Identification of α-tubulin as an autoantigen recognized by sera from patients with neuropsychiatric systemic lupus erythematosus

In a previous study we found in 50% of patients with neuropsychiatric manifestations of systemic lupus erythematosus (NP-SLE) organ specific antibodies to 45-56 kD proteins in a 100,000 g supernatant (SN) from bovine brain mitochondria. Aim of the present study was to identify the corresponding target antigen.A 100,000 g SN from bovine brain mitochondria was applied to SDS-gel electrophoresis. A 50 kD band recognized by sera from patients with NP-SLE in the Western blot (WB) was excised from the gels and applied to mass spectrometry. The identified protein was expressed in Escherichia coli and retested against sera from eleven patients with NP-SLE (severe symptoms n = 6, mild symptoms n = 5), 26 SLE-patients without NP manifestations and 53 controls (patients with multiple sclerosis, epilepsy, healthy blood donors).Mass spectrometry of the 50 kD band revealed the presence of α-tubulin. Applying the recombinant α-tubulin in the WB, four of the eleven NP-SLE patients (36%), one of the 26 patients with SLE without NP manifestations (4%) and none of the 53 controls reacted with α-tubulin. The antibodies were more frequently found in patients with severe (50%) than with mild NP-SLE (20%).α-tubulin may be a novel marker autoantigen for a neuropsychiatric manifestation at least in a subgroup of patients with SLE. Whether anti-α-tubulin antibodies are of pathogenetic relevance has still to be clarified.     

Validity of the montreal cognitive assessment (MoCA) as a screening test for mild cognitive impairment (MCI) in a cardiovascular population

While rates of mild cognitive impairment (MCI) are relatively high in populations with cardiovascular diseases and risk factors, screening tests for MCI have not been evaluated in this patient group. This study investigated the sensitivity and specificity of the Montreal Cognitive Assessment (MoCA) tool for detecting MCI in 110 patients (mean age 67.9 + 11.7 years; 60% female) recruited from hospital cardiovascular outpatient clinics. Mean MoCA performance was relatively low (22.8 + 3.8) in this group, with 72.1% of participants scoring below the recommended cutoff for cognitive impairment (<26). The presence of MCI was determined using the Neuropsychological Assessment Battery Screening Module (NAB-SM). Both amnestic MCI and multiple-domain MCI were identified. The optimum MoCA cutoff for detecting MCI in this group was <24. At this cutoff, the MoCA's sensitivity for detecting amnestic MCI was 100% and for multiple-domain MCI it was 83.3%. Specificity rates for amnestic MCI and multiple-domain MCI were 50.0% and 52% respectively. The poor specificity of the MoCA suggests that it will have limited value as a screening test for MCI in settings where the overall prevalence of MCI is low.     

Long-term exposure to music enhances the sensitivity of the auditory system in children

This event-related brain potential study aims to contribute to the present debate regarding the effect of musical training on the maturation of the human auditory nervous system. To address this issue, we recorded the mismatch negativity (MMN) evoked by violin and pure sine-wave tones in a group of 7.5- to 12-year-old children who had either several years of musical experience with Suzuki violin lessons, or no musical training. The strength of the MMN responses to violin tones evident in the Suzuki students clearly surpassed responses in controls; the reverse pattern was observed for sine-wave tones. Suzuki students showed significantly shorter MMN latencies to violin tones than to pure tones; the MMN latency did not differ significantly between pure tones and violin sounds in the control group. Thus, our data provide general evidence of how and to what extent extensive musical experience affects the maturation of human auditory function at multiple levels, namely, accuracy and speed of auditory discrimination processing. Our findings add to the present understanding of neuroplastic organization and function of the mammalian nervous system. Furthermore, behavioural recordings obtained from the participating children provide corroborating evidence for a relationship between the duration and intensity of training, the specific sensitivity to instrumental timbre, and pitch recognition abilities.     

