Biomarkers and longitudinal changes in lumbar spine degeneration and low back pain: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine if baseline biomarkers are associated with longitudinal changes in the worsening of disc space narrowing (DSN), vertebral osteophytes (OST), and low back pain (LBP). DESIGN: Paired baseline (2003-2004) and follow-up (2006-2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for severity of DSN and OST. LBP severity was self-reported. Concentrations of analytes (cytokines, proteoglycans, and neuropeptides) were quantified by immunoassay. Pressure-pain threshold (PPT), a marker of sensitivity to pressure pain, was measured with a standard dolorimeter. Binary logistic regression models were used to estimate odd ratios (OR) and 95% confidence intervals (CI) of biomarker levels with DSN, OST, or LBP. Interactions were tested between biomarker levels and the number of affected lumbar spine levels or LBP. RESULTS: We included participants (n = 723) with biospecimens, PPT, and paired lumbar spine radiographic data. Baseline Lumican, a proteoglycan reflective of extracellular matrix changes, was associated with longitudinal changes in DSN worsening (OR = 3.19 [95% CI 1.22, 8.01]). Baseline brain-derived neuropathic factor, a neuropeptide, (OR = 1.80 [95% CI 1.03, 3.16]) was associated with longitudinal changes in OST worsening, which may reflect osteoclast genesis. Baseline hyaluronic acid (OR = 1.31 [95% CI 1.01, 1.71]), indicative of systemic inflammation, and PPT (OR = 1.56 [95% CI 1.02, 2.31]) were associated with longitudinal increases in LBP severity. CONCLUSION: These findings suggest that baseline biomarkers are associated with longitudinal changes occurring in structures of the lumbar spine (DSN vs OST). Markers of inflammation and perceived pressure pain sensitivity were associated with longitudinal worsening of LBP.

BRD4S interacts with viral E2 protein to limit human papillomavirus late transcription.

The E2 protein encoded by human papillomaviruses (HPV) is a sequence-specific DNA-binding protein that recruits viral and cellular proteins. Bromodomain-containing protein 4 (BRD4) is a highly conserved interactor for E2 proteins that has been linked to E2's functions as transcription modulator, activator of viral replication and segregation factor for viral genomes. In addition to BRD4, a short form of BRD4 (BRD4S) is expressed from the BRD4 gene which lacks the C-terminal domain of BRD4. E2 proteins interact with the C-terminal motif (CTM) of BRD4, but a recent study suggested that the phospho-dependent interaction domain (PDID) and the basic interaction domain (BID) in BRD4 also bind to E2. These domains are also present in BRD4S. We now find that HPV31 E2 interacts with the isolated PDID domain in living cells and also with BRD4S which is present in detectable amounts in HPV-positive cell lines and is recruited into HPV31 E1 and E2 induced replication foci. Overexpression and knockdown experiments surprisingly indicate that BRD4S inhibits activities of E2. In line with that, the specific knockdown of BRD4S in the HPV31-positive CIN612-9E cell line induces mainly late viral transcripts. This occurs only in undifferentiated but not differentiated cells in which the productive viral replication cycle is induced. These data suggest that the BRD4S-E2 interaction is important to prevent HPV late gene expression in undifferentiated keratinocytes which may contribute to immune evasion and HPV persistence.ImportanceHuman papillomaviruses (HPV) have coevolved with their host by using cellular factors like bromodomain-containing protein 4 (BRD4) to control viral processes such as genome maintenance, gene expression and replication. We here show that, in addition to the C-terminal motif in BRD4, the phospho-dependent interaction domain in BRD4 interacts with E2 proteins which enable the recruitment of BRD4S, the short isoform of BRD4, to E2. Knock-down and overexpression of BRD4S reveals that BRD4S is a negative regulator of E2 activities. Importantly, the knockdown of BRD4S induces mainly L1 transcripts in undifferentiated CIN612-9E cells, which maintain replicating HPV31 genomes. Our study reveals an inhibitory role of BRD4S on HPV transcription, which may serve as an immune escape mechanism by the suppression of L1 transcripts and thus contribute to the establishment of persistent HPV infections.

Hip symptoms are associated with premature mortality: the Johnston County Osteoarthritis Project.

