Clinical indications and protocol considerations for selecting initial body weight support levels in gait rehabilitation: a systematic review.

BACKGROUND: Body weight support (BWS) training devices are frequently used to improve gait in individuals with neurological impairments, but guidance in selecting an appropriate level of BWS is limited. Here, we aim to describe the initial BWS levels used during gait training, the rationale for this selection and the clinical goals aligned with BWS training for different diagnoses. METHOD: A systematic literature search was conducted in PubMed, Embase and Web of Science, including terms related to the population (individuals with neurological disorders), intervention (BWS training) and outcome (gait). Information on patient characteristics, type of BWS device, BWS level and training goals was extracted from the included articles. RESULTS: Thirty-three articles were included, which described outcomes using frame-based (stationary or mobile) and unidirectional ceiling-mounted devices on four diagnoses (multiple sclerosis (MS), spinal cord injury (SCI), stroke, traumatic brain injury (TBI)). The BWS levels were highest for individuals with MS (median: 75%, IQR: 6%), followed by SCI (median: 40%, IQR: 35%), stroke (median: 30%, IQR: 4.75%) and TBI (median: 15%, IQR: 0%). The included studies reported eleven different training goals. Reported BWS levels ranged between 30 and 75% for most of the training goals, without a clear relationship between BWS level, diagnosis, training goal and rationale for BWS selection. Training goals were achieved in all included studies. CONCLUSION: Initial BWS levels differ considerably between studies included in this review. The underlying rationale for these differences was not clearly motivated in the included studies. Variation in study designs and populations does not allow to draw a conclusion on the effectiveness of BWS levels. Hence, it remains difficult to formulate guidelines on optimal BWS settings for different diagnoses, BWS devices and training goals. Further efforts are required to establish clinical guidelines and to experimentally investigate which initial BWS levels are optimal for specific diagnoses and training goals.

Notes on the margin of stability.

The concept of the 'extrapolated center of mass (XcoM)', introduced by Hof et al., (2005, J. Biomechanics 38 (1), p. 1-8), extends the classical inverted pendulum model to dynamic situations. The vector quantity XcoM combines the center of mass position plus its velocity divided by the pendulum eigenfrequency. In this concept, the margin of stability (MoS), i.e., the minimum signed distance from the XcoM to the boundaries of the base of support was proposed as a measure of dynamic stability. Here we describe the conceptual evolution of the XcoM, discuss key considerations in the estimation of the XcoM and MoS, and provide a critical perspective on the interpretation of the MoS as a measure of instantaneous mechanical stability.

The effect of walking with reduced trunk motion on dynamic stability in healthy adults.

BACKGROUND: Most people with Parkinson's disease (PD) walk with a smaller mediolateral base of support (BoS) compared to healthy people, but the underlying mechanisms remain unknown. Reduced trunk motion in people with PD might be related to this narrow-based gait. Here, we study the relationship between trunk motion and narrow-based gait in healthy adults. According to the extrapolated center of mass (XCoM) concept, a decrease in mediolateral XCoM excursion would require a smaller mediolateral BoS to maintain a constant margin of stability (MoS) and remain stable. RESEARCH QUESTION: As proof of principle, we assessed whether walking with reduced trunk motion results in a smaller step width in healthy adults, without altering the mediolateral MoS. METHODS: Fifteen healthy adults walked on a treadmill at preferred comfortable walking speed in two conditions. First, the 'regular walking' condition without any instructions, and second, the 'reduced trunk motion' condition with the instruction: 'Keep your trunk as still as possible'. Treadmill speed was kept the same in the two conditions. Trunk kinematics, step width, mediolateral XCoM excursion and mediolateral MoS were calculated and compared between the two conditions. RESULTS: Walking with the instruction to keep the trunk still significantly reduced trunk kinematics. Walking with reduced trunk motion resulted in significant decreases in step width and mediolateral XCoM excursion, but not in the mediolateral MoS. Furthermore, step width and mediolateral XCoM excursion were strongly correlated during both conditions (r = 0.887 and r = 0.934). SIGNIFICANCE: This study shows that walking with reduced trunk motion leads to a gait pattern with a smaller BoS in healthy adults, without altering the mediolateral MoS. Our findings indicate a strong coupling between CoM motion state and the mediolateral BoS. We expect that people with PD who walk narrow-based, have a similar mediolateral MoS as healthy people, which will be further investigated.