EFAS-Abstracts 2011

Abstracts

EFAS-Abstracts 2011     

Pituitary glucocorticoid receptor deletion reduces vulnerability to chronic stress

The incidence of chronic stress is frequently related to the development of psychiatric disorders like depression. The hypothalamic-pituitary-adrenal (HPA) axis is a major physiological system that mediates the stress response. Tight HPA axis regulation through negative feedback mechanisms is essential for health and environmental adaptation. This feedback regulation acts in part through the glucocorticoid receptor (GR) on several organizational levels, including the pituitary, the hypothalamus and the hippocampus. However, the precise role of the different anatomical structures, specifically the pituitary, in HPA axis regulation is yet largely unknown. Here, we show that a conditional pituitary GR knockout is not necessarily detrimental for the animal's ability to cope with chronic stress situations. Mice with a deletion of the GR at the pituitary (GR(POMCCre)) were subjected to 3 weeks of chronic social defeat stress. We analyzed both the behavioral and neuroendocrine phenotype as well as the central nervous system expression of genes involved in HPA axis function in these animals. Our results show a more resilient phenotype of GR(POMCCre) mice with respect to anxiety-related behavior and neuroendocrine parameters compared to stressed wild type animals. In light of the previously reported high corticosterone levels during postnatal development in GR(POMCCre) mice, our findings suggest that adverse early life events may have beneficial developmental effects on the organism to improve stress coping later in life.     

Development of quantitative and sensitive assessments of physiological and functional outcome during recovery from spinal cord injury: A Clinical Initiative

The ability to detect physiological changes associated with treatments to effect axonal regeneration, or novel rehabilitation strategies, for spinal cord injury will be challenging using the widely employed American Spinal Injuries Association (ASIA) impairment scales (AIS) for sensory and motor function. Despite many revisions to the AIS standard neurological assessment, there remains a perceived need for more sensitive, quantitative and objective outcome measures. The purpose of Stage 1 of the Clinical Initiative was to develop these tools and then, in Stage 2 to test them for reliability against natural recovery and treatments expected to produce functional improvements in those with complete or incomplete spinal cord injury (SCI). Here we review aspects of the progress made by four teams involved in Stage 2. The strategies employed by the individual teams were (1) application of repetitive transcranial magnetic stimulation (rTMS) to the motor cortex in stable (chronic) SCI with intent to induce functional improvement of upper limb function, (2) a tele-rehabilitation approach using functional electrical stimulation to provide hand opening and grip allowing incomplete SCI subjects to deploy an instrumented manipulandum for hand and arm exercises and to play computer games, (3) weight-assisted treadmill walking therapy (WAT) comparing outcomes in acute and chronic groups of incomplete SCI patients receiving robotic assisted treadmill therapy, and (4) longitudinal monitoring of the natural progress of recovery in incomplete SCI subjects using motor tests for the lower extremity to investigate strength and coordination.     

The Wilson films--MS tremor

Action tremor was for a long time considered to be a defining symptom of multiple sclerosis. The Wilson films include a short segment showing a female patient suffering from relatively severe action tremor. Tremor is the most common movement disorder in multiple sclerosis, and can be very disabling in some patients. Insights into the frequency and treatment of tremor in multiple sclerosis have changed since the Wilson films were taken, and are reviewed herein.     

Stabilization of chronic proximal tibiofibular joint instability with a semitendinosus graft

Although chronic proximal tibiofibular joint instability is a rare condition, it is associated with marked functional impairment. Various surgical options have been reported in literature, all associated with several problems and limitations. We describe a new technique of reconstruction of the proximal tibiofibular joint using the semitendinosus tendon. The key steps of the procedure are the preparation of a proximally released semitendinosus tendon, and its guidance through two transtibial tunnels and one transfibular tunnel. The semitendinosus tendon acts as a soft tissue sling and does not interfere with mobility at the proximal or distal tibiofibular joints as noted after fibular head resection or arthrodesis of the proximal tibiofibular joint. Further advantages are the easy accessibility of the semitendinosus graft and the small surgical scar with better cosmetic results as compared to ligamentous reconstructive procedures using a split biceps femoris tendon or a strip of the iliotibial band.     

Complement Factor H Is Expressed in Adipose Tissue in Association With Insulin Resistance

OBJECTIVE

Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance.

RESEARCH DESIGN AND METHODS

Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts.

RESULTS

Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels.

