Axial rotation and pain are associated with facet joint osteoarthritis in adolescent idiopathic scoliosis.

OBJECTIVE: Facet joints are crucial for spinal stability but develop premature osteoarthritis in patients with adolescent idiopathic scoliosis (AIS). Here, we evaluated the association between facet joint cartilage and subchondral bone homeostasis, perceived back pain and 3-dimensional spinal deformity to better understand the role of facet joint degeneration in AIS progression and pain. METHOD: The osteoarthritic state of cartilage and bone of AIS facet joint surgical samples were characterized using histological OARSI scoring, visual morphological grading and µCT analysis, respectively. Back pain was self-reported using a numerical rating scale and expressed relative to the location on the patient's back. The scoliotic curves from our patient cohort were digitally reconstructed using biplanar radiographs and the eOS system (EOS imaging). The deformity was then reduced to three intervertebral angles (coronal, sagittal and axial) for each pair of bilateral facet joints. Statistical associations between the intervertebral angles, osteoarthritis parameters and pain intensity were performed using the Spearman method and Friedman test. RESULTS: Facet joint cartilage degeneration was associated with decreased subchondral bone volume and quality. Most importantly, asymmetrical, and overall degeneration of facet joints was strongly correlated to intervertebral axial rotation. Additionally, kyphotic intervertebral segments in the sagittal plane were good predictors of increased facet joint degeneration and back pain. CONCLUSION: Facet joint degeneration is associated with axial deformity, kyphotic intervertebral angle and back pain intensity in AIS. These results suggest that facet joints are important features to consider for rotational instability in AIS spines and related disease progression and perceived back pain.

For whom the disc tolls: intervertebral disc degeneration, back pain and toll-like receptors.

Intervertebral disc (IVD) degeneration is characterised by catabolic and inflammatory processes that contribute largely to tissue degradation and chronic back pain. The disc cells are responsible for the pathological production of pro-inflammatory cytokines and catabolic enzymes leading to degeneration. However, this phenotypical change is poorly understood. Growing evidence in animal and human studies implicates Toll-like receptors (TLR) and their activation through danger-associated alarmins, found increasingly in degenerating IVDs. TLR signalling results in the release of pro-inflammatory cytokines and proteolytic enzymes that can directly cause IVD degeneration and back pain. This review aims to summarise the current literature on TLR activation in IVD degeneration and discuss potential treatment modalities to alleviate the inflammatory phenotype of disc cells in order to arrest IVD degeneration and back pain.

Differential regulation of TRP channel gene and protein expression by intervertebral disc degeneration and back pain.

Intervertebral disc (IVD) degeneration and consequent low back pain (LBP) are common and costly pathological processes that require improved treatment strategies. Transient Receptor Potential (TRP) channels constitute a family of multimodal ion channels that have recently emerged as contributors to disc pathologies and were thus proposed as potential therapeutic targets, although limited data on their presence and function in the IVD exist. The purpose of this study was to determine the mRNA and protein expression of TRP channels in non-degenerated and degenerated human IVD tissue (with different pain intensity and chronicity) using gene array, conventional qPCR and immunohistochemistry. We could demonstrate that 26 out of 28 currently known TRP channels are expressed in the IVD on the mRNA level, thereby revealing novel therapeutic candidates from the TRPC, TRPM and TRPML subfamilies. TRPC6, TRPM2 and TRPML1 displayed enhanced gene and protein expression in degenerated IVDs as compared to non-degenerated IVDs. Additionally, the gene expression of TRPC6 and TRPML1 was influenced by the IVD degeneration grade. Pain intensity and/or chronicity influenced the gene and/or protein expression of TRPC6, TRPM2 and TRML1. Interestingly, decreased gene expression of TRPM2 was observed in patients treated with steroids. This study supports the importance of TRP channels in IVD homeostasis and pathology and their possible application as pharmacological targets for the treatment of IVD degeneration and LBP. However, the exact function and activation of the highlighted TRP channels will have to be determined in future studies.

