Marrow fat may distribute the energy of impact loading throughout subchondral bone.

Most students of articular mechanics consider impact loads to be compressive forces that are borne by an intraosseous, trabecular scaffold. The possible role of marrow fat, which comprises about 75% of the structure, is generally ignored, and the potential contribution of type 1 collagen, the prototypic tensile protein, is not considered. Here, I question the evidence underlying these omissions and reject the conclusion of exclusive trabecular compression. Instead, I suggest that impact loading pressurizes the fat in subchondral compartments, and those pressures stretch the elastic trabecular walls, which are thereby subjected to tensile loading. The load-driven pressure pulses then diminish as they pass from each compartment to its adjoining neighbours. The resulting pressure gradient distributes the burden throughout the subchondrium, stores energy for ensuing recovery and subjects individual trabeculae only to the net pressure differences between adjacent compartments.

Impact-driven, pulmonary emboli of osseous fat in exercise-induced bronchospasm.

Exercise induced bronchospasm (EIB) affects approximately 10% of normal individuals with higher prevalence rates among children, obese adults, and competitive athletes. Although hyperpnea with dry air is the best known cause, the problem is multifactorial with atopy, asthma and chlorine all playing established roles. To date, no clear mechanism has connected musculoskeletal loading with the ensuing pulmonary compromise. This paper reviews evidence that impact-driven pulses in subchondral bone pressure may push osseous fat cells into the local venous sinusoids. The resultant showers of microemboli must then travel to the lung where lysis of membrane phospholipids leads to leukotriene formation with resultant inflammation and bronchial hypersensitivity. Concurrently, the same emboli deliver triglyceride fuels for further physical activity. Thus, pulmonary microemboli derived from osseous fat may resolve the seeming paradox of athletic excellence in persons afflicted with exercise-induced bronchospasm.

The human knee: A window on the microvasculature.

In synovial joints, the lining cells do not have tight junctions with their neighboring cells and they have no underlying basement membrane. Therefore, the synovial fluid within the articular cavity is continuous with the interstitial fluid of the synovial intima. These features, combined with ready access to the space via arthrocentesis, permit quantitative studies of microvascular function in the knees of unanesthetized, volunteer, human subjects both with and without chronic arthritis. This brief article reviews the principal findings of such work over ∼40 years at the University of Washington. Examined variables include bidirectional fenestral diffusion of small solutes, effective blood flow, lymphatic drainage, and endothelial pore size and permeability. The latter work introduced a new method using gel filtration chromatography of paired synovial fluid (SF) and serum (S) to obtain essentially continuous SF/S ratios over a range of radii between 1 and 12 nanometers.

Prevalence of birefringent crystals in cardiac and prostatic tissues, an observational study.

INTRODUCTION: The prevalence of urate crystals in residual tissue samples from coronary arteries, aortic valves and prostate glands was assessed. METHODS: Alcohol-fixed coronary arteries from 55 explanted hearts, alcohol-fixed aortic valves collected from 75 valve replacement surgeries and 40 frozen, unfixed prostate specimens resected during cancer surgery were examined for birefringent crystals with polarising microscopy. RESULTS: In the 55 explanted hearts, 6 (10.9%) contained a coronary artery with birefringent crystals. One of the 75 aortic valves (1.4%) contained negatively and positively birefringent crystals. Nineteen of the 40 (47.5%) prostates contained birefringent crystals. CONCLUSIONS: We found that a remarkable percentage of coronary arteries and prostate specimens contained birefringent crystals. Crystal presence is an obvious prerequisite for possible crystal induced-inflammation in these tissues, just as similar crystals elicit a gouty inflammatory cascade in synovial joints. Further studies are necessary to determine whether urate crystals may play this role in these tissues and, if so, to establish whether urate-lowering therapy may be beneficial in prostatitis and coronary disease.

Uricosuric drugs: the once and future therapy for hyperuricemia?