Comparison of ground reaction force and marker-based methods to estimate mediolateral center of mass displacement and margins of stability during walking.

Dynamic balance control during human walking can be described by the distance between the mediolateral (ML) extrapolated center of mass (XCoM) position and the base of support, the margin of stability (MoS). The ML center of mass (CoM) position during treadmill walking can be estimated based on kinematic data (marker-based method) and a combination of ground reaction forces and center of pressure positions (GRF-based method). Here, we compare a GRF-based method with a full-body marker-based method for estimating the ML CoM, ML XCoM and ML MoS. Fifteen healthy adults walked on a dual-belt treadmill at comfortable walking speed for three minutes. Kinetic and kinematic data were collected and analyzed using a GRF-based and marker-based method to compare the ML CoM, ML XCoM and ML MoS. High correlation coefficients (r > 0.98) and small differences (Root Mean Square Difference < 0.0072 m) in ML CoM and ML XCoM were found between the GRF-based and marker-based methods. The GRF-based method resulted in larger ML XCoM excursion (0.0118 ± 0.0074 m) and smaller ML MoS values (0.0062 ± 0.0028 m) than the marker-based method, but these differences were consistent across participants. In conclusion, the GRF-based method is a valid method to determine the ML CoM, XCoM and MoS. One should be aware of higher ML XCoM and smaller ML MoS values in the GRF-based method when comparing absolute values between studies. The GRF-based method strongly reduces measurement times and can be used to provide real-time CoM-CoP feedback during treadmill gait training.

Split-belt walking: An experience that is hard to forget.

BACKGROUND: The common paradigm to study the adaptability of human gait is split-belt walking. Short-term savings (minutes to days) of split-belt adaptation have been widely studied to gain knowledge in locomotor learning but reports on long-term savings are limited. Here, we studied whether after a prolonged inter-exposure interval (three weeks), the newly acquired locomotor pattern is subject to forgetting or that the pattern is saved in long-term locomotor memory. RESEARCH QUESTION: Can savings of adaptation to split-belt walking remain after a prolonged inter-exposure interval of three weeks? METHODS: Fourteen healthy adults participated in a single ten-minute adaptation session to split-belt walking and five-minute washout to tied-belt walking. They received no training after the first exposure and returned to the laboratory exactly three weeks later for the second exposure. To identify the adaptation trends and quantify saving parameters we used Singular Spectrum Analysis, a non-parametric, data-driven approach. We identified trends in step length asymmetry and double support asymmetry, and calculated the adaptation volume (reduction in asymmetry over the course of adaptation), and the plateau time (time required for the trend to level off). RESULTS: At the second exposure after three weeks, we found substantial savings in adaptation for step length asymmetry volume (61.6-67.6% decrease) and plateau time (76.3 % decrease). No differences were found during washout or in double support asymmetry. SIGNIFICANCE: This study shows that able-bodied individuals retain savings of split-belt adaptation over a three-week period, which indicates that only naïve split-belt walkers should be included in split-belt adaptation studies, as previous experience to split-belt walking will not be washed out, even after a prolonged period. In future research, these results can be compared with long-term savings in patient groups, to gain insight into factors underlying (un)successful gait training in rehabilitation.

Trial protocol for COLO-DETECT: A randomized controlled trial of lesion detection comparing colonoscopy assisted by the GI Genius™ artificial intelligence endoscopy module with standard colonoscopy.