Thermoreversible hyaluronan-hydrogel and autologous nucleus pulposus cell delivery regenerates human intervertebral discs in an ex vivo, physiological organ culture model.

Numerous studies show promise for cell-based tissue engineering strategies aiming to repair painful intervertebral disc (IVD) degeneration. However, clinical translation to human IVD repair is slow. In the present study, the regenerative potential of an autologous nucleus pulposus (NP)-cell-seeded thermoresponsive hyaluronic acid hydrogel in human lumbar IVDs was assessed under physiological conditions. First, agarose-encased in vitro constructs were developed, showing greater than 90 % NP cell viability and high proteoglycan deposition within HA-pNIPAM hydrogels following 3 weeks of dynamic loading. Second, a bovine-induced IVD degeneration model was used to optimise and validate T1ρ magnetic resonance imaging (MRI) for detection of changes in proteoglycan content in isolated intact IVDs. Finally, isolated intact human lumbar IVDs were pre-scanned using the established MRI sequence. Then, IVDs were injected with HA-pNIPAM hydrogel alone or autologous NP-cell-seeded. Next, the treated IVDs were cultured under cyclic dynamic loading for 5 weeks. Post-treatment T1ρ values were significantly higher as compared to pre-treatment scans within the same IVD and region of interest. Histological evaluation of treated human IVDs showed that the implanted hydrogel alone accumulated proteoglycans, while those that contained NP cells also displayed neo-matrix-surrounded cells within the gel. The study indicated a clinical potential for repairing early degenerative human IVDs using autologous cells/hydrogel suspensions. This unique IVD culture set-up, combined with the long-term physiological culture of intact human IVDs, allowed for a more clinically relevant evaluation of human tissue repair and regeneration, which otherwise could not be replicated using the available in vitro and in vivo models.

Comparative analysis in continuous expansion of bovine and human primary nucleus pulposus cells for tissue repair applications.

Autologous NP cell implantation is a potential therapeutic avenue for intervertebral disc (IVD) degeneration. However, monolayer expansion of cells isolated from surgical samples may negatively impact matrix production by way of dedifferentiation. Previously, we have used a continuous expansion culture system to successfully preserve a chondrocyte phenotype. In this work, we hypothesised that continuous expansion culture could also preserve nucleus pulposus (NP) phenotype. We confirmed that serial passaging drove NP dedifferentiation by significantly decreasing collagen type II, aggrecan and chondroadherin (CHAD) gene expression, compared to freshly isolated cells. Proliferation, gene expression profile and matrix production in both culture conditions were compared using primary bovine NP cells. Both standard culture and continuous culture produced clinically relevant cell populations. However, continuous culture cells maintained significantly higher collagen type II, aggrecan and CHAD transcript expression levels. Also, continuous expansion cells generated greater amounts of proteoglycan, collagen type II and aggrecan protein deposition in pellet cultures. To our surprise, continuous expansion of human intervertebral disc cells - isolated from acute herniation tissue - produced less collagen type II, aggrecan and CHAD genes and proteins, compared to standard culture. Also, continuous culture of cells isolated from young non-degenerate tissue did not preserve gene and protein expression, compared to standard culture. These data indicated that primary bovine and human NP cells responded differently to continuous culture, where the positive effects observed for bovine cells did not translate to human cells. Therefore, caution must be exercised when choosing animal models and cell sources for pre-clinical studies.

Dynamic loading, matrix maintenance and cell injection therapy of human intervertebral discs cultured in a bioreactor.

