoarthritis (OA) take us back to the concepts discussed at the naming of the disorder as "bone-joint-inflammation". By describing the joint as an organ, can OA be called an organ disease - similar to heart disease? Is there a systemic (which system?) involvement? Would this help with diagnosis or therapy? Hyperplasia of the joint tissues is one of the most notable early features of the disease: articular cartilage thickens, chondrocytes proliferate and increase matrix biosynthesis, but not its incorporation; the subchondral bone densifies but is hypomineralised and there is an increase in bone marrow fat content. Associations between OA and hypertension, hypercholesterolaemia and blood glucose suggest systemic and metabolic components are involved. The source of pain is still unknown but here is evidence for peripheral and central sensitisation. Joint deformity is difficult to quantify, but statistical shape modelling provides a tool to use as an imaging biomarker. A genome-wide association study meta-analysis has identified novel genes associated with hip shape with many genes related to tissue growth and development. There are associations between hip shapes and age of first walking as well as with obesity through adulthood. These life-course events and a recapitulation in old age of developmental processes suggest that the cradle may affect our path to the grave. These observations suggest that tissue regeneration approaches, treating only the cartilage in OA joints, may only be of limited benefit.

Environmental distribution of the trichloroethene reductive dehalogenase gene (tceA) suggests lateral gene transfer among Dehalococcoides.

The trichloroethene reductive dehalogenase gene (tceA) of Dehalococcoides spp. was detected in 12 of 21 trichloroethene-to-ethene dechlorinating enrichment cultures established from aquifer and sediment samples collected from diverse geographic locations in the USA. Analysis of the tceA chromosomal regions indicated that the tceA genes shared greater than 95% sequence identity, and all shared identical tceAB spacer sequences and tceB genes downstream of tceA. A putative transposable element (PTE) was present 1077 bp downstream of the tceB stop codon in three of eight chromosomal regions analyzed. Sequence identity was interrupted downstream of tceB and upstream or downstream of the PTE, suggesting that intrachromosomal or interchromosomal transfer of tceAB had occurred.

Sequestration of a fluorinated analog of 2,4-dichlorophenol and metabolic products by L. minor as evidenced by 19F NMR.

Fate of halogenated phenols in plants was investigated using nuclear magnetic resonance (NMR) to identify and quantify contaminants and their metabolites. Metabolites of 4-chloro-2-fluorophenol (4-Cl-2-FP), as well as the parent compound, were detected in acetonitrile extracts using 19F NMR after various exposure periods. Several fluorinated metabolites with chemical shifts approximately 3.5 ppm from the parent compound were present in plant extracts. Metabolites isolated in extracts were tentatively identified as fluorinated-chlorophenol conjugates through examination of signal-splitting patterns and relative chemical shifts. Signal intensity was used to quantify contaminant and metabolite accumulation within plant tissues. The quantity of 4-Cl-2-F metabolites increased with time and mass balance closures of 90-110% were achieved. In addition, solid phase 19F NMR was used to identify 4-Cl-2-FP which was chemically bound to plant material. This work used 19F NMR for developing a time series description of contaminant accumulation and transformation in aquatic plant systems.

Role of plant activity and contaminant speciation in aquatic plant assimilation of 2,4,5-trichlorophenol.

Aquatic plants uptake, transform and sequester organic contaminants and are used as a bioremediation strategy for the removal of pollutants from wastewaters. A better understanding of factors affecting rate of uptake of contaminants by aquatic plants is needed to improve engineered systems for removal of pollutants from wastewaters. This work focused on delineating sorption to plant surfaces and understanding effects of plant metabolic activity, inhibition, and media pH on the uptake of the ionizable contaminant 2,4,5-trichlorophenol (TCP) by aquatic plant Lemna minor. During L. minor exposure to TCP (0.5-13.9 mg l(-1)), a range of plant metabolic activities was measured using oxygen production rate (0-18.4 micromol h(-1)). A positive correlation was shown between contaminant uptake rate and plant activity. Contaminant uptake was examined at a range of media pH values (6-9) and uptake rates were linearly correlated to fraction of contaminant in protonated form. These results demonstrated a link between plant activity and uptake of contaminant by plants and stress the importance of incorporating plant metabolic activity and contaminant speciation in development of natural and engineered phytoremediation systems. This research also indicates that aquatic plants can actively accumulate trace-organic contaminants and may ultimately serve as a sink for these materials in the natural environment.

Expression of the pneumolysin gene in Escherichia coli: rapid purification and biological properties.

The gene for pneumolysin, the thiol-activated toxin from Streptococcus pneumoniae, has been expressed in Escherichia coli. The recombinant protein has been purified using a rapid, high yield, purification procedure and has been shown to be identical with respect to N-terminal amino-acid sequence, specific activity, effect on human polymorphonuclear phagocytes and effect on human complement to the native toxin purified from the pneumococcus. This provides a large enough source of material to begin investigation of pneumolysin as a candidate for inclusion in a pneumococcal vaccine.