OBJECTIVE: To investigate the impact of hip osteoarthritis (OA) and/or hip symptoms on excess mortality. DESIGN: We analyzed data from 3,919 individuals in a community-based prospective cohort of African Americans and Caucasians age ≥45 years. Women ≥50 years of age and all men underwent supine anteroposterior pelvic radiography at baseline, with the participant's feet in 15 degrees of internal rotation. Hip radiographic (rOA) was defined as a Kellgren-Lawrence grade of ≥2 in at least one hip. Participants completed questionnaires at baseline to determine presence of hip symptoms and covariate status. Participants with symptomatic hip rOA (SxOA) are a subset of individuals with hip rOA and symptoms in the same hip. Multiple imputation was used to impute missing values of covariates. Mortality was determined through 2015 and follow-up time was calculated from baseline assessment until death or censoring which took place when a participant was lost to follow-up or reached the end of study period. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We carried out additional analyses stratified by sex, race, age and obesity. RESULTS: Mean follow-up time was 14.2 years during which 1762 deaths occurred. There were 29.9% participants in our population with hip rOA at baseline. Compared to those with neither hip rOA nor hip symptoms, we observed an increased risk of all-cause mortality in participants with hip symptoms alone (HR = 1.28, 95% CI = 1.13-1.46), but no association for hip rOA either with or without symptoms. In stratified analyses we observed increased associations for hip symptoms alone and hip sxOA in those <65 years (43% and 39% increase, respectively) and in Caucasians (34% and 21% increase, respectively). CONCLUSIONS: Individuals who had hip symptoms without hip rOA had an increased risk of mortality. These effects were particularly strong for those who were <65 years of age and Caucasians. Effective interventions to identify those with hip pain in order to lessen it could reduce premature mortality.

Incidence and progression of hand osteoarthritis in a large community-based cohort: the Johnston County Osteoarthritis Project.

OBJECTIVE: To describe the incidence and progression of radiographic and symptomatic hand osteoarthritis (rHOA and sxHOA) in a large community-based cohort. DESIGN: Data were from the Johnston County OA Project (1999-2015, 12 ± 1.2 years follow-up, age 45+). Participants had bilateral hand radiographs each visit, read for Kellgren-Lawrence grade (KLG) at 30 joints. We defined rHOA as KLG ≥2 in ≥1 joint. SxHOA was defined in a hand/joint with rHOA and self-reported symptoms or tenderness on exam. Incidence was assessed in those without, while progression was assessed in those with, baseline rHOA. Proportions or medians are reported; differences by sex and race were assessed using models appropriate for dichotomous or continuous definitions, additionally adjusted for age, education, body mass index (BMI), and weight change. RESULTS: Of 800 participants (68% women, 32% African American, mean age 60 years), 327 had baseline rHOA and were older, more often white and female, than those without rHOA (n = 473). The incidence of HOA was high, for rHOA (60%) and for sxHOA (13%). Women were more likely than men to have incident HOA, particularly for distal interphalangeal joint radiographic osteoarthritis (DIP rOA) (adjusted odds ratios (aOR) 1.60 95% confidence intervals (95% CI) [1.03, 2.49]) and sxHOA (aOR 2.98 [1.50, 5.91]). Progressive HOA was more similar by sex, although thumb base rOA progressed more frequently in women than in men (aOR 2.56 [1.44, 4.55]). Particularly HOA incidence, but also progression, was more frequent among whites compared with African Americans. CONCLUSION: This study provides much needed information about the natural history of HOA, a common and frequently debilitating condition, in the general population.

[Ultrasound visualization of the guidewire and positioning of the central venous catheter : A prospective observational study]. / Sonographische Visualisierung des Führungsdrahtes und Positionierung des zentralen Venenkatheters : Eine prospektive Beobachtungsstudie.