AIM: Colorectal cancer is the second commonest cause of cancer death worldwide. Colonoscopy plays a key role in the control of colorectal cancer and, in that regard, maximizing detection (and removal) of pre-cancerous adenomas at colonoscopy is imperative. GI Genius™ (Medtronic Ltd) is a computer-aided detection system that integrates with existing endoscopy systems and improves adenoma detection during colonoscopy. COLO-DETECT aims to assess the clinical and cost effectiveness of GI Genius™ in UK routine colonoscopy practice. METHODS AND ANALYSIS: Participants will be recruited from patients attending for colonoscopy at National Health Service sites in England, for clinical symptoms, surveillance or within the national Bowel Cancer Screening Programme. Randomization will involve a 1:1 allocation ratio (GI Genius™-assisted colonoscopy:standard colonoscopy) and will be stratified by age category (<60 years, 60-<74 years, ≥74 years), sex, hospital site and indication for colonoscopy. Demographic data, procedural data, histology and post-procedure patient experience and quality of life will be recorded. COLO-DETECT is designed and powered to detect clinically meaningful differences in mean adenomas per procedure and adenoma detection rate between GI Genius™-assisted colonoscopy and standard colonoscopy groups. The study will close when 1828 participants have had a complete colonoscopy. An economic evaluation will be conducted from the perspective of the National Health Service. A patient and public representative is contributing to all stages of the trial. Registered at ClinicalTrials.gov (NCT04723758) and ISRCTN (10451355). WHAT WILL THIS TRIAL ADD TO THE LITERATURE?: COLO-DETECT will be the first multi-centre randomized controlled trial evaluating GI Genius™ in real world colonoscopy practice and will, uniquely, evaluate both clinical and cost effectiveness.

The relationship between the anteroposterior and mediolateral margins of stability in able-bodied human walking.

BACKGROUND: Control of dynamic balance in human walking is essential to remain stable and can be parameterized by the margins of stability. While frontal and sagittal plane margins of stability are often studied in parallel, they may covary, where increased stability in one plane could lead to decreased stability in the other. Hypothetically, this negative covariation may lead to critically low lateral stability during step lengthening. RESEARCH QUESTION: Is there a relationship between frontal and sagittal plane margins of stability in able-bodied humans, during normal walking and imposed step lengthening? METHODS: Fifteen able-bodied adults walked on an instrumented treadmill in a normal walking and a step lengthening condition. During step lengthening, stepping targets were projected onto the treadmill in front of the participant to impose longer step lengths. Covariation between frontal and sagittal plane margins of stability was assessed with linear mixed-effects models for normal walking and step lengthening separately. RESULTS: We found a negative covariation between frontal and sagittal plane margins of stability during normal walking, but not during step lengthening. SIGNIFICANCE: These results indicate that while a decrease in anterior instability may lead to a decrease in lateral stability during normal walking, able-bodied humans can prevent lateral instability due to this covariation in critical situations, such as step lengthening. These findings improve our understanding of adaptive dynamic balance control during walking in able-bodied humans and may be utilized in further research on gait stability in pathological and aging populations.

Long-term effects of combined B-cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results.

BACKGROUND: Anti-CD20 B-cell depletion has not shown superior efficacy to standard immunosuppression in patients with systemic lupus erythematosus (SLE). Besides trial design, potential explanations are incomplete B-cell depletion in relation to substantial surges in B-cell-activating factor (BAFF). To improve B-cell targeting strategies, we conducted the first study in SLE patients aimed at investigating immunological effects and feasibility of combining rituximab (RTX; anti-CD20) and belimumab (BLM; anti-BAFF). METHODS: Reported is the long-term follow-up of a Phase 2 proof-of-concept study in 15 patients with SLE including 12 (80%) with lupus nephritis (LN). RESULTS: In 10/15 (67%) patients, a clinical response was observed by achievement of lupus low disease activity state, of which 8 (53%) continued treatment (BLM + ≤7.5 mg prednisolone) for the complete 2 years of follow-up. Five patients (33%) were referred to as 'non-responders' due to persistent LN, major flare or repetitive minor flares. Out of 12 LN patients, 9 (75%) showed a renal response including 8 (67%) complete renal responders. All anti-dsDNA+ patients converted to negative, and both anti-C1q and extractable nuclear antigen autoantibodies showed significant reductions. CD19+ B cells showed a median decrease from baseline of 97% at 24 weeks, with a persistent reduction of 84% up to 104 weeks. When comparing responders with non-responders, CD20+ B cells were depleted significantly less in non-responders and double-negative (DN) B cells repopulated significantly earlier. CONCLUSIONS: Combined B-cell targeted therapy with RTX and BLM prevented full B-cell repopulation including DN B cells, with concomitant specific reduction of SLE-relevant autoantibodies. The observed immunological and clinical benefits in a therapy-refractory SLE population prompt further studies on RTX + BLM.

