Risk factors associated with exertional medial tibial pain: a 12 month prospective clinical study.

OBJECTIVE: To investigate in a military setting the potential role of intrinsic biomechanical and anthropometric risk factors for, and the incidence of, exertional medial tibial pain (EMTP). METHODS: A prospective clinical outcome study in a cohort of 122 men and 36 women at the Australian Defence Force Academy. Each cadet underwent measurements of seven intrinsic variables: hip range of motion, leg length discrepancy, lean calf girth, maximum ankle dorsiflexion range, foot type, rear foot alignment, and tibial alignment. Test-retest reliability was undertaken on each variable. A physician recorded any cadet presenting with diagnostic criteria of EMTP. Records were analysed at 12 months for EMTP presentation and for military fitness test results. RESULTS: 23 cadets (12 men, 11 women) met the criteria for EMTP after 12 months, with a cross gender (F/M) odds ratio of 3.1. In men, both internal and external range of hip motion was greater in those with EMTP: left internal (12 degrees, p = 0.000), right internal (8 degrees, p = 0.014), left external (8 degrees, p = 0.042), right external (9 degrees, p = 0.026). Lean calf girth was lower by 4.2% for the right leg (p = 0.040) but by only 2.9% for the left leg (p = 0.141). No intrinsic risk factor was associated with EMTP in women. EMTP was the major cause for non-completion of the run component of the ADFA fitness test in both men and women. CONCLUSIONS: Greater internal and external hip range of motion and lower lean calf girth were associated with EMTP in male military cadets. Women had high rates of injury, although no intrinsic factor was identified. Reasons for this sex difference need to be identified.

Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation.

Immune heparin-induced thrombocytopenia (HIT) is associated with antibodies directed against a complex of platelet factor 4 (PF4) and heparin. We were able to affinity purify anti-PF4-heparin IgG (HIT IgG) from the plasma of 2 patients with HIT. Under conditions that were more physiological and sensitive than those in previous studies, we observed that this HIT IgG caused platelet aggregation on the addition of heparin. Platelets activated with HIT IgG increased their release and surface expression of PF4. We quantitated, for the first time, the binding of affinity-purified HIT iodine 125-IgG to platelets as they activated in a plasma milieu. Binding of the HIT IgG was dependent on heparin and required some degree of platelet activation. Blocking the platelet FcgammaRII with the monoclonal antibody IV.3 did not prevent HIT IgG binding to activated platelets. We concluded that anti-PF4-heparin IgG is the component in these HIT plasmas that induces platelet aggregation. The Fab region of HIT IgG binds to PF4-heparin on the surface of activated platelets. We propose that only then does the Fc portion of the bound IgG further activate the same or adjacent platelets through the Fc receptor. Our data support a dynamic model of platelet activation in which released PF4 enhances further antibody binding and more release.

Further characterization of antibody and antigen in heparin-induced thrombocytopenia.

Patients with immune heparin-induced thrombocytopenia (HIT) possess antibodies that bind to a complex of platelet factor 4 (PF4) and heparin. We observed that HIT antibodies will also bind to PF4 alone adsorbed on polystyrene ELISA wells but not to soluble PF4 in the absence of heparin. Having developed a technique to affinity-purify anti-PF4-heparin HIT IgG, we are able to provide the first estimates of the avidity of HIT IgG. HIT IgG displayed relatively high functional affinity for both PF4-heparin (Kd = 7-30 nM) and polystyrene adsorbed PF4 alone (Kd = 20-70 nM). Furthermore, agarose beads coated with PF4 alone were almost as effective as beads coated with PF4 plus heparin in depleting HIT plasmas of anti-PF4-heparin antibodies. We conclude that the HIT antibodies which bind to polystyrene adsorbed PF4 without heparin are largely the same IgG molecules that bind PF4-heparin and therefore most HIT antibodies bind epitope(s) on PF4 and not epitope(s) formed by part of a PF4 molecule and part of a heparin molecule. Binding of PF4 to heparin (optimal) or polystyrene/agarose (suboptimal) promotes recognition of this epitope.