BACKGROUND: After insertion of a central venous catheter (CVC) the catheter position must be controlled and a pneumothorax ruled out. OBJECTIVE: The aim was to examine whether the use of two standard acoustic windows known from emergency sonography examination techniques is feasible to 1) verify the correct intravenous localization and direction of the guidewire before final CVC insertion and 2) correctly predict the required CVC length for positioning of the catheter tip in the lower third of the superior vena cava. MATERIAL AND METHODS: This single center prospective observational study included adult patients (age ≥18 years) with an indication for CVC insertion after institutional ethics approval was obtained. Puncture sites were restricted to bilateral internal jugular and subclavian veins and except for duplicate examinations no further exclusion criteria were defined. After vessel puncture and insertion of the guidewire, the vena cava was displayed by an additional ultrasound examiner (sector scanner 1.5-3.6 MHz) using the transhepatic or subcostal acoustic window to localize the guidewire. For positioning of the CVC tip, the required catheter length in relation to the cavoatrial junction was measured using the guidewire marks during slow retraction and consecutive disappearance of the J­shaped guidewire tip from each acoustic window. From the resulting insertion length of the guidewire 4 cm was subtracted for the transhepatic and 2 cm for the subcostal window under the assumption that this length correlates to the distance from the cavoatrial junction. The CVC was finally inserted and a chest radiograph was performed for radiological verification of the CVC position. RESULTS: Of 100 included patients, 94 could finally be analyzed. The guidewire could be identified in the vena cava in 91 patients (97%) within a time period of 2.2 ± 1.9 min. In three patients, the wire could not be visualized, although two catheters had the correct position, while one catheter was incorrectly positioned in the opposite axillary vein. In the second study part, positioning of the CVC was evaluated in 44 of the 94 patients. In 5 of these 44 patients, the correct direction and disappearance of the guidewire from the acoustic window could also be reliably visualized; however, with the left subclavian vein as the puncture site, the respective catheters were up to 6 cm too short for correct positioning. Thus, these 5 patients were excluded from this analysis. In the remaining 39 patients, the position of the CVC tip was optimally located in the lower third of the superior vena cava according to the chest radiograph in 20 patients (51%), while it was relatively too high in 5 patients (13%) and too low (entrance of the right atrium) in 9 patients. In the other 5 patients, disappearance of the guidewire from the acoustic window was not definitely detectable. CONCLUSION: The presented intraprocedural ultrasound-based method using two standard acoustic windows is reliable for verification of the correct intravenous location and direction of the guidewire even before dilatation of the vessel puncture site for insertion of the catheter. Furthermore, the method allows the clinically acceptable measurement of the required length for catheter positioning. A chest radiograph can be waived provided the ultrasound examination (identification of the guidewire and exclusion of puncture-related complications such as pneumothorax) is unambiguous.

The impact of painful knee osteoarthritis on mortality: a community-based cohort study with over 24 years of follow-up.

OBJECTIVE: To investigate the impact of knee osteoarthritis (OA) and/or knee pain on excess mortality. METHOD: We analyzed data from 4,182 participants in a community-based prospective cohort study of African American and Caucasian men and women aged ≥45 years. Participants completed knee radiographs and questionnaires at baseline and at up to three follow-ups to determine knee OA (rOA), knee pain and covariate status. Mortality was determined through 2015. We used Cox proportional hazards regression with time-varying covariates (TVC) to estimate hazard ratios (HR) and 95% confidence intervals (CI). Additional analyses stratified by sex, race and age were carried out. RESULTS: Median follow-up time was 14.6 years during which 1822 deaths occurred. Baseline knee radiographic osteoarthritis (rOA) was 27.7%, 38.8% at first follow-up, 52.6% at second follow-up and 61.9% at the third follow-up. Knee rOA with pain and knee pain alone were both associated with a >15% increase in premature all-cause mortality. In analyses stratified by sex, race and age, associations between knee pain, with or without knee rOA, and all-cause death were found among women, Caucasians, those ≤65 years of age, and those with a body mass index (BMI)≥30, with observed increased risks of death between 21% and 65%. We observed similar, somewhat attenuated, results for cardiovascular disease (CVD) deaths. CONCLUSION: In models taking into account variables that change over time, individuals who had knee pain, alone or with knee rOA, had increased mortality. These effects were particularly strong among those obese. Effective interventions to reduce knee pain, particularly those including weight management and prevention of comorbidities, could reduce mortality.

[Perioperative myocardial ischemia : Current aspects and concepts]. / Perioperative Myokardischämie : Aktuelle Aspekte und Konzepte.

