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To determine differences in hip geometry in adults with type 1 diabetes (T1D) compared with healthy adults without diabetes.In this cross-sectional study, 43 adults with T1D (mean age 56 years, 84 % female, 92 % White, mean duration of diabetes of 39 years, A1c of 7.8 %) and 40 adults without diabetes (mean age 60 years, 80 % female, 77 % white) who had hip dual-energy x-ray absorptiometry (DXA) scans from previous studies were included. Areal bone mineral density (aBMD) and measures of hip structural properties at the narrow neck, intertrochanteric and femoral shaft regions of the left proximal femur were analyzed between adults with T1D and controls using linear models controlled for age, sex, and body mass index.There were no significant differences in DXA-based aBMD at the hip (0.769 ± 0.132 vs. 0.900 ± 0.139 g/cmAdults with T1D have several significant differences in proximal femur morphology compared with controls. These morphological differences may adversely affect the mechanical integrity of the proximal femur, thereby contributing to an increased risk of fracture in the event of a fall.

Women with type 1 diabetes (T1D) are at increased risk for fracture. We studied the association of T1D and young age at T1D onset (T1D onset before 20 years) on bone structural quality. 24 postmenopausal women with T1D (mean age 60.9 years, mean T1D duration 41.7 years) and 22 age, sex- and body mass index (BMI)-matched controls underwent dual X-ray absorptiometry (DXA) measured areal bone mineral density (aBMD) at the lumbar spine, hip and distal radius. Bone mass, geometry and estimated bone strength were assessed at distal and shaft of non-dominant radius and tibia using peripheral quantitative computed tomography (pQCT). Postmenopausal women with T1D had lower trabecular volumetric bone mineral density (vBMD) (LSM ± SEM; 166.1 ± 8.2 vs 195.9 ± 8.3 mg/cm3, p = 0.02) and compressive bone strength (24.6 ± 1.8 vs 30.1 ± 1.9 mg2/mm4, p = 0.04) at the distal radius compared to controls adjusting for age, BMI and radius length. At the distal radius, patients with young onset T1D had lower total vBMD (258.7 ± 19.7 vs 350.8 ± 26.1 mg/cm3, p = 0.02) and trabecular vBMD (141.4 ± 11.6 vs 213.6 ± 15.4 mg/cm3, p = 0.003) compared to adult onset T1D patients adjusting for age, BMI and the radius length. At the tibial shaft, young onset T1D patients had larger endosteal circumference (39.1 ± 1.2 vs 32.1 ± 1.6 mm, p = 0.005) with similar periosteal circumference (67.1 ± 0.9 vs 65.1 ± 1.2 mm, p = 0.2) resulting in reduced cortical thickness (4.4 ± 0.1 vs 5.2 ± 0.1 mm, p = 0.004) compared to adult onset T1D patients adjusting for age, BMI and the tibia length. There was no difference in the lumbar spine, femoral neck, total hip and distal radius DXA-measured aBMD between subjects with T1D and controls. T1D is associated with lower trabecular vBMD at the distal radius. T1D onset before age 20 is associated with cortical bone size deficits at the tibial shaft.

Osteocytes can participate in systemic mineral homeostasis through perilacunar maintenance and remodeling, where changes to osteocyte lacunar morphology may affect bone structural integrity, tissue strains, and osteocyte mechanosensitivity. Though aging is associated with both decreased bone quality and altered mineral metabolism, it is not known if osteocyte lacunae undergo age-related changes in geometry. In order to survey lacunar changes with age, we developed an open-source program whereby 3D osteocyte lacunae are automatically segmented and then subsequently reconstructed from confocal laser scanning microscopy (CLSM) depth stacks for quantitative analysis of geometry and orientation. This approach takes advantage of the availability and speed of CLSM while avoiding time-consuming and bias-prone manual segmentation. Unlike conventional approaches used to quantify osteocyte lacunar morphology, CLSM enables facile analysis in three-dimensions with clear identification of osteocyte lacunae. We report that 3D osteocyte lacunae measured by CLSM become smaller, more spherical, more oblate, more spatially disorganized, and more sparsely populated with increased age in C57Bl/6 mouse cortical bone in groups spanning 6–24 months old. Critically, these age-related changes are in large part not observed in 2D analyses from the same samples. These results (1) demonstrate proof-of-concept of an efficient method to quantitatively assess osteocyte lacunae in 3D for application to a wide range of studies and (2) motivate further inquiry into how changes to osteocyte lacunar geometries and perilacunar material contribute to diminished bone quality in aging.