Low back pain originating from intervertebral disc (IVD) degeneration affects the quality of life for millions of people, and it is a major contributor to global healthcare costs. Long-term culture of intact IVDs is necessary to develop ex vivo models of human IVD degeneration and repair, where the relationship between mechanobiology, disc matrix composition and metabolism can be better understood. A bioreactor was developed that facilitates culture of intact human IVDs in a controlled, dynamically loaded environment. Tissue integrity and cell viability was evaluated under 3 different loading conditions: low 0.1-0.3, medium 0.1-0.3 and high 0.1-1.2 MPa. Cell viability was maintained > 80 % throughout the disc at low and medium loads, whereas it dropped to approximately 70 % (NP) and 50 % (AF) under high loads. Although cell viability was affected at high loads, there was no evidence of sGAG loss, changes in newly synthesised collagen type II or chondroadherin fragmentation. Sulphated GAG content remained at a stable level of approximately 50 µg sGAG/mg tissue in all loading protocols. To evaluate the feasibility of tissue repair strategies with cell supplementation, human NP cells were transplanted into discs within a thermoreversible hyaluronan hydrogel. The discs were loaded under medium loads, and the injected cells remained largely localised to the NP region. This study demonstrates the feasibility of culturing human IVDs for 14 days under cyclic dynamic loading conditions. The system allows the determination a safe range-of-loading and presents a platform to evaluate cell therapies and help to elucidate the effect of load following cell-based therapies.

Acute mechanical injury of the human intervertebral disc: link to degeneration and pain.

Excessive mechanical loading or acute trauma to intervertebral discs (IVDs) is thought to contribute to degeneration and pain. However, the exact mechanisms by which mechanical injury initiates and promotes degeneration remain unclear. This study investigates biochemical changes and extracellular matrix disruption in whole-organ human IVD cultures following acute mechanical injury. Isolated healthy human IVDs were rapidly compressed by 5% (non-injured) or 30% (injured) of disc height. 30% strain consistently cracked cartilage endplates, confirming disc trauma. Three days post-loading, conditioned media were assessed for proteoglycan content and released cytokines. Tissue extracts were assessed for proteoglycan content and for aggrecan integrity. Conditioned media were applied to PC12 cells to evaluate if factors inducing neurite growth were released. Compared to controls, IVD injury caused significant cell death. Injury also caused significantly reduced tissue proteoglycan content with a reciprocal increase of proteoglycan content in culture media. Increased aggrecan fragmentation was observed in injured tissue due to increased matrix metalloproteinase and aggrecanase activity. Injured-IVD conditioned media contained significantly elevated interleukin (IL)-5, IL-6, IL-7, IL-8, MCP-2, GROα, and MIG, and ELISA analysis showed significantly increased nerve growth factor levels compared to non-injured media. Injured-disc media caused significant neurite sprouting in PC12 cells compared to non-injured media. Acute mechanical injury of human IVDs ex vivo initiates release of factors and enzyme activity associated with degeneration and back pain. This work provides direct evidence linking acute trauma, inflammatory factors, neo-innervation and potential degeneration and discogenic pain in vivo.

Development of a whole disc organ culture system to study human intervertebral disc.