In the future an increasing number of older patients with significant comorbidities will have to undergo major surgical procedures. Perioperative cardiovascular events account for many major complications and even fatalities. While perioperative myocardial infarction (PMI) is a generally well-known and recognized complication, the less severe myocardial injury after non-cardiac surgery (MINS) has not gained widespread scientific attention until recently; however, two large observational trials (VISION 1 and VISION 2) have shown a significantly increased mortality after MINS with even subtle increases in troponin T being associated with an increased risk of death. This review summarizes the current knowledge pertaining to PMI and MINS and proposes a diagnostic and therapeutic framework for optimally guiding patients at risk through the perioperative period.

Population-based prevalence of multiple radiographically-defined hip morphologies: the Johnston County Osteoarthritis Project.

OBJECTIVE: To provide the first prevalence estimates of different radiographic hip morphologies relevant to dysplasia and femoroacetabular impingement in a well-characterized USA population-based cohort. METHODS: Cross-sectional data were from the baseline examination (1991-1997) of a large population-based prospective longitudinal cohort study (The Johnston County Osteoarthritis Project). HipMorf software (Oxford, UK) was used to assess hip morphology on anteroposterior (AP) pelvis radiographs. Weighted, sex-stratified prevalence estimates and 95% confidence intervals for four key hip morphologies (AP alpha angle, triangular index sign, lateral center edge angle (LCEA), and protrusio acetabula) were derived and further stratified by age, race and body mass index (BMI). RESULTS: A total of 5192 hips from 2596 individuals were included (31% African American, 43% male, mean age 63 years, mean BMI 29 kg/m2). Cam morphology was seen in more than 25% of men and 10% of women. Mild dysplasia was present in about 1/3 of men and women, while pincer morphology was identified in 7% of men and 10% of women. Femoral side (cam) morphologies were more common and more frequently bilateral among men, while pincer morphologies were more common in women; mixed morphologies were infrequent. African-Americans were more likely to have protrusio acetabula than whites. CONCLUSION: We report the first population-based prevalence estimates of radiographic hip morphologies relevant to femoroacetabular impingement (FAI) and dysplasia in the USA. These morphologies are very common, with » men and 1/10 women having cam morphology, 1/3 of all adults having mild dysplasia, and 1/15 men and 1/10 women having pincer morphology in at least one hip.

Associations between the chemokine biomarker CCL2 and knee osteoarthritis outcomes: the Johnston County Osteoarthritis Project.

OBJECTIVE: Our study analyzes the association between chemokine-ligand-2 (CCL2) serum concentrations at baseline and knee radiographic osteoarthritis (OA) (knee-rOA), knee-rOA progression, individual radiographic features and knee symptomatic OA at 5-year follow-up. DESIGN: OA outcomes were analyzed in a community-based cohort including a baseline enrollment and a 5-year follow-up. Baseline CCL2 serum concentrations were assessed by multiplex assay and associated with presence or progression of individual radiographic features at 5-year follow-up. Separate multiple logistic regression models were used to examine adjusted associations between baseline CCL2 and each of the knee OA variables at follow-up. CCL2 at baseline was modeled as an explanatory variable, whereas each of the knee OA variables at follow-up served as the response variables. Models were adjusted for age, BMI, race, and sex. Trend tests were conducted to assess any linear effect on outcomes across CCL2 tertiles. RESULTS: Participants (n = 168) had a median age of 57-years and median BMI of 29 kg/m2. About 63% of all participants were women, and 58% Caucasian (42% African American). In adjusted logistic models, continuous log-CCL2 was significantly associated with knee-rOA. For each unit increase in log CCL2, the odds of having knee-rOA at follow-up was increased by 72%. CCL2 tertiles showed significant linear associations with presence and progression of knee-rOA and medial joint space narrowing (JSN), but not with presence or progression of osteophytes, bone sclerosis, knee symptoms, or symptomatic knee-rOA. CONCLUSIONS: Serum CCL2 may help to elucidate some mechanisms of joint destruction and identify individuals with higher odds of structural knee changes.