Tibio-talo-calcaneal (TTC) arthrodesis is an end-stage treatment for patients with severe degeneration of the ankle joint. This treatment consists of using an intramedullary nail (IM) to fuse the calcaneus, talus, and tibia bones together into one construct. Poor bone quality within the joint prior to surgery is common and thus the procedure has shown complications due to non-union. However, a new FDA-approved IM nail has been released that houses a nickel titanium (NiTi) rod that uses its inherent pseudoelastic material properties to apply active compression across the fusion site. Finite element analysis was performed to model the mechanical response of the NiTi within the device. A bone model was then developed based on a quantitative computed tomography (QCT) image for anatomical geometry and bone material properties. A total bone and device system was modeled to investigate the effect of bone quality change and gather load-sharing properties during gait loading. It was found that during the highest magnitude loading of gait, the load taken by the bone was more than 50% higher than the load taken by the nail. When comparing the load distribution during gait, results from this study would suggest that the device helps to prevent stress shielding by allowing a more even distribution of load between bone and nail. In conditions where bone quality may vary patient-to-patient, the model indicates that a 10% decrease in overall bone modulus (i.e. material stiffness) due to reduced bone mineral density would result in higher stresses in the nail (3.4%) and a marginal decrease in stress for the bone (0.5%). The finite element model presented in this study can be used as a quantitative tool to further understand the stress environment of both bone and device for a TTC fusion. Furthermore, the methodology presented gives insight on how to computationally program and use the unique material properties of NiTi in an active compression state useful for bone fracture healing or fusion treatments.

To determine the long-term effects of long-duration spaceflight, we measured bone mineral density and bone geometry of International Space Station (ISS) crewmembers using quantitative computed tomography (QCT) before launch, immediately upon their return, one year after return, and 2–4.5 years after return from the ISS. Eight crew members (7 male, 1 female, mean age 45±4 years at start of mission) who spent an average of 181 days (range 161–196 days) aboard the ISS took part in the study. Integral bone mineral density (iBMD), trabecular BMD (tBMD), bone mineral content (BMC), and vertebral cross-sectional area (CSA) were measured in the lumbar spine, and iBMD, tBMD, cortical BMD (cBMD), BMC, CSA, volume, and femoral neck section modulus were measured in the hip. Spine iBMD was 95% of the average preflight value upon return from the ISS and reached its preflight value over the next 2–4.5 years. Spine tBMD was 97% of the average preflight value upon return from the ISS and tended to decrease throughout the course of the study. Vertebral CSA remained essentially unchanged throughout the study. Hip iBMD was 91% of the preflight value upon return from the ISS and was 95% of the preflight value after 2–4.5 years of recovery. Hip tBMD was 88% of the preflight value upon return and recovered to only 93% of the preflight value after 1 year. At the 2- to 4.5-year time point, average tBMD was 88% of the preflight value. During the recovery period the total volume and cortical bone volume in the hip reached values of 114% and 110% of their preflight values, respectively. The combination of age-related bone loss, long-duration spaceflight, and re-adaptation to the 1-g terrestrial environment presumably produced these changes. These long-term data suggest that skeletal changes that occur during long-duration spaceflight persist even after multiple years of recovery. These changes have important implications for the skeletal health of crew members, especially those who make repeat trips to space.

