Mohammed Ali Akhavani

Synovial Hypoxia as a Cause of Tendon Rupture in Rheumatoid Arthritis

PURPOSE Hypoxia and angiogenesis are now recognized as being important events in the perpetuation of joint destruction in rheumatoid arthritis (RA). In 50% of patients with RA, however, the disease also involves inflammation of the synovial tissue surrounding the tendons, which is associated with multiple ruptures and poor prognosis for long-term hand function. The aim of this study was to determine whether hypoxia and angiogenesis may also play a role in RA tendon disease. METHODS Matched in vivo synovial oxygen measurements (invasive and encapsulating tenosynovium and joint synovium) were taken intraoperatively using a microelectrode technique in patients having elective hand surgery for RA. Patients having elective hand surgery for indications other than inflammatory synovitis were recruited as controls. In parallel, RA synovial tissue was harvested and stained for vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-2alpha. Tissue was also cultured under either hypoxic (1% O(2)) or normoxic (21% O(2)) conditions to investigate the effect of hypoxia on the expression of VEGF and its soluble receptor, as well as on the key cytokines interleukin (IL)-6, IL-8, IL-10 and the chemokine monocyte chemoattractant protein-1. RESULTS Invasive tenosynovium was observed to be significantly more hypoxic than either noninvasive tenosynovium or joint synovium in the same patients. Furthermore, RA tenosynovium was shown to be more hypoxic than tenosynovium in patients without RA. This hypoxia was accompanied by expression of VEGF and hypoxia-inducible factor-2alpha. Using in vitro joint synovial cell cultures, upregulation of VEGF expression was shown to be a consequence of this in vivo hypoxia. Furthermore, hypoxia downregulated release of monocyte chemoattractant protein-1 and the immunoregulatory cytokine IL-10. CONCLUSIONS These data demonstrate that hypoxia is a feature of rheumatoid tendon disease and differentially regulates angiogenesis and the inflammatory cascade in RA.

Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is characterised by invasion of cartilage, bone and tendon by inflamed synovium. Previous studies in our laboratory have shown that hypoxia is a feature of RA synovitis. In the present study, we investigated the consequences of hypoxia on angiogenesis and synovial fibroblast migration in RA.MethodsSynovial tissue was harvested from RA patients, and synovial membrane cells were cultured under conditions either of hypoxia (1% oxygen) or normoxia (21% oxygen). Protein levels of matrix metalloproteinases (MMPs) and angiogenic factors were measured, while RNA was extracted for PCR quantification of MMPs/tissue inhibitors of MMP (TIMPs) and angiogenic factors. Migration of RA synovial fibroblasts through collagen, and the effect of RA synovial cell supernatants in an in vitro angiogenesis assay, were utilised to determine the functional relevance of changes in mRNA/protein.ResultsWe observed upregulation under hypoxic conditions of MMPs responsible for collagen breakdown, specifically collagenase MMP-8, and the gelatinases MMP-2 and MMP-9, at both mRNA and protein levels. Increased MT1-MMP mRNA was also observed, but no effect on TIMP-1 or TIMP-2 was detected. RA fibroblast migration across collagen was significantly increased under hypoxic conditions, and was dependent on MMP activity. Furthermore, expression of angiogenic stimuli, such as vascular endothelial growth factor (VEGF), and VEGF/placental growth factor heterodimer, was also increased. Crucially, we show for the first time that hypoxia increased the angiogenic drive of RA cells, as demonstrated by enhanced blood vessel formation in an in vitro angiogenesis assay.ConclusionsHypoxia may be responsible for rendering RA synovial lining proangiogenic and proinvasive, thus leading to the debilitating features characteristic of RA.

Angiogenesis and plastic surgery

SUMMARY Angiogenesis, the formation of new blood vessels from an existing vascular bed, is a normal physiological process which also underpins many--apparently unrelated--pathological states. It is an integral factor in determining the success or failure of many procedures in plastic and reconstructive surgery. As a result, the ability to control the process would be of great therapeutic benefit. To appreciate the potential benefits and limitations of recent advances in our understanding of angiogenesis, it is important to comprehend the basic physiology of blood vessel formation. This review aims to summarise current knowledge of the way in which angiogenesis is controlled and to look at how disordered vessel development results in pathology relevant to plastic surgery. Through this we hope to provide a comprehensive overview of the recent advances in angiogenesis as they relate to plastic surgery, particularly the promotion of flap survival, tendon healing, nerve regeneration, fracture healing and ulcer treatments.