Biomarkers reflect differences in osteoarthritis phenotypes of the lumbar spine: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine differences in biomarker levels between radiographic phenotypes of facet joint osteoarthritis (FOA) only, spine OA only ((disc space narrowing (DSN) and vertebral osteophytes (OST)) or the combination of FOA and spine OA. DESIGN: A cross-sectional analysis of data from 555 participants in the Johnston County Osteoarthritis Project was performed. Lumbar spine levels were graded by severity (OST and DSN) and presence (FOA) of degeneration. Biomarkers included hyaluronan (HA) and type II collagen (CTX-II). Adjusted risk ratios (aRRR) were estimated using multinomial regression, with adjustment for age, race, sex, body mass index (BMI), and radiographic OA (knee, hip, hand). Interactions were tested between sex, race and low back symptoms. RESULTS: FOA only was present in 22.4%, 14.5% had spine OA only, and 34.6% had the combination of FOA and spine OA. Compared to the reference group of neither FOA or spine OA, a one unit higher ln HA level was associated with 31% higher relative risk ratio (RRR = 1.31 (95% 1.03, 1.67)) of having FOA only, while, a one unit higher lnuCTX-II level was associated with 84% higher relative risk ratio (RRR = 1.84 (95% CI 1.19, 2.84)) of having spine OA only. No significant interactions were identified. CONCLUSION: Interestingly, OA affecting the synovial facet joint was associated with a marker of inflammation (HA). Spine OA, affecting intervertebral discs that contain collagen type II, was associated with a marker reflecting collagen type II degradation (CTX-II). These findings suggest that biomarkers may reflect the different pathophysiologic processes of lumbar spine OA phenotypes.

Non-invasive assessment of fluid responsiveness using CNAP™ technology is interchangeable with invasive arterial measurements during major open abdominal surgery.

BACKGROUND: Dynamic variables of fluid responsiveness (FR), such as pulse pressure variation (PPV), have been shown to predict the response to a fluid challenge accurately. A recently introduced non-invasive technology based on the volume-clamp method (CNAP™) offers the ability to measure PPV continuously (PPVCNAP). However, the accuracy regarding the prediction of FR in the operating room has to be proved. METHODS: We compared PPVCNAP with an invasive approach measuring PPV using the PiCCO technology (PPVPiCCO). We studied 47 patients undergoing major open abdominal surgery before and after a passive leg-raising manoeuvre and i.v. fluid resuscitation. A positive response to a volume challenge was defined as ≥15% increase in stroke volume index obtained with transpulmonary thermodilution. Bootstrap methodology was used with the grey zone approach to determine the area of inconsistency regarding the ability of PPVPiCCO and PPVCNAP to predict FR. RESULTS: In response to the passive leg-raising manoeuvre, PPVPiCCO predicted FR with a sensitivity of 81% and a specificity of 72% [area under the curve (AUC) 0.86] compared with a sensitivity of 76% and a specificity of 72% (AUC 0.78) for PPVCNAP Regarding the volume challenge in the operating room, PPVPiCCO predicted FR with a sensitivity of 87% and a specificity of 100% (AUC 0.97) compared with a sensitivity of 91% and specificity of 93% (AUC 0.97) for PPVCNAP The grey zone approach identified a range of PPVPiCCO values (11-13%) and PPVCNAP values (7-11%) for which FR could not be predicted reliably. CONCLUSIONS: Non-invasive assessment of FR using PPVCNAP seems to be interchangeable with PPVPiCCO in patients undergoing major open abdominal surgery. CLINICAL TRIAL REGISTRATION: NCT02166580.

Novel statistical methodology reveals that hip shape is associated with incident radiographic hip osteoarthritis among African American women.

INTRODUCTION: Hip shape is a risk factor for the development of hip osteoarthritis (OA), and current methods to assess hip shape from radiographs are limited; therefore this study explored current and novel methods to assess hip shape. METHODS: Data from a prior case-control study nested in the Johnston County OA Project were used, including 382 hips (from 342 individuals). Hips were classified by radiographic hip OA (RHOA) status as RHOA cases (baseline Kellgren Lawrence grade [KLG] 0 or 1, follow-up [mean 6 years] KLG ≥ 2) or controls (KLG = 0 or 1 at both baseline and follow-up). Proximal femur shape was assessed using a 60-point model as previously described. The current analysis explored commonly used principal component analysis (PCA), as well as novel statistical methodologies suited to high dimension low sample size settings (Distance Weighted Discrimination [DWD] and Distance Projection Permutation [DiProPerm] hypothesis testing) to assess differences between cases and controls. RESULTS: Using these novel methodologies, we were able to better characterize morphologic differences by sex and race. In particular, the proximal femurs of African American women demonstrated significantly different shapes between cases and controls, implying an important role for sex and race in the development of RHOA. Notably, discrimination was improved with the use of DWD and DiProPerm compared to PCA. CONCLUSIONS: DWD with DiProPerm significance testing provides improved discrimination of variation in hip morphology between groups, and enables subgroup analyses even under small sample sizes.