Simulated partial weight bearing during magnetic resonance imaging of the knee was used to measure patellar tilt, medial-lateral patellar shift, and patellofemoral contact area in three groups of subjects; patients with posterior cruciate retaining (PCR) TKA, patients with bicruciate substituting (BCS) TKA, and healthy controls. Contact stress was also calculated based on the contact area and body weight-based estimates of contact force. Contact stress was significantly (p0.05) higher in PCR knees (2.5+/-3.0 MPa) than in BCS knees (0.2+/-0.1 MPa) when knees were fully extended, but this difference was not significant (3.7+/-3.5 MPa for PCR knees vs. 1.4+/-1.9 MPa for BCS knees; p0.05) in early flexion. The results also indicate that patellar tilt (normal=2.4 degrees +/-4.8 degrees, BCS=5.5 degrees +/-5.5 degrees, PCR=-3.0 degrees +/-6.9 degrees change in lateral tilt when moving from full extension to early flexion) and contact area (full extension: normal=267+/-111 mm(2), BCS=344+/-201 mm(2), PCR=83+/-80 mm(2); early flexion: normal=723+/-306 mm(2), BCS=417+/-290 mm(2), PCR=246+/-108 mm(2)) in BCS TKA mimic those in the normal knees more closely than PCR knees do. These results suggest that the patellar component in BCS TKA may be expected to experience less wear than the patellar component in PCR TKA over time.

Purpose The purpose of this study was to use magnetic resonance imaging (MRI) to determine 3-dimensional knee kinematics after anterior cruciate ligament (ACL) reconstruction. Methods Nine ACL-reconstructed and contralateral knees were tested 12 ± 8 months after surgery. MRI was performed at full extension and 40° of knee flexion under simulated weight-bearing conditions. Femoral condyle positions, tibial rotation, contact area, and contact location were analyzed by use of MRI-based 3-dimensional models. Results When knees were fully extended, tibiae in ACL-reconstructed knees were externally rotated by 3.6° ± 4.2° compared with contralateral knees. The external rotation was due to anterior subluxation of the medial side of the tibia. At 40° of knee flexion, tibiae in ACL-reconstructed knees and contralateral knees were both internally rotated by 5.3°. There were no significant differences in contact area or contact location between ACL-reconstructed and contralateral knees. When moving from extension to flexion, ACL-reconstructed knees exhibited 3.5° ± 5.9° more internal tibial rotation than contralateral knees. Conclusions Reconstruction of the ACL restored normal motion on the lateral side of the knee but not on the medial side, resulting in increased internal tibial rotation when moving from full extension to 40° of flexion. These results suggest that ACL reconstruction does not restore normal kinematics on the medial side of the knee, which may lead to early cartilage degeneration. Level of Evidence Level IV, therapeutic case series.

Background We evaluated military personnel who developed dermatologic reactions suggestive of generalized vaccinia (GV) after smallpox vaccination. Methods We conducted surveillance and retrospective analysis of cases from the Vaccine Adverse Event Reporting System (a passive reporting system managed by the Centers for Disease Control and Prevention), and the military's preventive medicine channels, vaccine healthcare centers, clinical laboratory network, dermatology clinics, and pathology departments from December 2002 to December 2004. Results Of 74 cases investigated in 753,226 vaccinations, 50 (67.6%) met the case definition of possible GV (rate 66/million), 95% confidence interval (49-88/million), consistent with historically reported rates. Cases of possible GV occurred more frequently in primary vaccinees (81/million) than in those revaccinated (32/million) (relative risk 2.6, 95% confidence interval 1.2-5.9, P = .013). None met the case definition of probable or confirmed GV, including 15 with virologically negative laboratory evaluations (eg, culture, skin biopsy, or polymerase chain reaction). Limitations The methods of case collection and retrospective nature of this study are its limitations. The clinical diagnosis of possible GV was made on the basis of the authors' interpretation of clinical notes and adverse events submitted by more than 100 different providers. Only 15 of the 74 cases of possible GV had laboratory attempts for virological confirmation. Conclusion GV is still a rarely reported complication of smallpox vaccination. True GV, strictly defined, may be even less common than previously reported. We named one self-limited dermatologic manifestation confused with GV "postvaccinial nonviral pustulosis." Properly screened individuals considering smallpox vaccination may be assured most exanthemata after vaccination are benign.

