A case-control pilot study of stress fracture in adolescent girls: the discriminative ability of two imaging technologies to classify at-risk athletes.

Since stress fractures are common among adolescent athletes, it is important to identify bone assessment tools that accurately identify risk. We investigated the discriminative ability of two imaging technologies to classify at-risk athletes. Findings suggested that peripheral quantitative computed tomography (pQCT) has the ability to distinguish differences in bone structure in injured vs. uninjured limbs. INTRODUCTION: Given the high stress fracture (SFX) prevalence among adolescent girls, an understanding of the most informative assessment tools to identify SFX risks are required. We investigated the discriminative ability of pQCT vs. dual-energy X-ray absorptiometry (DXA) to classify athletes with or without SFX. METHODS: Twelve adolescent athletes diagnosed with a lower-extremity SFX were compared with 12 matched controls. DXA measured areal bone mineral density (aBMD) and content of the total body, and lumbar spine. Bilateral tibiae were assessed with pQCT. At the metaphysis (3%), total density (ToD), trabecular density (TrD), trabecular area (TrA), and estimated bone strength in compression (BSIc), and at the diaphysis (38% and 66%), total bone area (ToA), cortical density (CoD), cortical area (CoA), estimated bone strength in torsion (SSIp), and peri- and endocortical and muscle area (MuA) were obtained. Cortical bone mass/density around the center of mass and marrow density (estimate of adiposity) were calculated using ImageJ software. General estimated equations adjusting for multiple comparisons (Holm-Bonferroni method) were used to compare means between (1) injured limb of the case athletes vs. uninjured limb of the control athletes and (2) uninjured limb of the case athletes vs. uninjured limbs of the controls and injured vs. uninjured limb of case athletes with a SFX. RESULTS: aBMD and content showed no significant differences between cases and controls. When comparing the injured vs. uninjured leg in the case athletes by pQCT at the 3% tibia, unadjusted TrD, total density, and BSIc were significantly lower (p < 0.05) in the injured vs. uninjured leg. Marrow density at the 66% site was 1% (p < 0.05) lower in the injured vs. uninjured leg. CONCLUSIONS: These preliminary data in athletes with SFX suggest that pQCT has the ability to distinguish differences in bone structure in injured vs. uninjured limbs. No discriminative bone parameter classifications were identified between adolescent athletes with or without SFX.

Opportunistic screening for bone disease using abdominal CT scans obtained for other reasons in newly diagnosed IBD patients.

Bone disease is prevalent among patients with inflammatory bowel disease (IBD), though bone density screening remains underutilized. We used CT scans performed for other indications in IBD patients to identify and monitor osteopenia using CT attenuation values at the lumbar spine. Significant rates of bone disease were detected which would have otherwise gone undiagnosed. INTRODUCTION: Osteoporosis affects about 14-42% of patients with IBD. Though screening is recommended in IBD patients with risk factors, it remains underutilized. In patients with newly diagnosed IBD, we used CT scans performed for other indications to identify and monitor progression of osteopenia. METHODS: Using the Ocean State Crohn's and Colitis Area Registry, we identified adult patients with one or more abdominal CT scans. Each patient had two age- and gender-matched controls. Radiologists measured attenuation through trabecular bone in the L1 vertebral body recorded in Hounsfield units (HU). Generalized estimating equations were used to measure how HU varied as a function of gender, type of IBD, and age. RESULTS: One hundred five IBD patients were included, and 72.4% were classified as "normal" bone mineral density (BMD) and 27.6% as potentially osteopenic: 8.6% with ulcerative colitis and 19.0% with Crohn's disease. We found a decrease in bone density over time (p < 0.001) and that BMD decreases more in Crohn's disease than in ulcerative colitis (p < 0.004). Sixty patients had two CT scans, and mean loss of 9.3 HU was noted. There was a non-significant decrease in BMD over time in patients exposed to > 31 days of steroids and BMD was stable with < 30 days of steroid exposure (p < 0.09). CONCLUSION: Using CT scans obtained for other indications, we found low rates of osteopenia and osteoporosis that may otherwise have gone undiagnosed. Refinement of opportunistic screening may have advantages in terms of cost-savings and earlier detection of bone loss.

A comprehensive study of umbilical cord blood cell developmental changes and reference ranges by gestation, gender and mode of delivery.