STUDY TYPE: Basic science Objective: Low back pain is one of the most common health problems1 and is strongly associated with intervertebral disc degeneration, (IVD). Current treatments remove the symptoms without reversing or even retarding the underlying problem. Development of new therapy for the regeneration of the degenerative IVD is complicated by the lack of a validated long-term organ culture model in which therapeutic candidates can be studied. The object of this study was to develop, optimize, and validate an organ culture model for human IVD, allowing for the study of degeneration and the potential for regeneration of the human IVD. METHODS: From eleven donors, an average of 5-6 IVDs were obtained. Inclusion criteria were; age between 50 and 70 years old, no history of cancer, chemotherapy, diabetes, or liver cirrhosis. An x-ray of the harvested spine was done to assess the grade of degeneration. Three different methods for isolating the discs were studied: with bony endplate (BEP), without endplate (NEP), and with cartilage endplate (CEP). Discs were cultured for 4 weeks without external load, in Dulbecco's modified eagle media with glucose and fetal bovine serum (FBS). Four different combinations of concentrations of glucose and FBS were compared: low glucose-low FBS, low glucose-high FBS, high glucose-low FBS, and high glucose-high FBS.2 Short-term cultures (1 week) were performed to compare the cell viability of the three methods of isolating the discs. Swelling potential on NEP and CEP discs from the same donor were evaluated. After four weeks of culture, a 4 mm punch was taken from CEP discs and cell viability was evaluated using a live/dead assay with confocal microscopy. RESULTS: Analyzing the potential of swelling in CEP discs, there was an increase in volume to a maximum of 25% and retention of shape and morphology. Whereas in NEP discs, there was an excessive deformation and a two-fold time increase in volume than CEP discs. The cell viability in short-term cultures is around 40%-50% in the BEP model, 50%-60% in the NEP model and > 96% in the CEP model. BEP isolated discs show endplate necrosis that begins after 4 days of culture. Cell viability in CEP discs was evaluated at 4 weeks in three different areas of the disc: nucleus pulposus, inner annulus fibrosus, and outer annulus fibrosus. We found no difference in live cells (> 96%) between the four different concentrations of FBS and glucose (Table 1). [Table: see text] CONCLUSIONS: We have developed a novel method to isolate human IVDs and optimized the culture conditions. The CEP method has been proven to be superior to the previous models (NEP and BEP) in cell viability and maintaining physiologic swelling.3 In the long-term cultures, the CEP system maintained sufficient nutrient supply and high cell survival in all regions of the discs even with low concentrations of FBS and glucose. The availability of an intact disc organ culture system has a considerable advantage over the culture of isolated disc cells, as it maintains the cells in their unique microenvironment, making any response to catabolic or anabolic agents more physiologically relevant.

Functional status and quality of life in patients with first-episode major depression.

The aim of this study was to analyse the level of severity of major depression and its relation to functioning and health-related quality of life over time in patients treated for their first episode of major depression. Thirty-three adult patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depression were included in the study. Semi-structured interviews and self-assessment questionnaires were used at baseline and at 6-monthly intervals in a 2-year follow-up, in order to measure the level of severity of depression, functioning and quality of life. The results showed that the first episode of major depression was rated as severe in 43% of cases. Multiple domains of functioning as well as quality of life were strongly affected in patients at baseline, although the level of functioning increased significantly over the study period, as did quality of life, but not concurrently with the decrease in the level of severity of the depression. Psychosocial functioning is an important outcome measure related to major depression, which underlines the importance of separate evaluations initiated and conducted by mental health nurses in order to determine whether or not patients have actually achieved a state of health.

Hand function in women and men with early rheumatoid arthritis. A prospective study over three years (the Swedish TIRA project).

OBJECTIVE: To describe the course of hand function in women and men during the first 3 years after diagnosis of recent-onset rheumatoid arthritis (RA), to investigate sex differences in hand function, and to study correlations between and within hand function assessments. METHODS: A total of 276 patients (69% women) with RA of a maximal duration of 12 months were recruited to the study. Hand function was assessed by the Grip Ability Test (GAT) and Signals of Functional Impairment (SOFI). Peak and average grip force over 10 s in the right and left hand was measured by an electronic device. RESULTS: Hand function was affected at diagnosis, but had improved significantly at the 3-months' follow-up and then remained stable (but still affected) in both women and men. As assessed by SOFI, hand function was worse in men than in women, whereas women had significantly lower grip force. GAT, grip force, and SOFI correlated weakly. The average and peak values of grip force correlated strongly, as did the grip force in the right and the left hand. CONCLUSION: Hand function was profoundly affected at diagnosis of RA, but improved significantly within 3 months and remained stable (but still affected) over 3 years. As expected, women on average had significantly lower grip force than men.

A critical analysis of the Model of Human Occupation.

The aim of this paper is to begin a dialogue regarding the use of the Model of Human Occupation (MOHO) (Kielhofner, 1995). Three questions formed the basis for discussion: 1. Is the MOHO consistent with the values and beliefs of occupational therapy?; 2. Does the MOHO support the intervention process in occupational therapy? and; 3. Is the MOHO consistent and applicable to the current regulations and societal values in Sweden? The authors propose that the MOHO must be further developed in order to support assessment and intervention in occupational therapy. Specifically, they find the MOHO lacking with regard the influence of the environment on human behaviour, appreciation of the dialectic process between the human and the environment, and of the importance of the subsystem volition in the intervention process.