In activated neutrophils NADPH oxidase is regulated through various signaling intermediates, including heterotrimeric G proteins, kinases, GTPases, and phospholipases. ADP-ribosylation factor (ARF) describes a family of GTPases associated with phospholipase D (PLD) activation. PLD is implicated in NADPH oxidase activation, although it is unclear whether activation of PLD by ARF is linked to receptor-mediated oxidase activation. We explored whether ARF participates in NADPH oxidase activation by formyl-methionine-leucine-phenylalanine (fMLP) and whether this involves PLD. Using multicolor forward angle light scattering analyses to measure superoxide production in differentiated neutrophil-like PLB-985 cells, we tested enhanced green fluorescent fusion proteins of wild-type ARF1 or ARF6, or their mutant counterparts. The ARF6(Q67L) mutant defective in GTP hydrolysis caused increased superoxide production, whereas the ARF6(T27N) mutant defective in GTP binding caused diminished responses to fMLP. The ARF1 mutants had no effect on fMLP responses, and none of the ARF proteins affected phorbol 12-myristate 13-acetate-elicited oxidase activity. PLD inhibitors 1-butanol and 2, 3-diphosphoglycerate, or the ARF6(N48R) mutant assumed to be defective in PLD activation, blocked fMLP-elicited oxidase activity in transfected cells. The data suggest that ARF6 but not ARF1 modulates receptor-mediated NADPH oxidase activation in a PLD-dependent mechanism. Because PMA-elicited NADPH oxidase activation also appears to be PLD-dependent, but ARF-independent, ARF6 and protein kinase C may act through distinct pathways, both involving PLD.

Purpose: The purpose of the study is to delineate the visual prognosticators in sarcoid-associated uveitis given the current standards of care. Methods: The records of 60 patients with sarcoid-associated uveitis who were observed for at least 6 months were studied retrospectively. Multivariate regression models using the generalized estimating equations approach to adjust for the correlation between fellow eyes were applied to determine disease, patient, and treatment characteristics that altered the odds of visual rehabilitation. Results: One hundred twelve eyes of 43 women and 17 men who met the inclusion criteria were identified. Seventy-seven percent of patients were white, 15% black, and 8% of Hispanic origin. Uveitis developed in the patients at a mean age of 42 (range, 482) years. Of the 112 affected eyes, 81% had granulomatous and 15% nongranulomatous uveitis. Most patients (66%) had anterior or intermediate uveitis alone. Ninety-one percent had chronically smoldering disease; another 7% had recurrent flares, and only 1 patient had a monophasic acute course to her uveitis. Vision-threatening complications developed in many patients, including 58% in whom cystoid macular edema developed and 25% in whom media opacities developed, requiring cataract surgery or vitrectomy or both. Overall, 34% of treated eyes and 51% of patients had final visual acuities that were superior to their acuities at presentation. The factors most significantly associated with a final visual acuity of worse than 20/40 after controlling for potential confounders were as follows: delay in presentation to a subspecialist (odds ratio [OR] = 2.94, P=0.05), total duration of uveitis (OR = 1.04, P = 0.09), development of cystoid macular edema (OR = 0.37, P = 0.07) or glaucoma (OR = 4.54, P = 0.02), presence of intermediate (OR = 5.00, P = 0.01) or posterior uveitis (OR = 8.33, P = 0.04), and systemic steroid use (OR = 0.30, P = 0.03) were the parameters most strongly correlated with a lack of visual acuity improvement. Delay in presentation to a subspecialist (OR = 20.00, P = 0.01), development of glaucoma (OR = 50.00, P = 0.005), presence of intermediate (OR = 25.00, P = 0.02) or posterior uveitis (OR = 50.00, P = 0.02), black race (OR = 11.11, P = 0.02), (log) visual acuity at presentation (OR = 0.05, P = 0.0001), and use of systemic steroids (OR = 0.07, P = 0.02). Conclusion: Multivariate outcomes analysis, particularly after correcting for the correlation between fellow eyes, is a useful analytic tool for optimization of standards of care and for disease risk stratification to aid both physicians and patients.

