IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells.

Overuse injuries and trauma in tendon often involve acute or chronic pain and eventual matrix destruction. Anti-inflammatory drugs have been used as a treatment, however, the cellular and molecular mechanisms of the destructive processes in tendon are not clearly understood. It is thought that an inflammatory event may be involved as an initiating factor. Mediators of the inflammatory response include cytokines released from macrophages and monocytes. Interleukin-1 beta (IL-1 beta) is a candidate proinflammatory cytokine that is active in connective tissues such as bone and cartilage. We hypothesized that tendon cells would express receptors and respond to IL-1 beta in an initial "molecular inflammation" cascade, that is, connective tissue cell expression of cytokines that induce matrix destructive enzymes. This cascade results in expression of matrix metalloproteinases (MMPs) and aggrecanases that may lead to matrix destruction. Normal human tendon cells from six patients were isolated, grown to quiescence and treated with human recombinant IL-1 beta in serum-free medium for 16 h. Total RNA was isolated and mRNA expression assessed by semiquantitative RT-PCR. IL-1 beta (1 nM) induced mRNAs for cyclooxygenase 2 (COX2), MMP-1, -3, -13 and aggrecanase-1 as well as IL-1 beta and IL-6, whereas mRNAs for COX1 and MMP-2 were expressed constitutively. The IL-1 beta-treated tendon cells released prostaglandin E(2) (PGE(2)) in the medium, suggesting that the inducible COX2 catalyzed this synthesis. Induction of PGE(2) was detectable at 10 pM IL-1 beta. IL-1 beta also stimulated MMP-1 and -3 protein secretion. Induction of MMP-1 and -3 was detectable at 10 pM IL-1 beta. Post-injury or after some other inciting events, exogenous IL-1 beta released upon bleeding or as leakage of local capillaries may drive a proinflammatory response at the connective tissue cell level. The resulting induction of COX2, MMP-1 and -3 may underscore a potential for nonlymphocyte-mediated cytokine production of MMPs that causes matrix destruction and a loss of tendon biomechanical properties. Endogenous IL-1 beta might contribute to the process through a positive feedback loop by stimulating expression and accumulation of MMPs in the tendon matrix.

Theoretical limitations of the AOFAS scoring systems: an analysis using Monte Carlo modeling.

The AOFAS foot scores are four related outcome instruments based on the use of quantitative interval data and have seen increasing use in the literature. The mathematical construction of the scales is particularly notable for a very small number of intervals available to answer each component item and for quantitatively unequal intervals for some items. Monte Carlo computer modeling techniques were used to simulate the responses to each item for a variety of idealized patient populations with several different means, standard deviations, and levels of interaction between items. The continuous data describing each patient's responses were categorized into the finite number of available intervals in the AOFAS Hindfoot score. The resultant distributions of net scores often demonstrated bizarre, skewed behavior that bore little resemblance to the original distributions of continuous data. The effects were magnified as the ends of the scale were approached and when strong correlations between the items measuring pain and function were present. The distributions did not become distorted when the original continuous data were not rounded off into intervals but were simply weighted by their relative contribution to the AOFAS score and summed. The AOFAS scores, therefore, have inherently limited precision which is entirely due to the small number of response intervals available to answer each component item of the scale. Minor changes in a patient's response to a series of correlated questions can potentially make a drastic difference in their total score. Because the population distributions may be badly skewed, the use of parametric statistics with the AOFAS scores should be regarded with genuine suspicion, and appropriate refinements of the scales should be sought.

Flexor digitorum longus transfer and medial displacement calcaneal osteotomy for posterior tibial tendon dysfunction: a middle-term clinical follow-up.