Annual incidence rates of hip symptoms and three hip OA outcomes from a U.S. population-based cohort study: the Johnston County Osteoarthritis Project.

OBJECTIVE: Estimate annual incidence rates (IRs) of hip symptoms and three osteoarthritis (OA) outcomes (radiographic, symptomatic, and severe radiographic) overall and by race, sociodemographic characteristics, and hip OA risk factors. DESIGN: Analyze baseline (1991-1997) and first follow-up (1999-2003) data (n = 1446) from the Johnston County Osteoarthritis Project, a population-based, prospective study of adults ≥45 years in North Carolina. Hip symptoms were pain, aching, and/or stiffness on most days, or groin pain. Radiographic and severe radiographic OA were Kellgren-Lawrence (KL) grades ≥2 and ≥3, respectively. Symptomatic OA was radiographic OA with symptoms in the same hip. Sociodemographics were age, gender, race, highest attained education, and annual household income. Hip OA risk factors were self-reported body mass index (BMI) at age 18 years, clinically measured BMI at baseline, and history of hip injury. RESULTS: Annual IRs (median = 5.5 years follow-up) were 37, 23, 13, and 2.9 per 1000 person-years for hip symptoms, and radiographic, symptomatic, and severe radiographic hip OA, respectively. We found low IRs of radiographic and symptomatic hip OA among African Americans and high IRs of hip symptoms among the obese and the very poor. Across outcomes, IRs were highest for those with hip injury. CONCLUSION: No prior studies have reported IRs of hip symptoms; IRs of radiographic and severe radiographic hip OA were similar to, and the IR of symptomatic hip OA was higher than, previous estimates. Prevention efforts should target low socioeconomic status (SES) populations and obese adults; interventions for hip OA and hip symptoms are imperative for those with hip injuries.

Measures of hip morphology are related to development of worsening radiographic hip osteoarthritis over 6 to 13 year follow-up: the Johnston County Osteoarthritis Project.

OBJECTIVES: We sought to describe the effect of alterations in hip morphology with respect to worsening hip OA in a community-based sample including African American (AA) and white men and women. METHODS: This nested case-control study defined case hips as Kellgren Lawrence grade (KLG) <3 on baseline supine pelvis radiographs and KLG ≥3 or THR for OA at the 1st or 2nd follow-up visit (mean 6 and 13 years, respectively); control hips had KLG <3 at both visits, with gender/race distribution similar to cases. Hip morphology was assessed using HipMorf software (Oxford, UK). Descriptive means and standard errors were obtained from generalized estimating equation (GEE) models. Sex-stratified GEE regression models (accounting for within-person correlation), adjusted for age, race, BMI, and side were then employed. RESULTS: A total of 120 individuals (239 hips; 71 case/168 control) were included (25% male, 26% AA, mean age 62 years, BMI 30 kg/m(2)). Case hips tended to have greater baseline AP alpha angles, smaller minimum joint space width (mJSW) and more frequent triangular index signs. Adjusted results among men revealed that higher AP alpha angle, Gosvig ratio, and acetabular index were positively associated with case hips; coxa profunda was negatively associated. Among women, greater AP alpha angle, smaller mJSW, protrusio acetabuli, and triangular index sign were associated with case hips. CONCLUSIONS: We confirmed an increased risk of worsening hip OA due to baseline features of cam deformity among men and women, as well as protrusio acetabuli among women, and provide the first estimates of these measures in AAs.

Atlas of radiographic features of osteoarthritis of the ankle and hindfoot.