2D-gel analysis of proteins in chronic lymphocytic leukemia cells and normal B-lymphocytes.

Protein synthesis was analysed in leukaemic cells from 10 chronic lymphocytic leukaemia (CLL) patients by 2D-gel electrophoresis of 14C-labelled proteins. There appeared to be only minor differences between each of the CLL samples, but there was evidence that the level of expression of a few of the proteins might have correlated to the stage of the disease. Comparison of the CLL samples to populations of normal B-lymphocytes demonstrated marked differences in protein synthesis between the leukaemic and non-malignant cells. We subsequently used the fluorescence activated cell sorter (FACs) to separate CD5+ from CD5- B-lymphocytes, but observed that the protein synthesis exhibited by these two populations was essentially the same, and both were very different to that observed in CLL cells. The significance of these observations with respect to the origins of CLL is discussed.

Quality of life and behavioral adjustment after pediatric bone marrow transplantation.

The purpose of this study was two-fold: to describe the quality of life and behavioral adjustment of survivors of pediatric bone marrow transplantation (BMT) prior to and 6 months post-BMT; and, to identify correlates of survivors' quality of life and behavioral adjustment. Participants were 26 children and adolescents who underwent BMT, and their mothers. At pre- and 6 months post BMT, mothers completed standardized measures of their children's behavioral adjustment, quality of life, and adaptive functioning. Self-report questionnaires were completed to determine levels of maternal anxiety and depression, and family functioning. Information was also gathered about demographic variables, medical history, and symptom severity. Children's overall quality of life improved 6 months post BMT and was most strongly associated with pre-BMT levels of family cohesion. Children's behavioral adjustment remained within the normal range across time and was associated with pre-BMT levels of family cohesion and child adaptive functioning. Mothers' psychological adjustment improved over time and was associated with quality of life, but unrelated to children's behavioral adjustment. Pre-BMT levels of family cohesion and child adaptive functioning appear to be important in understanding quality of life and behavioral adjustment of pediatric BMT survivors.

Matched unrelated bone marrow transplantation for combined immunodeficiency.

Bone marrow transplantation (BMT) from siblings is the treatment of choice for severe combined immunodeficiency (SCID). The objective of this study was to evaluate the efficiency of BMT from matched unrelated donors (MUD) in congenital immunodeficiencies when a sibling donor is unavailable. Sixteen consecutive patients with SCID (n = 9) and CID (n= 7), were referred for an unrelated donor search. Acceptable donors were found for all patients. Fifteen patients received busulfan and cyclophosphamide pretransplant conditioning. One patient had an early loss of graft and was reconditioned using cyclophosphamide and total body irradiation. The graft-versus-host disease (GVHD) prophylaxis used was methylprednisolone, cyclosporin A with or without methotrexate. Neutrophil engraftment was rapid and was achieved in all patients within a mean of 15.4 days. Only 13 episodes of fever were recorded shortly after BMT. GVHD of grade II or more was apparent in 2/9 (22%) of SCID patients and in 4/7 (57%) of CID patients. Overall survival was 75% with a mean follow-up of 47.4 months (range 18-101). Six out of nine SCID patients (67%) and 6/7 (86%) of CID patients are alive and well. Eleven patients had normal humoral immunity, and cell-mediated immunity as measured by flow cytometry and mitogenic responses, was intact in all patients. Intradermal candida skin test was positive in 9/10 patients tested. We conclude that BMT from MUD results in rapid engraftment and is therefore associated with a low rate of infection contributing to the improved survival rate. The protocol used is especially favorable for patients with combined immunodeficiency.

Low-intensity hematopoietic stem-cell transplantation across human leucocyte antigen barriers in dyskeratosis congenita.

Since the results of conventional hematopoietic stem-cell transplantation (HSCT) for patients with dyskeratosis congenita (DC) are poor owing to the high incidence of transplant-related complications, we explored the use of a low-intensity HSCT regimen. We report two children with DC with severe cytopenia, who underwent successful HSCT from a matched unrelated donor after conditioning with fludarabine, cyclophosphamide, and antithymocyte globulin. Graft-versus-host-disease (GVHD) prophylaxis consisted of corticosteroids and cyclosporin A. The regimen was well tolerated, no significant transplant-related complications were observed, and engraftment was rapid and complete. At 15 and 16 months after HSCT, the children were fully engrafted, in excellent clinical condition, full-donor chimerism, and no signs of GVHD. We conclude that a low-intensity regimen is sufficient to induce durable engraftment using matched unrelated donor HSCT in DC patients, with minimal 1-year transplant-related toxicity. Longer follow-up will determine whether this regimen also reduces long-term toxicity.

The utility of plasma polymerase chain reaction for human herpes virus-6 among pediatric bone marrow transplant recipients: results of a pilot study.