Maintaining sagittal plane balance compromises frontal plane balance during reactive stepping in people post-stroke.

BACKGROUND: Maintaining balance in response to perturbations during walking often requires the use of corrective responses to keep the center of mass within the base of support. The relationship between the center of mass and base of support is often quantified using the margin of stability. Although people post-stroke increase the margin of stability following perturbations, control deficits may lead to asymmetries in regulation of margins of stability, which may also cause maladaptive coupling between the sagittal and frontal planes during balance-correcting responses. METHODS: We assessed how paretic and non-paretic margins of stability are controlled during recovery from forward perturbations and determined how stroke-related impairments influence the coupling between the anteroposterior and mediolateral margins of stability. Twenty-one participants with post-stroke hemiparesis walked on a treadmill while receiving slip-like perturbations on both limbs at foot-strike. We assessed anteroposterior and mediolateral margins of stability before perturbations and during perturbation recovery. FINDINGS: Participants walked with smaller anteroposterior and larger mediolateral margins of stability on the paretic versus non-paretic sides. When responding to perturbations, participants increased the anteroposterior margin of stability bilaterally by extending the base of support and reducing the excursion of the extrapolated center of mass. The anteroposterior and mediolateral margins of stability in the paretic limb negatively covaried during reactive steps such that increases in anteroposterior were associated with reductions in mediolateral margins of stability. INTERPRETATION: Balance training interventions to reduce fall risk post-stroke may benefit from incorporating strategies to reduce maladaptive coupling of frontal and sagittal plane stability.

Adaptive Control of Dynamic Balance across the Adult Lifespan.

INTRODUCTION: The ability to adapt dynamic balance to perturbations during gait deteriorates with age. To prevent age-related decline in adaptive control of dynamic balance, we must first understand how adaptive control of dynamic balance changes across the adult lifespan. We examined how adaptive control of the margin of stability (MoS) changes across the lifespan during perturbed and unperturbed walking on the split-belt treadmill. METHODS: Seventy-five healthy adults (age range, 18-80 yr) walked on an instrumented split-belt treadmill with and without split-belts. Linear regression analyses were performed for the mediolateral (ML) and anteroposterior (AP) MoS, step length, single support time, step width, double support time, and cadence during unperturbed and perturbed walking (split-belt perturbation), with age as predictor. RESULTS: Age did not significantly affect dynamic balance during unperturbed walking. However, during perturbed walking, the ML MoS of the leg on the slow belt increased across the lifespan due to a decrease in bilateral single support time. The AP MoS did not change with aging despite a decrease in step length. Double support time decreased and cadence increased across the lifespan when adapting to split-belt walking. Age did not affect step width. CONCLUSIONS: Aging affects the adaptive control of dynamic balance during perturbed but not unperturbed treadmill walking with controlled walking speed. The ML MoS increased across the lifespan, whereas bilateral single support times decreased. The lack of aging effects on unperturbed walking suggests that participants' balance should be challenged to assess aging effects during gait. The decrease in double support time and increase in cadence suggests that older adults use the increased cadence as a balance control strategy during challenging locomotor tasks.

Bilateral temporal control determines mediolateral margins of stability in symmetric and asymmetric human walking.

Human bipedal gait requires active control of mediolateral dynamic balance to stay upright. The margin of stability is considered a measure of dynamic balance, and larger margins are by many authors assumed to reflect better balance control. The inverted pendulum model of gait indicates that changes in the mediolateral margin of stability are related to changes in bilateral single support times. We propose updated equations for the mediolateral margin of stability in temporally symmetric and asymmetric gait, which now include the single support times of both legs. Based on these equations, we study the relation between bilateral single support times and the mediolateral margin of stability in symmetric, asymmetric, and adaptive human gait. In all conditions, the mediolateral margin of stability during walking followed predictably from bilateral single support times, whereas foot placement co-varied less with the mediolateral margin of stability. Overall, these results demonstrate that the bilateral temporal regulation of gait profoundly affects the mediolateral margin of stability. By exploiting the passive dynamics of bipedal gait, bilateral temporal control may be an efficient mechanism to safeguard dynamic stability during walking, and keep an inherently unstable moving human body upright.