OBJECTIVE: To develop a radiographic atlas of osteoarthritis (OA) for use as a template and guide for standardized scoring of radiographic features of OA of the ankle and hindfoot joints. METHOD: Under Institutional Review Board approval, ankle and hindfoot images were selected from a cohort study and from among cases that underwent ankle radiography during a 6-month period at Duke University Medical Center. Missing OA pathology was obtained through supplementation of cases with the assistance of a foot and ankle specialist in Orthopaedic surgery and a musculoskeletal radiologist. Images were obtained and reviewed without patient identifying information. Images went through multiple rounds of review and final images were selected by consensus of the study team. For intra-rater and inter-rater reliability, the kappa statistic was calculated for two readings by three musculoskeletal radiologists, a minimum of two weeks apart, of ankle and hindfoot radiographs from 30 anonymized subjects. RESULTS: The atlas demonstrates individual radiographic features (osteophyte and joint space narrowing (JSN)) and Kellgren-Lawrence grade for all aspects of the talocrural (ankle joint proper) and talocalcaneal (subtalar) joints. Reliability of scoring based on the atlas was quite good to excellent for most features indicated. Additional examples of ankle joint findings are illustrated including sclerosis, os trigonum, subchondral cysts and talar tilt. CONCLUSIONS: It is anticipated that this atlas will assist with standardization of scoring of ankle and hindfoot OA by basic and clinical OA researchers.

Radiographic features of hand osteoarthritis in adult Kashin-Beck Disease (KBD): the Yongshou KBD study.

OBJECTIVE: Kashin-Beck Disease (KBD) is a rare and severe osteoarthropathy endemic to China. We evaluated the frequency and patterns of hand radiographic osteoarthritis (rOA) in adults with and without KBD. METHODS: Han Chinese (N = 438) from Yongshou County of central China underwent right hand radiography for determining case status. Presence of KBD was based on characteristic radiographic deformities of articular ends of bones including articular surface depression, carpal crowding, any subchondral bone deformities in the proximal end of phalanges or first metacarpal bone, or the distal ends of metacarpal bones 2-5, and any bony enlargement with deformity of the distal ends of phalanges. Hand rOA severity was determined by osteophyte (OST), joint space narrowing (JSN), and Kellgren and Lawrence (KL) grades. RESULTS: This study included 127 KBD and 311 non-KBD adults of similar mean age (39 years) and body mass index (BMI) (21 kg/m(2)). Inter- and intra-rater reliability for radiographic determination of case status and rOA features was high (kappa 0.72-0.96). Compared to non-KBD, KBD adults had significantly more severe hand rOA of the thumb, distal interphalangeal (DIP), proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints. Only KBD adults had end-stage carpometacapal (CMC) disease. In KBD, DIPs and PIPs were more affected than MCPs and the frequency of OSTs was significantly higher in PIPs than DIPs. CONCLUSIONS: Compared with age-matched adults from the same area and farming occupation, KBD hand rOA was more widespread and severe, particularly of PIPs and CMCs. The ability to differentiate adult KBD from non-KBD hand rOA will facilitate genetic analyses of the vast majority of affected individuals.

Postural hypotension in type 1 diabetes: the influence of glycemic control and duration of illness.

BACKGROUND: Postural hypotension (PH) indicates the presence of cardiac autonomic neuropathy and in diabetes mellitus (DM) is associated with adverse outcome. Nonetheless, PH has been rarely characterized in young persons in Sub-saharan Africa where suboptimal care of DM is prevalent. AIMS: The aim of the study was to determine the prevalence of PH in young patients with type 1DM and its relationship with the duration of DM and glycemic control. SETTINGS AND DESIGN: It was a cross-sectional, case control study carried out in the pediatric out-patient clinic. MATERIALS AND METHODS: Each study participant had blood pressure (BP) measured in the supine and standing positions. Glycated hemoglobin (HbA1c) levels were determined and disease duration was documented. STATISTICAL ANALYSIS: The mean BP in the different positions was determined. The occurrence of PH, duration of disease and HbA1c levels was determined with logistic regression analysis. RESULTS: A total of 26 diabetic subjects and 26 age and sex matched controls were studied. 12 (46.2%) diabetic subjects had evidence of PH while none of the controls had PH. Diabetic subjects with PH had significantly longer duration of DM than those diabetics without PH (6.79 ± 4.81 vs. 2.83 ± 2.36, P = 0.023). The mean HbA1c level was similar in both groups of diabetic subjects (9.79 ± 2.07 vs. 9.17 ± 2.35). On logistic regression, age, duration of disease, HbA1c level and body mass index were not significant predictors of PH. CONCLUSION: PH is common in young persons with type 1 DM, with higher frequency in those with long standing disease.