Circulating endothelial progenitor cells as a link between synovial vascularity and cardiovascular mortality in rheumatoid arthritis

Cardiovascular disease refers to the class of diseases that involve the heart and/or blood vessels (arteries and veins). Most Western countries face high and ever‐increasing rates of cardiovascular disease. Each year, more Americans are killed by heart disease than by cancer. Diseases of the heart alone cause 30% of all deaths, with other diseases of the cardiovascular system causing substantial further deaths and disability. Indeed, cardiovascular disease is the major cause of death and disability in the USA and most European countries. The development of the vascular systems requires an intricate interplay of molecules such as vascular endothelial growth factor and endothelial progenitor cells. A defective vascular repair/regeneration is thought to be responsible for propagation of atherosclerosis, a key feature of cardiovascular disease. This is partly attributed to a reduction in the circulating endothelial progenitor cells in peripheral blood. Patients with rheumatoid arthritis (RA) have a higher than average incidence of cardiovascular disease in comparison with the general population, with an increased risk of stroke and myocardial infarction, and an increased risk of fatality following myocardial infarction. This review focuses on the current evidence linking the role played by endothelial progenitor cells to the development of cardiovascular disease and why this might relate to the increased risk observed in RA patients.

A review of the classification of Dupuytren’s disease

Although much has been published about the treatment of Dupuytren’s disease, there is no clear consensus regarding the most effective form of treatment. Part of this uncertainty may result from the absence of a universal method of assessing this condition. We undertook a review of the literature in order to summarize the various methods by which Dupuytren’s disease has been measured and quantified. We included all articles that offered a classification or assessment system for the disease. We excluded articles that dealt solely with surgical technique (although inevitably there was some overlap). We conclude that there are many methods of assessment, but that none of them is perfect and that further work is needed in the field.

Gene Expression Studies to Investigate Disease Mechanisms in Rheumatoid Arthritis: Does Angiogenesis Play a Role?

Gene expression studies represent a new and challenging approach that allows molecular dissection of complex diseases such as rheumatoid arthritis (RA). Optimally, gene analysis should be conducted in isolated populations of cells so that the differential gene expression may be directly correlated with transcription of genes. RA fibroblasts constitute the majority of the expanding synovial cell mass in the RA joint, and alterations in their phenotype are likely to be important in the pathogenic process. However, RA involves many cell types from tissues adjacent to the synovium and the important cell types are not known. Analysis of gene expression profiles by processing a complex tissue such as whole paws can provide useful information about dysregulated genes, not only in the synoviocytes but also in other, neighbouring cells (monocytes, osteocytes and chondrocytes) that may contribute to disease pathology. This review will focus on the use of gene expression studies, both in isolated cells and in whole tissue, as a means of studying the molecular mechanisms involved particularly in the angiogenic process in RA. In particular, we will focus on synovial angiogenesis, since the synovial vascular density is altered in RA. This will provide an increased surface area for inflammatory cell trafficking, as well as delivering nutrients and oxygen to the proliferating synovial cells. Therapeutic approaches targeting angiogenic factors such as vascular endothelial growth factor (VEGF), which is increased in RA, have already shown some clinical success in oncology, and in mouse models of arthritis.

Technical Tip for Proximal Release During Open Carpal Tunnel Release Using a Subcutaneous Pocket.

Technical steps to avoid incomplete proximal release of the carpal tunnel are described. Local anaesthesia is infiltrated as a subcutaneous bleb over the distal wrist crease and extending 2-3 cm over the forearm fascia. Tumescence of local anaesthesia into the subcutaneous plane helps create a pocket between the forearm fascia and subcutaneous tissues. Intraoperatively a subcutaneous pocket is made above the transverse carpal ligament and antebrachial fascia with blunt dissection. A retractor is placed under the pocket, which facilitates optimal visualization to allow reliable complete proximal release of compression.The authors have found that this technique is reproducible and reliable across their collective experience.

The lymphocyte in inflammatory angiogenesis

The ability of immune cells to recognise foreign pathogens, while simultaneously maintaining tolerance towards proteins produced by the body’s own cells, forms the basis of mammalian immunity. At the heart of the immune system are the lymphocytes, which orchestrate the adaptive immune response through clonal expansion upon recognition of a specific antigen. The plasticity of the immune system allows exquisite control of the body’s defences. However, the adaptive immune system can also be directed towards host proteins (‘self antigens’). The reasons for this failure in immunity are varied, and include a genetic basis or evasion of the host immune response by viruses. Nevertheless, the consequences — autoimmune diseases such as rheumatoid arthritis (RA) — are frequently associated with inflammation, immune cell dysfunction and changes in the vasculature.