HYPOTHESES/PURPOSE: The medial displacement calcaneal osteotomy has recently become a popular addition to flexor digitorum longus transfer for stage II posterior tibial tendon dysfunction. We reviewed the results of 26 patients who had undergone the procedure at an average of 32 months prior to follow-up (range 12 to 70 months) with particular attention to objective functional parameters. CONCLUSIONS/SIGNIFICANCE: FDL transfer and medial displacement calcaneal osteotomy provides good functional and symptomatic results in the middle-term. The operation preserves the majority of subtalar motion and is objectively durable as assessed by the continued ability to perform a single-leg toe rise. Although moderate radiographic improvement in the arch is frequent, often patients fail to notice this clinically. A prolonged period of steady improvement in symptoms after surgery is common. SUMMARY OF METHODS/RESULTS: Between 1993 and 1998, 26 patients underwent flexor digitorum longus transfer and medial displacement calcaneal osteotomy performed by the senior author. Sixteen returned for the study and were seen for physical exams. Three were included on the basis of chart review including one who was deceased and two who could not be contacted. Five further patients included on the basis of chart review were also contacted for telephone interviews. For the survival analysis, however, their last physical examination was used as the follow-up date. Two patients who had early technical failures were not interviewed but were counted as early failures of the procedure in the survival analysis. Functionally, all patients except three could perform a single-leg toe rise at follow-up, a maneuver none could perform preoperatively. Of these three, two cases were technical failures with loss of fixation of the FDL transfer early in the postoperative course, ultimately requiring revision procedures including one subtalar fusion. Another patient was a late failure after developing increasing pain and weakness during a pregnancy 69 months after the procedure. Clinically assessed subtalar motion remained 81 +/- 15% of the contralateral side in those patients with unilateral disease. Although improvement in the radiographic alignment of the foot was commonly noted, only 50% of patients felt the conformation of their foot had noticeably changed, and only one (4%) felt the improvement to be significant. Pain relief was rated excellent by 75% and good by 16%; the average AOFAS Hindfoot pain subscale score was 35.2 (out of 40 possible). Function was felt to be markedly improved by all patients except the three who were unable to perform a single-leg toe rise. The average score for the four functional symptom categories of the AOFAS score was 26.8 (out of 28 possible). Most patients noted that although they were able to perform daily activities after their postoperative immobilization was liberalized, there was a prolonged period of steady improvement in symptoms and function after surgery. The median length of time to self-rated maximal medical improvement was 10 months.

The compartments of the foot revisited. Rethinking the validity of cadaver infusion experiments.

Previous dye-infusion experiments on cadavers have suggested that the hindfoot should be divided into four muscle compartments including a newly described 'calcaneal' element containing quadratus plantae. Since there are no clinical data to support this proposed division, we re-examined the validity of the infusion experiment. We made infusions of dilute Omnipaque at a constant rate into flexor digitorum brevis of four cadaver feet. We monitored the spread of the infusate by real-time CT imaging and measured the pressures at the infusion site by side-ported needles. In all feet, the barrier between flexor digitorum brevis and quadratus plantae became incompetent at pressures of less than 10 mmHg. Pressure gradients in this range cannot be expected to affect tissue perfusion significantly and independently generate compartment syndromes. These results do not confirm those of previous studies carried out by uncontrolled and unmonitored injections made by hand. Injection studies in cadaver limbs can give dramatically different results depending upon the assumptions made when designing the experiment. The technique cannot adequately act as a model of the physiology of the compartment syndrome. As the existence of a physiologically significant compartmental boundary between flexor digitorum brevis and quadratus plantae is based solely on a cadaver infusion experiment the presence of a 'calcaneal' compartment has not been confirmed.

Compartmental divisions of the hand revisited. Rethinking the validity of cadaver infusion experiments.

The results of a cadaver dye-infusion experiment suggested that the hand has ten muscle compartments and that the volar interossei occupy a separate anatomical compartment from the adjacent dorsal interossei. This is not supported by clinical findings. With various minor modifications, we repeated the experiment, infusing Omnipaque into the second dorsal interosseus muscle of four cadaver hands. We used real-time CT imaging to monitor the spread of contrast medium and side-ported needles to measure compartmental pressures. In all four hands, the tissue barrier between dorsal and volar interossei became incompetent at pressures of less than 15 mmHg. Our data indicate that, although cadaver infusion studies can delineate potentially significant musculoskeletal barriers, their physiological relevance must be confirmed clinically.

Cumulative industrial trauma as an etiology of seven common disorders in the foot and ankle: what is the evidence?

The concept of cumulative industrial trauma as an etiology of orthopaedic disease has recently generated considerable attention in both the medical and legal communities. To clarify the current state of knowledge about the issue as applied to the foot and ankle, we critically reviewed the literature on the etiology of seven foot and ankle disorders commonly involved in compensation litigation in the practice of the senior author: hallux valgus, interdigital neuroma, tarsal tunnel syndrome, lesser toe deformity, heel pain, adult acquired flatfoot, and foot and ankle osteoarthritis. Koch's postulates were appropriately modified and used as a logistic framework to analyze the potential for cumulative industrial trauma to cause foot pathology. In none of the disorders analyzed could cumulative industrial trauma reasonably satisfy even one of Koch's three postulates. We conclude there is currently no unequivocal literature support upon which to invoke cumulative industrial trauma as a clear etiology of these disorders of the adult foot and ankle. The superb evolutionary adaptation of the human foot to prolonged ambulation and the absence of industrial demands that significantly differ from this task likely account for this dramatically reduced vulnerability of the foot to industrial repetitive motion disorders compared to the upper extremity.

The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease.