High prevalence of contralateral ankle abnormalities in association with knee osteoarthritis and malalignment.

OBJECTIVE: To evaluate ankle joint abnormalities in a knee osteoarthritis (OA) cohort. METHODS: Participants (n = 159) with symptomatic and radiographic OA in at least one knee underwent technetium-99m methylene diphosphonate bone scan (scored 0-3) of the ankles and forefeet. Knee radiographs were graded for OA features of joint space narrowing (JSN) and osteophyte (OST). Ankle symptoms and history of ankle injury were assessed by self-report. Knee alignment was measured from a long-limb radiograph. Ankle radiographs were obtained on those who returned for follow-up (n = 138) and were graded for ankle tibiotalar JSN and OST. DESIGN: Ankle scintigraphic abnormalities were frequent (31% of individuals, one-third bilateral). Ankle symptoms were reported by 23% of individuals and history of ankle injury by 24%. Controlling for gender, age, body mass index (BMI), and contralateral predictor, ankle scintigraphic abnormalities were associated with: ipsilateral ankle symptoms (P = 0.005); contralateral knee JSN (P = 0.001), knee OST (P = 0.006) and knee malalignment (P = 0.08); and history of ankle injury or surgery of either ankle (P < 0.0001). At follow-up, scintigraphic abnormalities of the ankle were strongly associated with presence of tibiotalar radiographic OA (P < 0.0001). CONCLUSIONS: Although considered rare, we observed a high prevalence of radiographic features of ankle OA in this knee OA cohort. History of overt ankle injury did not appear to account for the majority of ankle abnormalities. These results are consistent with a probable kinematic association of knee OA pathology and contralateral ankle abnormalities and suggest that interventions targeting mechanical factors may be needed to prevent ankle OA in the setting of knee OA.

IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort.

OBJECTIVE: Within the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time. DESIGN: 1153 Caucasian adults (age range: 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective. RESULTS: Of 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression [odds ratio (OR) 1.91 (95%CI 1.16-3.15); P = 0.012]. Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype. CONCLUSION: A significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development.

Association between serum and urine biomarkers and lumbar spine individual radiographic features: the Johnston County Osteoarthritis Project.

OBJECTIVE: (1) To determine associations between radiographic features of lumbosacral (LS) spine disc space narrowing (DSN) and osteophytes (OST) and joint metabolism biomarkers (serum cartilage oligomeric matrix protein (COMP), hyaluronic acid (HA), collagen neoepitope (C2C), C-propeptide of type II procollagen (CP-II), urine C-terminal cross-linking telopeptide (CTX-II) and N-terminal telopeptide (NTX-I)). (2) To explore interactions with race, gender and low back symptoms. DESIGN: Cross-sectional analysis of 547 participants enrolled in the Johnston County (JoCo) Osteoarthritis Project from 2003 to 2004. Mean biomarker levels were estimated with linear regression. Proportional and partial-proportional odds models were used to estimate associations. Interactions were tested with likelihood ratio tests at a P-value < 0.10. Biomarkers were natural log (ln) transformed. RESULTS: Significant differences in mean biomarker levels were found across severity of DSN for lnHA and lnC2C and lnCTX-II across severity of both DSN and OST. Moderate-to-strong associations were found between biomarkers of type II collagen and DSN, whereas associations with OST were weak. An association between lnHA and DSN was seen in women (adjusted odds ratio [aOR] = 1.34 (95% confidence intervals (CI) 1.08, 1.65)) but no association among men (aOR = 0.90 (95% CI 0.63, 1.26)). In Caucasians there was a decreased association with NTX-I and OST (aOR = 0.67 (95% CI 0.49, 0.91)) and no association in African Americans (AAs) (aOR = 1.06 (95% CI 0.76, 1.47)). There was a positive association of lnCOMP with DSN among those with low back symptoms (aOR = 1.82 (95% CI 1.02, 3.27)), but no association in those without low back symptoms (aOR = 0.65 (95% CI 0.35, 1.20)). CONCLUSION: Joint metabolism biomarkers suggest biological differences in the pathologic process involved in DSN and OST that may be gender (HA) and ethnicity (NTX-I) specific.