Handrail Holding During Treadmill Walking Reduces Locomotor Learning in Able-Bodied Persons.

Treadmills used for gait training in clinical rehabilitation and experimental settings are commonly fitted with handrails to assist or support persons in locomotor tasks. However, the effects of balance support through handrail holding on locomotor learning are unknown. Locomotor learning can be studied on split-belt treadmills, where participants walk on two parallel belts with asymmetric left and right belt speeds, to which they adapt their stepping pattern within a few minutes. The aim of this study was to determine how handrail holding affects the walking pattern during split-belt adaptation and after-effects in able-bodied persons. Fifty healthy young participants in five experimental groups were instructed to hold handrails, swing arms freely throughout the experiment or hold handrails during adaptation and swing arms freely during after-effects. Step length asymmetry and double support asymmetry were measured to assess the spatiotemporal walking pattern. The results showed that holding handrails during split-belt adaptation reduces magnitude of initial perturbation of step length asymmetry and reduces after-effects in step length asymmetry upon return to symmetric belt speeds. The findings of this study imply that balance support during gait training reduces locomotor learning, which should be considered in daily clinical gait practice and future research on locomotor learning.

Effects of Aging and Task Prioritization on Split-Belt Gait Adaptation.

Background: Age-related changes in the sensorimotor system and cognition affect gait adaptation, especially when locomotion is combined with a cognitive task. Performing a dual-task can shift the focus of attention and thus require task prioritization, especially in older adults. To gain a better understanding of the age-related changes in the sensorimotor system, we examined how age and dual-tasking affect adaptive gait and task prioritization while walking on a split-belt treadmill. Methods: Young (21.5 ± 1.0 years, n = 10) and older adults (67.8 ± 5.8 years, n = 12) walked on a split-belt treadmill with a 2:1 belt speed ratio, with and without a cognitive Auditory Stroop task. Symmetry in step length, limb excursion, and double support time, and strategy variables swing time and swing speed were compared between the tied-belt baseline (BL), early (EA) and late split-belt adaptation (LA), and early tied-belt post-adaptation (EP). Results: Both age groups adapted to split-belt walking by re-establishing symmetry in step length and double support time. However, young and older adults differed on adaptation strategy. Older vs. young adults increased swing speed of the fast leg more during EA and LA (0.10-0.13 m/s), while young vs. older adults increased swing time of the fast leg more (2%). Dual-tasking affected limb excursion symmetry during EP. Cognitive task performance was 5-6% lower during EA compared to BL and LA in both age groups. Older vs. young adults had a lower cognitive task performance (max. 11% during EA). Conclusion: Healthy older adults retain the ability to adapt to split-belt perturbations, but interestingly age affects adaptation strategy during split-belt walking. This age-related change in adaptation strategy possibly reflects a need to increase gait stability to prevent falling. The decline in cognitive task performance during early adaptation suggests task prioritization, especially in older adults. Thus, a challenging motor task, like split-belt adaptation, requires prioritization between the motor and cognitive task to prevent adverse outcomes. This suggests that task prioritization and adaptation strategy should be a focus in fall prevention interventions.

Adaptive control of dynamic balance in human gait on a split-belt treadmill.

Human bipedal gait is inherently unstable, and staying upright requires adaptive control of dynamic balance. Little is known about adaptive control of dynamic balance in reaction to long-term, continuous perturbations. We examined how dynamic balance control adapts to a continuous perturbation in gait, by letting people walk faster with one leg than the other on a treadmill with two belts (i.e. split-belt walking). In addition, we assessed whether changes in mediolateral dynamic balance control coincide with changes in energy use during split-belt adaptation. In 9 min of split-belt gait, mediolateral margins of stability and mediolateral foot roll-off changed during adaptation to the imposed gait asymmetry, especially on the fast side, and returned to baseline during washout. Interestingly, no changes in mediolateral foot placement (i.e. step width) were found during split-belt adaptation. Furthermore, the initial margin of stability and subsequent mediolateral foot roll-off were strongly coupled to maintain mediolateral dynamic balance throughout the gait cycle. Consistent with previous results, net metabolic power was reduced during split-belt adaptation, but changes in mediolateral dynamic balance control were not correlated with the reduction of net metabolic power during split-belt adaptation. Overall, this study has shown that a complementary mechanism of relative foot positioning and mediolateral foot roll-off adapts to continuously imposed gait asymmetry to maintain dynamic balance in human bipedal gait.