PURPOSE OF REVIEW: Although uricosuric agents provide the most time-honoured approach to the control of hyperuricemia, their place in the armamentarium has been eclipsed by that of xanthine oxidase inhibitors. This review considers the potential for uricosuric agents from the perspective of recent progress in the understanding of urate transport systems. RECENT FINDINGS: No new agents have yet become available, but promising new drugs are under development. Better understanding of the transporters URAT1 and ABCG2 in particular would appear to provide opportunities for more selective, better tolerated agents to increase the renal clearance of uric acid and thereby control hyperuricemia. SUMMARY: Conceptually, modest inhibition of renal tubular reabsorption should provide effective relief for the millions of individuals who are now hyperuricemic and who suffer from its principal consequence, gout.

Treatment of acute gouty arthritis in complex hospitalized patients with anakinra.

OBJECTIVE: To report our experience with the efficacy and safety of anakinra for acute gouty arthritis in medically complex hospitalized patients. METHODS: We reviewed the hospital charts of 26 patients treated with anakinra for crystal-induced arthritis since 2007. Demographics, comorbid conditions, reason for anakinra use, response to treatment, and any adverse outcomes were recorded. RESULTS: Twenty-six patients received 40 courses of anakinra therapy. In 67% of patients, pain improved significantly within 24 hours, and complete resolution of signs and symptoms of gout occurred by day 5 in 72.5% of patients. Seven patients received multiple courses with no decrement in response with repeated treatments. Anakinra was well tolerated and no adverse outcomes were attributed to the medication. Only 1 patient appeared to be refractory to this form of interleukin-1 inhibition. CONCLUSION: Anakinra is an effective and safe alternative treatment for acute gouty arthritis in medically complex hospitalized patients who fail or cannot undergo more conventional therapy.

A perspective on diet and gout.

The epidemiology of gout has changed dramatically over the past century. Once thought of as a disease of the nobility, it is now an egalitarian disease that affects patients across the socioeconomic spectrum. The incidence of gout has also risen in recent years, to the point that we are now seeing what is regarded by some as a "second epidemic" of gout. This change coincides with a significant dietary shift for many Americans - in particular, the advent of high-fructose corn syrup as the most prominent sweetener in the modern American diet and what may be a related rise in obesity. Fructose is a powerful driver of ATP catabolism that, in turn, leads to the production of uric acid. The new epidemic of gout is likely secondary in significant part to the rise in fructose consumption, as well as to the increase in obesity, the endurance of other dietary and non-dietary gout risk factors such as consumption of meat and alcohol, the continued use of culprit medications and potentially to the under-recognition of the benefits of certain foods and drinks (such as dairy products and coffee). Though the exact reasons for the rise in gout are yet unproven, this reopens the opportunity for dietary control of hyperuricemia through restraints that curtail not only exogenous but also endogenous pathways of purine production.

Pathways of microvascular permeability in the synovium of normal and diseased human knees.

OBJECTIVE: Our study uses the entire proteomes of serum and synovial fluid (SF) to characterize the avenues of microvascular egress of plasma proteins, and quantifies that traffic in normal and diseased human knees. METHODS: Paired aliquots of serum and SF were collected from 17 knees of 11 subjects who died without evident joint disease and 16 patients with clinical effusions, fractionated by gel filtration chromatography and analyzed as continuous plots of the SF/serum concentration ratio versus molecular radius from 1 to 12 nanometers (nm). Curve-stripping methodology, a 3-pore model, and known protein kinetics were then applied to estimate the dimensions of and the net outflow through fenestral, "small," and "large" apertures in the microvascular endothelium. RESULTS: The 3-pore model correlated highly with the observed data (r = 0.992 in normal and 0.980 in arthritis), yielding the following mean values: for the fenestra, the normal radius (nm) was 1.75 and the effused 3.5, and the normal flow (µl/min) was 1.74 and the arthritic 22.0; for the small pore, the normal radius was 8.6 and the effused 8.5, and the normal flow was 1.5 and the arthritic flow 9.1; for the large pore, the normal radius was 40 and the effused 36, and the normal flow was 0.24 and the arthritic flow 15.5. CONCLUSION: These findings provide the first functional definition of synovial, endothelial fenestrae; reveal that the "increased vascular permeability" of inflammation is not limited to interendothelial gaps; present evidence suggesting that glycocalyceal damage and aquaporin upregulation may affect permeability in arthritic synovium; and define a straightforward methodology for interpretation of biomarker concentrations in arthritic SF.