Purpose: A multicenter study was undertaken to delineate the indications for and outcome of pediatric keratoplasty. Methods: The authors retrospectively studied 164 grafts in 131 eyes of 108 children younger than 12 years of age, with an average follow-up of 45 months. Multivariate linear and logistic regression was performed to evaluate potential risk factors for poor visual outcome and graft failure. Graft survival was depicted in terms of the KaplanMeier survival curve. Results: Corneal opacities were grouped into three diagnostic categories: congenital (64%), traumatic (17%), and acquired nontraumatic (19%) opacities. Overall graft survival was 80% at 12 months and 67% at 24 months postoperatively. There was no significant difference in retention of clarity among diagnostic groups. Vitrectomy-lensectomy, regrafts, and postoperative complications were associated significantly with poor allograft survival. Eighteen percent of all eyes had worse vision at the time of the last visit than preoperatively. Amblyopia treatment was the only independently significant prognosticator for visual improvement after surgery. Timing of keratoplasty was not demonstrated to be associated with visual outcome. Visual acuity in 33% of eyes that could be quantified was better than 20/200 at the last visit, whereas 62% of eyes retained full graft clarity. Conclusion: The authors conclude that keratoplasty can be successful in most children, especially when combined with appropriate amblyopia management.

Surgery is indicated for keratoconus when management with contact lenses fails. The authors sought to determine the relative contribution of various preoperative patient and ocular factors to the ultimate causes of contact lens failure.The records of unoperated eyes of keratoconus patients whose contact lenses were managed intensively before undergoing penetrating keratoplasty (PK) at the authors' institution between 1981 and 1990 were selected for study. Univariate and multivariate analyses were performed to identify risk factors for early contact lens failure.The records of 99 keratoconic eyes of 75 patients with an average age of 34 years and average keratometry readings of 57.5 diopters at presentation were studied. Cases had been followed for an average of 27 months before PK. The primary reasons for PK were a best-corrected visual acuity of under 20/40 (despite good contact lens fit) causing disability for the patient (43%), contact lens intolerance (32%), frequent lens displacement (13%), and significant peripheral thinning of the cornea (12%). The referral source of the patient, sex, a history of PK in the fellow eye, or of contact lens wear in either eye did not alter the relative contributions of these parameters to surgery.Poor best-corrected visual acuity at presentation, higher keratometry readings (greater than or equal to 55 D), age (greater than or equal to 40 years), and duration of disease (greater than 5 years) were significantly associated with failure due to poor functional acuity and peripheral thinning, frequently leading to surgery within the first 12 months after presentation.

14C-labeled tributyltin-chloride (TBT-Cl) was delivered to the water column of seagrass microcosms held in the laboratory under flow-through conditions. Benthic macroinvertebrate abundances across a three treatment, logarithmic dose gradient were compared to untreated control microcosms. Within 3 to 6 weeks, statistically significant mortality appeared in the high treatment. Sensitive species included surface deposit feeders of several phyla, as well as a suspension feeding mollusc. Results suggest that effects can arise because TBT is rapidly accumulated in surface sediments, as well as in Thalassia tissues. Concentration of tracer in plant tissues, animals, and sediments suggests that measurement of TBT (and total butyltin) in these components of seagrass beds would provide a better indicator of exposure regimes than occasional measurements in the water. A propensity for accumulation, along with a biological vulnerability, suggests a sentinel role for seagrass ecosystems in some shallow coastal areas. Experimental findings demonstrate concern for some key invertebrates within beds proximal to TBT sources, and ecological risks could radiate through coastal food webs dependent on these productive vegetated shallows.

A three-dimensional finite-element analysis treating the mechanical response of thick laminated composite plates in bending is presented. An isoparametric solid element with a cubic displacement expansion in planform and a linear variation through the thickness is used to model each layer of the laminate. The degrees-of-freedom of the element are retained at its boundaries so that interconnections between lamina with different fiber orientations can be made at their interfaces. An incore version of the conjugate gradient technique, which does not have bandwidth restrictions, is used to minimize the total potential energy of the system with the number of iterations to convergence being about one-fifth the total global degrees-of-freedom. Because a three-dimensional analysis is used, the effects of thickness-stretching, transverse shear, extension, and bending deformations are obtained. Comparisons with three-dimensional elasticity solutions are in excellent agreement and show the necessity of having individual elements for each layer when they have different fiber orientations and when the plates are thick.