The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus.

OBJECTIVE: In systemic lupus erythematosus (SLE) patients, excessive formation of neutrophil extracellular traps (NETs) is observed and their degradation is impaired. In vitro, immune complexes (ICx) trigger NET formation while NET-derived DNA is a postulated autoantigen for anti-nuclear autoantibodies (ANAs), found in SLE. Based on these self-perpetuating mechanisms in SLE, this study investigates whether interfering with ICx formation using a combination of rituximab (RTX) and belimumab (BLM) could decrease NET formation and ameliorate disease. METHODS: A phase 2A, open-label, single arm proof-of-concept study was performed wherein 16 SLE patients with severe, refractory disease were treated with a combination of CD20-mediated B-cell depletion with rituximab and sustained inhibition of B-cell activating factor BlyS with belimumab. Besides safety, the study's endpoints were chosen to address the concept of autoantibodies in relation to excessive NET formation. RESULTS: We demonstrated a surge of BlyS levels upon RTX-mediated B-cell depletion which was abrogated by subsequent BLM treatment. As such, therapeutic intervention with RTX + BLM led to specific reductions in ANAs and regression of excessive NET formation. RTX + BLM appeared to be safe and achieved clinically significant responses: low lupus disease activity state was achieved in 10 patients, renal responses in 11 patients and concomitant immunosuppressive medication was tapered in 14 out of the 16 patients. CONCLUSIONS: This study provides novel insights into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX + BLM. Altogether putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology. TRIAL REGISTRATION: ClinicalTrials.gov NCT02284984.

Synergistic Structure in the Speed Dependent Modulation of Muscle Activity in Human Walking.

Recently, a modular organisation has been proposed to simplify control of the large number of muscles involved in human walking. Although previous research indicates that a single set of modular activation patterns can account for muscle activity at different speeds, these studies only provide indirect evidence for the idea that speed regulation in human walking is under modular control. Here, a more direct approach was taken to assess the synergistic structure that underlies speed regulation, by isolating speed effects through the construction of gain functions that represent the linear relation between speed and amplitude for each point in the time-normalized gait cycle. The activity of 13 muscles in 13 participants was measured at 4 speeds (0.69, 1.00, 1.31, and 1.61 ms(-1)) during treadmill walking. Gain functions were constructed for each of the muscles, and gain functions and the activity patterns at 1.00 ms(-1) were both subjected to dimensionality reduction, to obtain modular gain functions and modular basis functions, respectively. The results showed that 4 components captured most of the variance in the gain functions (74.0% ± 1.3%), suggesting that the neuromuscular regulation of speed is under modular control. Correlations between modular gain functions and modular basis functions (range 0.58-0.89) and the associated synergistic muscle weightings (range 0.6-0.95) were generally high, suggesting substantial overlap in the synergistic control of the basic phasing of muscle activity and its modulation through speed. Finally, the combined set of modular functions and associated weightings were well capable of predicting muscle activity patterns obtained at a speed (1.31 ms(-1)) that was not involved in the initial dimensionality reduction, confirming the robustness of the presently used approach. Taken together, these findings provide direct evidence of synergistic structure in speed regulation, and may inspire further work on flexibility in the modular control of gait.

Update on autoantibodies to modified proteins.