Feasibility of a tetracycline-binding method for detecting synovial fluid basic calcium phosphate crystals.

OBJECTIVE: Basic calcium phosphate (BCP) crystals are common components of osteoarthritis (OA) synovial fluid. Progress in understanding the role of these bioactive particles in clinical OA has been hampered by difficulties in their identification. Tetracyclines stain calcium phosphate mineral in bone. The aim of this study was to investigate whether tetracycline staining might be an additional or alternative method for identifying BCP crystals in synovial fluid. METHODS: A drop of oxytetracycline was mixed with a drop of fluid containing synthetic or native BCP, calcium pyrophosphate dihydrate (CPPD), or monosodium urate (MSU) crystals and placed on a microscope slide. Stained and unstained crystals were examined by light microscopy, with and without a portable broad-spectrum ultraviolet (UV) pen light. A small set of characterized synovial fluid samples were compared by staining with alizarin red S and oxytetracycline. Synthetic BCP crystals in synovial fluid were quantified fluorimetrically using oxytetracycline. RESULTS: After oxytetracycline staining, synthetic and native BCP crystals appeared as fluorescent amorphous aggregates under UV light. Oxytetracycline did not stain CPPD or MSU crystals or other particulates. Oxytetracycline staining had fewer false-positive test results than did alizarin red S staining and could provide estimates of the quantities of synthetic BCP crystals in synovial fluid. CONCLUSION: With further validation, oxytetracycline staining may prove to be a useful adjunct or alternative to currently available methods for identifying BCP crystals in synovial fluid.

A concise history of gout and hyperuricemia and their treatment.

First identified by the Egyptians in 2640 BC, podagra (acute gout occurring in the first metatarsophalangeal joint) was later recognized by Hippocrates in the fifth century BC, who referred to it as 'the unwalkable disease'. The term is derived from the Latin word gutta (or 'drop'), and referred to the prevailing medieval belief that an excess of one of the four 'humors'--which in equilibrium were thought to maintain health--would, under certain circumstances, 'drop' or flow into a joint, causing pain and inflammation. Throughout history, gout has been associated with rich foods and excessive alcohol consumption. Because it is clearly associated with a lifestyle that, at least in the past, could only be afforded by the affluent, gout has been referred to as the 'disease of kings'. Although there is evidence that colchicine, an alkaloid derived from the autumn crocus (Colchicum autumnale), was used as a powerful purgative in ancient Greece more than 2000 years ago, its first use as a selective and specific treatment for gout is attributed to the Byzantine Christian physician Alexander of Tralles in the sixth century AD. Uricosuric agents were first used at the end of the 19th century. In the modern era, nonsteroidal anti-inflammatory drugs are usually the drugs of choice for treating acute gout. Perhaps the most important historical advance in the treatment of hyperuricemia was the development of xanthine oxidase inhibitors, which are effective in reducing plasma and urinary urate levels and have been shown to reverse the development of tophaceous deposits.

Epidemiology of hyperuricemia and gout.

Gout is an increasingly common medical problem. The traditional risk factors of male sex and high red meat or alcohol consumption have been joined by a wave of newer risk factors, such as increased longevity, the metabolic syndrome (hypertension, diabetes, dyslipidemia, truncal obesity, increased cardiovascular disease risk), use of diuretics, low-dose aspirin, or cyclosporine, and end-stage renal disease. Atypical presentations of gout in the elderly can mimic osteoarthritis and rheumatoid arthritis. There is a resurgence of interest in hyperuricemia as an independent and potentially modifiable cardiovascular risk factor. The pharmacologic management of gout in general practice suffers from a number of quality-control issues. This article reviews these and other new epidemiologic data on this ancient disease.