CONCLUSIONS

Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances.Obesity is closely associated with a cluster of metabolic diseases, such as dyslipidemia, hypertension, insulin resistance, type 2 diabetes, and atherosclerosis (1). Adipose tissue is well known for its essential role as an energy storage depot and for secreting adipokines that influence sites as diverse as brain, liver, muscle, β-cells, gonads, lymphoid organs, and systemic vasculature (2,3). Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for most of the proinflammatory cytokines (4). In recent years, it has become evident that alterations in the function of the innate immune system are intrinsically linked to metabolic pathways in humans (5–8).The complement system is a major component of the innate immune system, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement deficiency and abnormalities in the regulation of the complement system lead to increased susceptibility to infection and chronic inflammatory diseases (9,10,11).Factor H (fH) is a relatively abundant plasma glycoprotein that is essential to maintain complement homeostasis and to restrict the action of complement to activating surfaces. fH acts as a cofactor for factor I–mediated cleavage of C3b (the active fragment of the third component of complement C3), accelerates the dissociation of the alternative pathway C3 convertases (a bimolecular enzymatic complex formed by active fragments of C3 and factor B [fB]), and competes with fB for binding to C3b. fH regulates complement both in fluid phase and on cellular surfaces (12–16).It has been suggested that activation of the alternative pathway of the complement system could be a link between obesity and metabolic disorders (17–21). Moreover, fB and factor D (fD, adipsin) are produced by adipose tissue where they likely influence formation of the alternative pathway component C3 convertase and the production of the anaphylatoxin C3a and its carboxypeptidase B-anaphylatoxic–inactivated derivative C3adesArg (acylation-stimulating protein [ASP]). Both ASP/C3adesArg and C3a interact with the receptor C5L2 to effectively stimulate triglyceride synthesis in cultured adipocytes (22). C3 knockout (C3KO) mice are obligatorily ASP deficient and present lipid abnormalities (23). In humans, ASP levels are increased in obesity, type 2 diabetes, and in individuals at risk of arterial disease, including those with hypertension, type 2 diabetes, dyslipidemia, and coronary artery disease, whereas exercise or weight loss decreases ASP levels (24,25). These data suggest a relationship between these conditions and activation of the alternative pathway of complement. There is also a correlation between increased C3 concentration and decreased insulin action (26,27). Levels of C3 and fB were higher in subjects with insulin resistance and other features of the metabolic syndrome (28,29).Given these interactions among activation of the alternative pathway of complement, metabolic disturbances, and a chronic low-level inflammatory state, we designed experiments to study the associations among circulating fH, fB, insulin resistance, lipid parameters, and inflammatory markers. We found that circulating fH and fB are strongly associated with obesity. For that reason, we also studied whether adipose tissue could constitute a source of circulating fH and fB.     

Percutaneous Radiofrequency Epiphysiodesis in a Rabbit Model: A Pilot Study

Background

Techniques for epiphysiodesis have evolved from open surgical techniques requiring direct observation of the physis to percutaneous techniques performed with fluoroscopy.

Questions/purposes

Our purposes were to (1) describe a new minimally invasive surgical technique used to achieve epiphysiodesis using radiofrequency ablation, (2) document the effect of radiofrequency ablation on tibia length at 2, 6, and 12 weeks after ablation in a skeletally immature rabbit model, and (3) assess the effects of radiofrequency ablation on the histologic appearance of the proximal tibia physis and proximal tibia articular cartilage.

Materials and Methods

We performed epiphysiodesis of the rabbit proximal tibia on 15 skeletally immature male New Zealand White rabbits using a 22-gauge radiofrequency probe. The probe was positioned percutaneously and heated to 90°C for 4 minutes on the medial and lateral ½ of the physis. The opposite tibia was used as a control. Five animals were sacrificed at 2, 6, or 12 weeks postoperatively. Tibia length was compared using Faxitron® radiographs and electronic calipers. Histology of the growth plate was assessed with light microscopy.

Results

We observed differences in tibia length between 4.16 mm and 11.59 mm (average 7.86 mm) at 12 weeks. The proximal tibia physis closed radiographically and histologically in all animals by 12 weeks. Histologic analysis showed no evidence of articular cartilage injury.

Conclusions

This technique was reproducible and resulted in bone fusion of the rabbit proximal tibial growth plate. The use of radiofrequency ablation as described in this report may be used as an alternative to other surgical epiphysiodesis techniques.

Clinical Relevance

This technique may be useful for epiphysiodesis of small tubular bones of the hands and feet in humans.