PURPOSE OF REVIEW: This article provides an update on the recent findings on autoantibodies to modified proteins in rheumatoid arthritis (RA). RECENT FINDINGS: In the past few years, the knowledge on the autoantibodies to citrullinated antigens has expanded considerably. More specifically, it is now clear that many different citrullinated protein antigens present in the synovial compartment can be recognized by anticitrullinated protein antibody (ACPA). This is most likely a consequence of the cross-reactivity the ACPA response displays to citrullinated proteins. It is now also clear that the isotype usage and the citrullinated epitope repertoire recognized by ACPA expands before the manifestation of full-blown RA and that this goes hand in hand with a rise in ACPA level. Next to ACPA, several other autoantibody systems directed against other posttranslationally modified proteins, such as proteins containing a homocitrulline residue resulting from protein carbamylation, have been identified. On the whole, the evolution of these autoantibody systems in time mimics the evolution of the ACPA response, indicating that the break of tolerance underlying different autoimmune responses present in RA occurs before disease onset, with a further maturation of these responses shortly before or concurrent with the manifestation of clinical symptoms. SUMMARY: Since the discovery of rheumatoid factor over 65 years ago, our knowledge on autoantibodies and their relevance for rheumatic disease has expanded enormously. Especially, the realization that next to rheumatoid factor, also other autoantibodies recognizing posttranslationally modified proteins are present in RA patients has contributed significantly to the understanding of disease. In the past few years, several new autoantibody systems to differentially modified proteins have been identified and their relation to clinical outcome has been scrutinized. Here, we provide an update on the recent developments in our knowledge on the presence and consequences of autoantibodies to modified proteins in RA.

Fine-mapping the human leukocyte antigen locus in rheumatoid arthritis and other rheumatic diseases: identifying causal amino acid variants?

PURPOSE OF REVIEW: To provide an update on and the context of the recent findings obtained with novel statistical methods on the association of the human leukocyte antigen (HLA) locus with rheumatic diseases. RECENT FINDINGS: Novel single nucleotide polymorphism fine-mapping data obtained for the HLA locus have indicated the strongest association with amino acid positions 11 and 13 of HLA-DRB1 molecule for several rheumatic diseases. On the basis of these data, a dominant role for position 11/13 in driving the association with these diseases is proposed and the identification of causal variants in the HLA region in relation to disease susceptibility implicated. SUMMARY: The HLA class II locus is the most important risk factor for several rheumatic diseases. Recently, new statistical approaches have identified previously unrecognized amino acid positions in the HLA-DR molecule that associate with anticitrullinated protein antibody-negative and anticitrullinated protein antibody-positive rheumatoid arthritis. Likewise, similar findings have been made for other rheumatic conditions such as giant-cell arteritis and systemic lupus erythematosus. Interestingly, all these studies point toward an association with the same amino acid positions: amino acid positions 11 and 13 of the HLA-DR ß chain. As both these positions influence peptide binding by HLA-DR and have been implicated in antigen presentation, the novel fine-mapping approach is proposed to map causal variants in the HLA region relevant to rheumatoid arthritis and several rheumatic diseases. If these interpretations are correct, they would direct the biological research aiming to address the explanation for the HLA-disease association. Here, we provide an overview of the recent findings and evidence from literature that, although relevant new insights have been obtained on HLA-disease associations, the interpretation of the biological role of these amino acids as causal variants explaining that such associations should be taken with caution.

Quantitative echotexture analysis of bovine corpora lutea.

A study was designed to evaluate the attributes of ultrasound images of bovine ovarian CL throughout the estrous cycle. The ovaries of 8 heifers were examined daily by transrectal ultrasonography for 2 interovulatory intervals (ovulation = Day 0). Ultrasonographic examinations of the ovaries were videotaped daily, and recorded images of the CL were digitized for computer analysis of echotexture (mean pixel value and heterogeneity). Blood samples were taken daily and to determine plasma progesterone concentrations. Corpora lutea were of 2 morphological types, those with a central fluid-filled cavity (n = 6) and those without (n = 9). No differences were detected between CL with or without a fluid-filled cavity; therefore, data were combined. Mean pixel values of ultrasound images of the CL changed (P = 0.0001) during the interovulatory interval; values decreased (P < 0.05) from Day 0 to Day 3 during early growth of the CL, reached a plateau when increases in luteal diameter ceased, and decreased (P < 0.05) to minimal levels at the onset of regression of the CL. The mean pixel value subsequently increased (P < 0.05) after Day 17 to values similar to those at the beginning of the interovulatory interval. A time-dependent effect was not observed for heterogeneity of images of the CL (P > 0.5). The results supported the hypothesis that quantitative changes in luteal echotexture are reflective of changes in the physiologic status of the CL.