We evaluated the utility of plasma polymerase chain reaction (PCR) for surveillance of human herpes virus 6 (HHV-6) infection among pediatric bone marrow transplant (BMT) recipients. We used a prospective, non-interventional design involving a study group and controls. BMT recipients and healthy controls were evaluated. BMT subjects had HHV-6 PCR done biweekly for 12 weeks post transplantation, while a single PCR test was done on controls. For the PCR assay, EDTA blood was collected and DNA extracted from whole blood and cell-free plasma using standard procedures. The PCR was first performed on DNA from whole blood and if a positive result was obtained, the test was repeated on the DNA from the plasma. Thirty BMT recipients (13 autologous and 17 allogeneic) were enrolled, on whom a total of 156 PCR tests were performed, while six tests were done on six healthy controls. The median age of BMT subjects was 6.2 years (range 0.5-17.5 years). The median age of the control subjects was 6.6 years (range 2-10 years). Among asymptomatic BMT patients who had PCR surveillance, the positivity rate was 3.3% (1/30) on whole blood and 0% (0/30) on plasma. None of the six healthy subjects had a positive PCR test on whole blood. During the period of the surveillance study, 14 patients had diagnostic evaluations for HHV-6 disease because of clinical symptoms. Two of these patients were diagnosed with disease associated with HHV-6 (graft failure and encephalitis) and had positive PCR tests on whole blood and plasma and whole blood and cerebrospinal fluid, respectively. We conclude that despite the fact that HHV-6 seropositivity rates are high among children, the frequency of HHV-6 plasma PCR positivity is low in pediatric BMT subjects who are asymptomatic for HHV-6 disease. Given that a positive test on plasma is consistent with active infection, this increases the utility of the PCR test as a diagnostic aid in evaluating syndromes presumed to be due to HHV-6 in pediatric bone marrow transplant recipients.

2D-gel analysis of protein synthesis profiles of different stages of chronic lymphocytic leukaemia.

Protein synthesis profiles of leukaemic cells from 15 chronic lymphocytic leukaemia (CLL) patients were analysed by 2D-electrophoresis of 35S-methionine labelled proteins. This series of CLL included patients with stage A (7), B (4) and C (4) disease. Although the protein synthesis profiles were similar in all cases, some consistent differences were noted between the different stages. The levels of synthesis of three proteins (approximately 35 kD size) were of particular interest. Two of these were always expressed in stage C CLL but either infrequently or not at all in stage A or B CLL. By contrast a third protein was expressed at a much reduced level in stage C compared to stages A or B. This type of analysis could prove invaluable for identifying proteins whose expression was intimately associated with the evolution of CLL.

Scar prevention in peripheral nerve surgery.

Constriction of a peripheral nerve may precipitate a primary problem of prevent recovery from a pre-existing one. Any surgical technique to minimize subsequent constrictive scar formation would be advantageous. In this study, using rat femoral nerves, various modes of protection were evaluated. Wrapping the nerve with free fat seemed to offer the best prophylaxis.

New intraventricular catheter for volume pressure response measurements.

Measurements of the volume-pressure response (VPR) to determine the relative position of a patient on the graphic volume-pressure curve have been used to derive clinically useful information. One reason that these measurements have not been used more frequently has been the fear of introducing infection into the ventricular system. We have designed an intraventricular catheter that allows repeated VPR measurements and reduces the risk of infection.

The carotid siphon: a scanning electron microscope assessment of its embolic potential.

The role of the carotid siphon as a source of embolic material has had limited morphological or clinical study. The morphologic data available suggests that the siphon plays only a small role in embolic cerebrovascular disease. Clinical studies, however, suggest that it has a significant ischemic potential. To clarify this apparent discrepancy, we have designed a scanning electron microscope study of the carotid siphon. Eighty percent of the specimens from the carotid bifurcation and 30% of the siphon specimens showed evidence of damaged endothelium with attached red cell and platelet debris. The embolic potential of the siphon is estimated to be between 1/3 to 1/2 that of the carotid bifurcation. This supports the most recent clinical studies.

Rotational acceleration measurements--evaluating helmet protection.

PURPOSE: Current helmet testing standards do not address the rotational components of an impact to the head. We describe a new testing paradigm used to measure the rotational acceleration of a headform and a protective helmet following an impact to the head in the horizontal plane. This impact simulation allows for the testing of currently available head protection devices in conditions thought to be important for the generation of cerebral concussion. The degree to which a particular helmet dampens rotational acceleration, and thus protects against concussion, can be assessed. METHODS: Our testing device consists of a pneumatic piston that provides a measured impact to a standard headform. Four different helmets were tested using the described paradigm. RESULTS: Acceleration curves for each helmet and the corresponding headform are presented. CONCLUSIONS: Clear differences in rotational acceleration were demonstrated. Possible avenues of further investigation are discussed.

Diltiazem: dose it affect vasospasm?

Calcium antagonists are being investigated for their role in preventing or ameliorating the vasospasm associated with subarachnoid hemorrhage. We have done a phase I and phase II type trial of diltiazem. No effect on spasm was documented. A tendency to increase the bleeding time was noted, but no detrimental clinical effect occurred. The rebleed rate was not changed. It appears that further study of diltiazem through a proper randomized study would not be cost- or time-effective.