OBJECTIVE: The purpose of this study was to determine the normal hematological values in cord blood during gestation, the impact of the type of delivery and differences in gender. STUDY DESIGN: The database included 10 287 live births of 30-44 weeks gestation from cesarean or vaginal deliveries. Cord blood was collected into bags containing lyophilized heparin. Specimens were stored for 24 h or less and analyzed using the SysmexXE-2100. Data from cesarean births were used to evaluate developmental hematopoietic changes. RESULT: Increases during maturation occurred in hemoglobin, hematocrit, red blood cell count, and decreases in mean corpuscular volume and mean corpuscular hemoglobin. The number of nucleated red blood cells per 100 white blood cells decreased but absolute counts remained constant. Quantitative counts of white blood cells, neutrophils, monocytes (MON), eosinophils and lymphocytes (LYMP) increased, but percentages of lymphocytes and monocytes decreased. Platelets increased from 30-35 weeks. CONCLUSION: Reference ranges were established for cord blood. Erythroid and myeloid cells show developmental changes. Mode of delivery has a significant effect on hematologic values. Only a rare parameter showed differences based on gender. The cord blood complete blood cell count has the potential for providing relevant clinical information for managing neonatal patients.

Imaging characteristics of cerebrovascular arteriopathy and stroke in Hutchinson-Gilford progeria syndrome.

BACKGROUND AND PURPOSE: HGPS is a rare disorder of segmental aging, with early morbidity from cardiovascular and cerebrovascular disease. The goal of this study was to identify the neurovascular features, infarct type, topography, and natural history of stroke in the only neurovascular imaging cohort study of HGPS. MATERIALS AND METHODS: We studied 25 children with confirmed diagnoses of HGPS and neuroimaging studies available for review. Relevant clinical information was abstracted from medical records. RESULTS: We identified features suggestive of a vasculopathy unique to HGPS, including distinctive intracranial steno-occlusive arterial lesions, basal cistern collateral vessels, and slow compensatory collateral flow over the cerebral convexities. The arterial pathology in the neck consisted of distal vertebral artery stenosis with prominent collateral vessel formation as well as stenosis and calcification of both the cervical internal and common carotid arteries. Radiographic evidence of infarction was found in 60% of patients, of which half were likely clinically silent. Both large- and small-vessel disease was observed, characterized by arterial territorial, white matter, lacunar, and watershed infarcts. CONCLUSIONS: We report a unique intracranial and superior cervical arteriopathy in HGPS distinct from other vasculopathies of childhood, such as Moyamoya, and cerebrovascular disease of aging, including atherosclerosis. Arterial features of the mid and lower neck are less distinctive. For the first time, we identified early and clinically silent strokes as a prevalent disease characteristic in HGPS. Longitudinal analysis of stroke incidence and vasculopathy may provide an outcome measure for future treatment interventions for children with HGPS.

Pharmaceutical nanocarrier association with chondrocytes and cartilage explants: influence of surface modification and extracellular matrix depletion.

OBJECTIVE: To evaluate cartilage diffusion and isolated chondrocyte association of micelles and liposomes and to determine the effect of cell-penetrating peptide (CPP) surface functionalization and extracellular matrix depletion on chondrocyte association and cartilage diffusion, respectively. METHODS: Rhodamine-labeled micelles and liposomes were incubated with bovine chondrocytes and cell-associated fluorescence was quantified using flow cytometry. Rhodamine-labeled CPP-modified micelles and liposomes were incubated with chondrocytes and cell-associated fluorescence was compared to unmodified nanocarriers. Rhodamine-labeled micelles and liposomes were incubated with bovine cartilage explants for 1, 2 and 4 h and cartilage-associated fluorescence was compared across groups. Cartilage explants were treated with interleukin-1 alpha (IL-1α) or with 0.25% trypsin. Rhodamine-labeled micelles and liposomes were incubated with control, IL-1 and trypsin-treated explants and cartilage-associated fluorescence was compared across groups. RESULTS: Chondrocyte-associated fluorescence following treatment with micelles was significantly higher (P < 0.001) than fluorescence in the cells treated with liposomes while there was no difference between cell-associated fluorescence in the liposomes-treated and untreated controls. CPP-modified nanocarriers exhibited a significant increase in chondrocyte association compared to unmodified nanocarriers (P < 0.001). Micelles exhibited a time and concentration-dependent diffusion in cartilage explants while liposomes showed no diffusion. Following IL-1 and trypsin treatments, micelle diffusion in articular cartilage was significantly higher (P < 0.001) than their diffusion in untreated explants. CONCLUSION: Micelles exhibit superior association with isolated chondrocytes compared to liposomes. Surface modification with a CPP enhances chondrocyte association of both nanocarriers. 15 nm diameter micelles are better than 138 nm diameter liposomes in penetrating articular cartilage and extracellular matrix depletion enhances micelle penetration.