The foot deformities in CMT follow certain general patterns; however, like the underlying motor failures that cause them, the deformities present in each patient are unique, and care must be individualized. There is no simple algorithm that can be applied to all patients. The hindfoot, forefoot, and toe deformities in CMT all ultimately are interconnected. As a general rule, it makes sense to address the plantar fascia, then proceed from the hindfoot to the forefoot in analyzing the deformities and in surgery. Releasing the plantar fascia may alter the amount of bony correction required in any concomitant hindfoot procedure. Likewise, only after the heel is realigned can any residual forefoot valgus be assessed, and a hindfoot procedure may alter the resting tension of the digital flexors and extensors. Finally, if a patient has purely dynamic clawtoes preoperatively, the toes may appear perfectly normal in the operating room with the ankle plantar flexed. Tightness of the flexor digitorum longus should be elicited by bringing the ankle up to neutral as a final check. The variety of foot deformities in CMT present a unique challenge to the orthopedic foot and ankle surgeon. It is vital for the patient and physician to remember that CMT is an inexorably progressive disease, and an initially good result can deteriorate with changing motor function. With meticulous attention to the neurologic examination and the balance of supple and fixed deformities in the foot, very satisfying outcomes usually can be obtained.

Stulberg classification system for evaluation of Legg-Calvé-Perthes disease: intra-rater and inter-rater reliability.

BACKGROUND: Researchers and clinicians commonly use the classification system of Stulberg et al. as a basis for treatment decisions during the active phase of Legg-Calvé-Perthes disease because of its putative utility as a predictor of long-term outcome. It is generally assumed that this system has an acceptable degree of reliability. This assumption, however, is not convincingly supported by the literature. METHODS: The purpose of the present study was to assess the inter-rater and intra-rater reliability of the classification system of Stulberg et al. with use of a pre-test, post-test design. During the pre-test phase, nine raters independently used the system to evaluate the radiographs of skeletally mature patients who had been managed for Legg-Calvé-Perthes disease. The intervention between the pre-test and post-test phases consisted of a consensus-building session during which all raters jointly arrived at standardized definitions of the various joint structures that are assessed with use of the classification system. The effect of these definitions on reliability then was assessed by reevaluating the radiographs during the post-test phase. RESULTS: The pre-test intra-rater reliability coefficients ranged from 0.709 to 0.915, and the post-test coefficients ranged from 0.568 to 0.874. The pre-test inter-rater reliability coefficients ranged from 0.603 to 0.732, and the post-test coefficients ranged from 0.648 to 0.744. Contributing to the variance was a lack of agreement concerning the assessment of joint structures and the way in which the raters translated these evaluations into a classification according to the system of Stulberg et al. CONCLUSIONS: Although intra-rater reliability was marginally acceptable, the degree of variability between the classifications assigned by different raters even after the intervention - calls into question the reliability of the system of Stulberg et al.; consequently, the validity of any treatment decisions, outcome evaluations, or epidemiological studies based on this system is also in question.

Splenic contraction, catecholamine release, and blood volume redistribution during diving in the Weddell seal.

The spleen of the Weddell seal (Leptonychotes weddelli) may contract and inject red blood cells (RBCs) into the peripheral circulation during diving, but evidence for this hypothesis is indirect. Accordingly, we measured splenic dimensions by ultrasonography, plasma catecholamine concentrations, hemoglobin concentration, and hematocrit in five Weddell seals before and after intravenous epinephrine during halothane anesthesia and while awake at the surface after voluntary dives. Spleen size was reduced immediately after epinephrine injection or after the seal surfaced. Within the first 2 min after the seal surfaced, cephalocaudal splenic length was 71 +/- 2% (mean +/- SD; P < 0.05) and splenic thickness was 71 +/- 4% (P < 0.05) of the maximal resting values. Splenic size increased (half-time = 6-9 min) after the seal surfaced and was inversely correlated with plasma epinephrine and norepinephrine concentrations. Hemoglobin concentration increased from 17.5 +/- 5.3 g/dl (measured during general anesthesia) to 21.9 +/- 3.7 g/dl (measured in the first 2 min after surfacing). At these same times, the hematocrit increased from 44 +/- 12 to 55 +/- 8%. These values decreased (half-time = 12-16 min) after the seal surfaced. We estimate 20.1 liters of RBCs were sequestered at rest, presumably in the spleen, and released either on epinephrine injection or during diving. Catecholamine release and splenic contraction appear to be an integral part of the voluntary diving response of Weddell seals.

Hormonal regulatory adjustments during voluntary diving in Weddell seals.