Occupational Case Analysis Interview and Rating Scale. An examination of construct validity.

The Occupational Case Analysis Interview and Rating Scale (OCAIRS) was developed based on the Model of Human Occupation with the intention of assessing patients' occupational adaptation. Several studies examining the quality of this instrument have been completed; however, none have discussed the internal validity of the instrument or the appropriateness of the rating scale. The purpose of this study is to validate the internal validity of the OCAIRS and to test the quality of the rating scale. The results indicate that the OCAIRS is a valid measure of occupational adaptation. Each item was shown to have its own rating scale structure, however, all items together still shared the same five-point rating scale.

The perinatal assessment of psychosocial risk.

Although evaluation of psychosocial risk factors prior to perinatal hospital discharge has been advocated, the means for accomplishing such an evaluation are not well established. This article reviews several major psychosocial risk factors together with instruments that have been utilized to assess them during the perinatal period. Formal constructs reviewed include anxiety, depression, self-concept, general attitudes, life events, stress, adaptation, social support, marital and family functioning, and the home environment. Ongoing assessment of psychosocial status using formal instruments during routine perinatal care may provide a more complete picture of the psychosocial needs of the individual mother and her family, allowing for more appropriate, timely intervention and utilization of social and health care resources.

Effects of mefloquine alone and with alcohol on psychomotor and driving performance.

OBJECTIVE: To determine whether mefloquine, a quinoline antimalarial drug, affects psychomotor and actual driving performance when given in prophylactic regimen, alone or in combination with alcohol. METHODS: Forty male and female volunteers were randomly assigned in equal numbers to two groups, and were treated double-blind for one month with mefloquine and placebo. The medication was taken in a 250 mg dose on the evenings of Days 1, 2, 3, 8, 15, 22 and 29. Testing was done on Days 4, 23 and 30, the latter after repeated doses of alcohol sufficient to sustain a blood concentration of about 0.35 mg.ml-1. Two real driving tests were used to measure prolonged (1 h) road tracking and car following performance. Critical Flicker/Fusion Frequency (CFF), critical instability tracking and body sway were also measured in the laboratory. RESULTS: Mefloquine caused no significant impairment in any test at any time relative to placebo. It significantly improved road tracking performance on Day 4. A significant interaction between prior treatment and alcohol was found in the body sway test, as the alcohol-induced change was less after mefloquine than placebo. The sensitivity of the driving test and the CFF test were shown by the significant overall effect of alcohol which did not discriminate between the two prior treatments. CONCLUSION: Mefloquine did not impair driving performance but rather improved it in the longer test, suggesting that the drug may possess psychostimulating properties.

Activity--from action to activity.

In this article, existing terminology concerning occupational performance is reviewed. The authors conclude that the occupational therapy terminology available is insufficient to describe levels of complexity in the performance of an activity. Concepts are suggested to describe the different aspects of an activity, namely operations, single actions, generated actions, action sequences, and simultaneous actions. The suggested concepts are not intended to replace, but to supplement existing terminology.

Testing a Swedish version of OCAIRS on two different patient groups.

Occupational Case Analysis Interview and Rating Scale (OCAIRS) is an instrument for assessing occupational performance. Consisting of a semi-structured interview and a rating scale, OCAIRS is based on the Model of Human Occupation (Kielhofner 1985) and has been translated into Swedish. The rater reliability of the Swedish version (OCAIRS-S) was tested on two different populations: acute psychiatric in-patients and patients suffering from chronic muscular pain. The Intraclass Correlation Coefficient and the Percentage Agreement methods were used to calculate the strength of agreement between raters. Content validity was tested using the Percentage Agreement method. Research results indicate that the instrument has a reasonable rater reliability. Although the content validity study produced insufficient information, it nevertheless supports the use of OCAIRS-S as a reliable instrument. Further research and development on the instrument is recommended.