The Role of preload and leakage correction in gadolinium-based cerebral blood volume estimation determined by comparison with MION as a criterion standard.

BACKGROUND AND PURPOSE: Contrast extravasation in DSC-MRI potentiates inaccurate and imprecise estimates of glioma rCBV. We tested assertions that preload and postprocessing algorithms minimize this error by comparing Gd-rCBV using permutations of these 2 techniques with criterion standard rCBV using MION, an intravascular agent. MATERIALS AND METHODS: We imaged 7 Fisher rats with 9L gliosarcomas, by using 3T gradient-echo DSC-MRI with MION (2.0 mg Fe/kg) and staged injection of Gd-diethylene triamine pentaacetic acid: a 0.1-mmol/kg bolus provided no preload (P-) data and served as preload (P+) for a subsequent 0.2-mmol/kg bolus. We computed MION-rCBV (steady-state ΔR2*, tumor versus normal brain) and Gd-rCBV ΔR2* [t] integration) without (C-) and with (C+) postprocessing correction, thereby testing 4 correction permutations: P-C-, P-C+, P+C-, and P+C+. We tested whether each permutation reduced bias and variance of the Gd/MION rCBV differences by using generalized estimating equations and Fmax statistics (P < .05 significant). RESULTS: Gd-rCBV progressively better approximated MION-rCBV with increasing leakage correction. There was no statistically significant bias for the mean percentage deviation of Gd-rCBV from MION-rCBV for any correction permutation, but there was significantly reduced variance by using P+C- (22-fold), P-C+ (32-fold), and P+C+ (267-fold) compared with P-C-. P+C+ provided significant additional variance reduction compared with P+C- (12-fold) and P-C+ (8-fold). Linear regression of Gd-rCBV versus MION-rCBV revealed P+C+ to have the closest slope and intercept compared with the ideal, substantially better than P+C-. CONCLUSIONS: Preload and postprocessing correction significantly reduced the variance of Gd-rCBV estimates, and bias reduction approached significance. Postprocessing correction provide significant benefit beyond preload alone.

High dietary fat and the development of osteoarthritis in a rabbit model.

OBJECTIVE: Osteoarthritis (OA) is associated with obesity, although this relationship remains unclear. Proposed etiologies of OA in obesity include mechanical loading of malaligned joints and possible toxicity of dietary fat. The hypothesis tested in the present study was that increased dietary fat worsens OA in both malaligned and normal joints, detected by biochemical and histological cartilage markers. METHOD: 83 New Zealand white rabbits were divided among two conditions related to OA: bowing of the knee and a 14%kcal vs 47.8%kcal fat diet. Rabbit weights and knee angles were compared throughout the experiment. At 28 and 38 weeks, intra-articular forces were measured, animals sacrificed, and knee cartilage examined for histological changes, glycosaminoglycan content, 35S uptake, and aggrecanase-1 expression. RESULTS: There were no differences in animal weights or intra-articular forces between the two diets. Despite increased fat content in their diet, animals on the 47.8%kcal fat diet did not gain excess weight. Representative histology showed atypical shearing of articular cartilage among animals on the high fat diet. Animals on the 47.8%kcal fat diet had suppression of protein synthesis compared to the 14%kcal fat diet: lower glycosaminoglycan content and aggrecanase-1 expression in all knee compartments at both times, and lower 35S uptake at 38 weeks. CONCLUSION: These results suggest dietary fat, independent of animal weight, results in altered chondrocyte function. Increased dietary fat was associated with changes in rabbit cartilage in vivo and appears to be a risk factor for the development of OA.

Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures.

OBJECTIVE: There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. METHODS: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG-confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables. RESULTS: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline. CONCLUSIONS: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. LEVEL OF EVIDENCE: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25-1.05, p = 0.29), adjusting for differences at baseline.