Subadult male Weddell seals were instrumented with microcomputer-based backpacks and were then monitored during voluntary diving and recovery periods in McMurdo Sound, Antarctica. Depth and duration of diving, swim speed, and dive pattern were routinely monitored. An indwelling venous catheter was used to collect plasma samples at various time periods before and following diving episodes, so that changes in plasma concentrations of hormones and of metabolites could be measured. Adrenergic and nitroxidergic regulatory effects were assessed indirectly by measuring concentration changes in catecholamine and cyclic guanosine monophosphate (cGMP), respectively. The studies found that (i), except for dives of less than several minutes, epinephrine and norepinephrine both increased as a function of diving duration, then rapidly decreased during recovery (with a half time of about 10 min), (ii) that the changes in catecholamine concentrations correlated with splenic contraction and an increase in circulating red blood cell mass (hematocrit), (iii) that the changes in catecholamines, especially [epinephrine], were inversely related to insulin/glucagon ratios, which mediated a postdiving hyperglycemia, and (iv) that in long dives (but not short ones) the changes in catecholamines correlated with increasing reliance on anaerobic metabolism, indicated by increased plasma lactate concentrations. These diving-catecholamine relationships during voluntary diving at sea were similar to those observed during enforced submergence (simulated diving) under controlled laboratory conditions. At the end of diving, even while catecholamine concentrations were still high, many of the above effects were rapidly reversed and the reversal appeared to correlate with accelerated nitric oxide production, indirectly indicated by increased plasma cGMP concentrations. Taken together, the data led to the hypothesis of important adrenergic regulation of the diving response in seals, with rapid reversal at the end of diving and during recovery being regulated by nitroxidergic mechanisms.

Myoglobin saturation in free-diving Weddell seals.

Although the consumption of myoglobin-bound O2 (MbO2) stores in seal muscles has been demonstrated in seal muscles during laboratory simulations of diving, this may not be a feature of normal field diving in which measurements of heart rate and lactate production show marked differences from the profound diving response induced by forced immersion. To evaluate the consumption of muscle MbO2 stores during unrestrained diving, we developed a submersible dual-wavelength laser near-infrared spectrophotometer capable of measuring MbO2 saturation in swimming muscle. The probe was implanted on the surface of the latissimus dorsi of five subadult male Weddell seals (Leptonychotes weddelli) released into a captive breathing hole near Ross Island, Antarctica. Four seals had a monotonic decline of muscle O2 saturation during free diving to depths up to 300 m with median slopes of -5.12 +/- 4.37 and -2.54 +/- 1.95%/min for dives lasting < 17 and > 17 min, respectively. There was no correlation between the power consumed by swimming and the desaturation rate. Two seals had occasional partial muscle resaturations late in dives, indicating transfer of O2 from circulating blood to muscle myoglobin. Weddell seals partially consume their MbO2 stores during unrestrained free diving.

Continuous pulse oximetry in the breath-hold diving women of Korea and Japan.

Arterial oxygen saturation during breath-hold diving has not previously been measured continuously. We devised a submersible, waterproof, backpack computer to continuously record heart rate, depth, and arterial oxygen saturation (SPO2) as determined by earlobe pulse oximetry. Our measurements showed that one assisted (Funado) diver had reduced SPO2 values immediately after surfacing from 22 dives which lasted 23-76 s, from a mean of 99 +/- 1% SPO2 to 96 +/- 3% SPO2. SPO2 returned to 97 +/- 2% within 15 s after surfacing (P < 0.05 surface value differs from predive base line). Four unassisted (Cachido) divers showed no significant reduction of mean predive SPO2 below 98 +/- 2% at any time during the dive or recovery period in 92 routine dives lasting from 15 to 44 s. Upon surfacing from diving, mean SPO2 was 98 +/- 2% and the mean SPO2 15 s after surfacing was 97 +/- 3% for the unassisted divers. Three Cachido divers were asked to dive and breath hold for as long as possible. Mean SPO2 at the conclusion of breath holding was 73% after an average dive and breath hold lasting 69 s.

Arterial blood gas tensions during breath-hold diving in the Korean ama.

Korean female unassisted divers (cachido ama) breath-hold dive > 100 times to depths of 3-7 m during a work day. We sought to determine the extent of arterial hypoxemia during normal working dives and reasonable time limits for breath-hold diving by measuring radial artery blood gas tensions and pH in five cachido ama who dove to a fixed depth of 4-5 m and then continued to breath hold for various times after their return to the surface. Eighty-two blood samples were withdrawn from indwelling radial artery catheters during 37 ocean dives. We measured compression hyperoxia [arterial PO2 = 141 +/- 24 (SD) Torr] and hypercapnia (arterial PCO2 = 46.6 +/- 2.4 Torr) at depth. Mean arterial PO2 near the end of breath-hold dives lasting 32-95 s (62 +/- 14 s) was decreased (62.6 +/- 13.5 Torr). Mean arterial PCO2 reached 49.9 +/- 5.4 Torr. Complete return of these values to their baseline did not occur until 15-20 s after breathing was resumed. In dives of usual working duration (< 30 s), blood gas tensions remained within normal ranges. Detailed analysis of hemoglobin components and intrinsic oxygenation properties revealed no evidence for adaptive changes that could increase the tolerance of the ama to hypoxic or hypothermic conditions associated with repetitive diving.