Delayed Gadolinium-Enhanced MR Imaging of Cartilage (dGEMRIC) following ACL injury.

OBJECTIVE: Early detection of glycosaminoglycan (GAG) loss may provide insight into mechanisms of cartilage damage in the anterior cruciate ligament (ACL)-injured patient. We hypothesized that tibial and femoral Delayed Gadolinium-Enhanced MR Imaging of Cartilage (dGEMRIC) indices would be lower in the medial compartment of the ACL-injured knee than in the contralateral, uninjured knee, and that scan order (i.e., whether the injured or the uninjured knee was imaged first) would not affect the indices. METHODS: 15 subjects with unilateral ACL injuries received a double dose of gadolinium [Gd(DTPA)(2-)] intravenously. After 90 min, both knees were sequentially imaged. The injured knee was scanned first in the odd-numbered subjects and second in the even-numbered subjects. The dGEMRIC indices of the median slice of the medial compartment were determined using the MRIMapper software. Index comparisons were made between knee status (ACL-injured vs uninjured), scan order (ACL-injured first vs uninjured first), and cartilage location (tibia vs femur) using a mixed model. RESULTS: There was a significant difference in the mean dGEMRIC indices of the medial compartment between injured and uninjured knees (P<0.007). On average, there was a 13% decrease in the dGEMRIC index of the injured knee compared to the uninjured knee. There were no significant effects due to test order (P=0.800) or cartilage location (P=0.439). CONCLUSIONS: The results demonstrate lower GAG concentrations in the medial compartment of the femoral and tibial articular cartilage of the ACL-injured knee when compared to the contralateral uninjured knee. The dGEMRIC indices were not sensitive to scan order; thus, sequential imaging of both knees is possible in this patient population.

Highly active antiretroviral therapy and employment status in accra, ghana.

OBJECTIVES: This study investigated the immunologic responses and employment history of highly-active antiretroviral therapy (HAART) patients. DESIGN: We interviewed patients and reviewed medical records to collect demographic, clinical, and employment history while on HAART. Demographic characteristics were tested as predictors of immunological response while on HAART using hierarchical linear models. SETTING: Fevers Unit, Korle-Bu Teaching Hospital, Accra, Ghana PARTICIPANTS: Subjects comprised a convenience sample of adult HAART patients receiving therapy for at least 9 months. 270 patients were interviewed. 38 were excluded due to inadequate time on HAART or inability to locate all necessary patient information. INTERVENTION: This was an observational study. MAIN OUTCOME MEASURES: We investigated the change in CD4 cell count and weight since the initiation of therapy, and their ability to maintain or regain employment as well as the reasons for this. RESULTS: The estimated mean ± standard error increase in CD4 cell count from baseline at 6, 12, and 18 months were 102 ± 5, 204 ± 11, and 236 ± 10 cells/µL, respectively. Overall, 147 patients (63.4%) reported remaining employed or obtaining new employment while on HAART. Patients who were asymptomatic at initial presentation were more likely to remain employed or returned to work while on HAART than those who were symptomatic (66.4% vs. 48.8%, P = 0.009). Most patients were employed in the informal sector, which made their economic situation particularly vulnerable to HIV-associated illness. CONCLUSION: The findings suggest that patients receiving HAART experience good clinical and immunological responses as well as improvement in employment status.

The impact of anterior cruciate ligament injury on lubricin metabolism and the effect of inhibiting tumor necrosis factor alpha on chondroprotection in an animal model.

OBJECTIVE: To examine the effects of anterior cruciate ligament transection (ACLT) in a rat model on lubricin metabolism and its relationship to markers of inflammation and cartilage damage, and to determine whether blocking the metabolic effects of tumor necrosis factor alpha (TNFalpha) by etanercept increases the chondroprotection provided by lubricin. METHODS: Unilateral ACLT was performed in Lewis rats. Levels of lubricin, TNFalpha, interleukin-1beta (IL-1beta), and sulfated glycosaminoglycans (sGAG) in synovial fluid (SF) lavage specimens and synovial tissue lubricin gene expression were evaluated at 1 week and 4 weeks following ACLT. Histologic evaluation of articular cartilage included staining with lubricin-specific monoclonal antibody 9G3 and Safranin O. The percentage of lubricin staining on the surface of articular cartilage in weight-bearing areas was estimated by digital imaging. Blocking of TNFalpha was performed using etanercept, which was administered subcutaneously at a dose of 0.5 mg/kg around the ACL-transected joints, using different dosing strategies. The ACL-transected and contralateral joints of these rats were harvested 4 weeks following surgery. RESULTS: Four weeks following ACLT, SF lubricin concentrations and the percentage of cartilage surface lubricin staining were significantly lower in the injured joints compared with the contralateral joints. A significant decrease in synovial tissue lubricin gene expression was associated with elevated TNFalpha and IL-1beta concentrations in SF lavage samples. With all of the etanercept treatment strategies, blocking of TNFalpha significantly increased the amount of lubricin bound to cartilage, coupled with a significant decrease in sGAG release. However, changes in the concentrations of lubricin in SF were variable. CONCLUSION: Blocking TNFalpha resulted in a chondroprotective effect, exemplified by increased lubricin deposition on articular cartilage and a decrease in sGAG release from articular cartilage in an animal model of posttraumatic arthritis.

Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury.

OBJECTIVE: To study the effect of anterior cruciate ligament (ACL) injury on lubricin concentrations in synovial fluid (SF) and its correlation with time postinjury, inflammatory cytokines, lubricin-degrading enzymes, and SF proteoglycan content. METHODS: SF samples were obtained from both knees of 30 patients with unilateral ACL insufficiency, 32-364 days postinjury. Lubricin, inflammatory cytokines (interleukin-1beta [IL-1beta], tumor necrosis factor alpha [TNFalpha], and IL-6), and catabolic enzymes (procathepsin B and neutrophil elastase) were measured in SF from injured and contralateral (uninjured) joints, by enzyme-linked immunosorbent assay. Sulfated glycosaminoglycan (sGAG) levels in the SF were measured by Alcian blue binding assay. RESULTS: SF lubricin concentrations were significantly (P < 0.001) reduced at an early stage following ACL injury when compared with those in the contralateral joint. Within 12 months, the lubricin concentration in the injured knee (slope = 0.006, SE = 0.00010, P < 0.001) approached that in the contralateral knee, which did not change with time (slope = -0.0002, SE = 0.00050, P = 0.71). TNFalpha levels showed a significant negative relationship with log2 lubricin levels. IL-1beta, TNFalpha, IL-6, procathepsin B, and neutrophil elastase concentrations in SF from injured knees were greater in samples from recently injured knees compared with those that were chronically injured. There were no detectable cytokines or enzymes in the SF of contralateral joints. Concentrations of sGAG were significantly (P = 0.0002) higher in the SF from injured knees compared with the contralateral joints. CONCLUSION: The decrease in SF lubricin concentrations following ACL injury may place the joint at an increased risk of wear-induced damage as a consequence of lack of boundary lubrication, potentially leading to secondary osteoarthritis. The decrease in SF lubricin was associated with an increase in levels of inflammatory cytokines.

Infrequency of "pure" GAD: impact of psychiatric comorbidity on clinical course.

The widespread occurrence of psychiatric comorbidity among patients with generalized anxiety disorder (GAD) has been well documented. However, there is a paucity of studies examining the impact comorbid disorders have on the clinical course of GAD. In this study, 179 patients with GAD at intake, 12 patients with a past history of GAD, and 109 patients who subsequently onset a first episode of GAD during the course of follow-up were followed for 8 years in this naturalistic, prospective study of anxiety disorders. Results indicate that comorbid anxiety, mood, and substance use disorders are very common with GAD and increased during follow-up. For example, 39% of participants with GAD also had a comorbid diagnosis of major depressive disorder at intake and increased to 65% at 4 years and 74% at the 8-year follow-up. Inspection of "pure" cases of GAD indicated that out of 20 patients with GAD alone at intake, all but 1 went on to develop some comorbidity. Results also indicate that being in episode of comorbid MDD or panic disorder with agoraphobia decreased the probability that a subject would remit from their GAD. The findings highlight the need for such long-term, prospective research since results show that patients with GAD at intake had increasing risk for developing other mental disorders during subsequent follow-ups. Additionally, results of such high comorbidity and the impact of these comorbid disorders on the clinical course of GAD should have a notable impact on research into the treatment of GAD.