Heparin-induced thrombocytopenia: IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid.

Early diagnosis of heparin-induced thrombocytopenia (HIT) is essential to reduce morbidity and mortality. We report an enzyme immunoassay which detects the binding of HIT IgG to PF4-heparin in the fluid phase. Our fluid phase assay produces consistently low background and can detect low levels of anti-PF4-heparin. It is suited to testing alternative anticoagulants because, unlike in an ELISA, a clearly defined amount of antigen is available for antibody binding. We were able to detect anti-PF4-heparin IgG in 26/28 (93%) HIT patients. We investigated cross-reactivity of anti-PF4-heparin antibodies with PF4 complexed to alternative heparin-like anticoagulants. Low molecular weight heparins cross-reacted with 23/26 (88%) of the sera from HIT patients while half of the HIT sera weakly cross-reacted with PF4-danaparoid (Orgaran). The thrombocytopenia and thrombosis of most of these patients resolved during danaparoid therapy, indicating that detection of low affinity antibodies to PF4-danaparoid by immunoassay may not be an absolute contraindication for danaparoid administration.

Regulation of adhesion molecule expression by human synovial microvascular endothelial cells in vitro.

OBJECTIVE: To examine the in vitro expression of E-selectin, P-selectin, intercellular adhesion molecule 1 (ICAM-1), ICAM-2, vascular cell adhesion molecule 1 (VCAM-1), and platelet-endothelial cell adhesion molecule 1 (PECAM-1) by synovial microvascular endothelial cells (SMEC) in comparison with microvascular neonatal foreskin endothelial cells (FSE) and macrovas- cular human umbilical vein endothelial cells (HUVE). METHODS: Cultured endothelial cells were treated for 4 hours with medium alone or tumor necrosis factor alpha (TNF alpha). The expression of endothelial adhesion molecules was evaluated by flow cytometry, cell enzyme-linked immunosorbent assay, and Northern blot analysis. RESULTS: SMEC continuously expressed E-selectin under basal culture conditions, whereas FSE and HUVE did not. TNF alpha treatment of rheumatoid arthritis (RA) SMEC resulted in sustained peak expression of E- selectin for up to 24 hours, which subsequently declined but remained elevated even at 72 hours. In contrast, peak E-selectin expression in FSE and HUVE occurred between 4 hours and 16 hours after TNF alpha treatment and then declined to near basal levels by 24-48 hours. SMEC expressed significantly higher levels of ICAM-1 compared with HUVE under basal culture conditions. There was no difference between SMEC, FSE, and HUVE in the expression of P-selectin, VCAM-1, ICAM-2, or PECAM-1. Northern blot analysis demonstrated that the levels of E-selectin expression by TNF alpha stimulated endothelial cells correlated with their respective messenger RNA levels. CONCLUSION: Regulation of E-selectin and ICAM-1 expression in RA synovial endothelium is different from that in neonatal foreskin and human umbilical vein endothelium. The augmented expression of adhesion molecules in RA synovial endothelium may facilitate the recruitment of leukocytes to this site.

Single tooth, implant-stabilized crowns replacing anterior teeth: a clinical comparison of two systems.

Implant-supported single-tooth crowns are suitable alternative restorations to partial dentures and bridges. A number of systems have been developed to create a good aesthetic result without the display of the standard titanium abutment traditionally used in restorations with complete fixed prostheses supported by titanium endosseous implants. This paper reviews two such systems.

Effect of gold sodium thiomalate and its thiomalate component on the in vitro expression of endothelial cell adhesion molecules.

Endothelial adhesion molecules play an important role in the tissue recruitment of leukocytes in inflammatory conditions such as rheumatoid arthritis. We have investigated the effect of the antirheumatic drug gold sodium thiomalate on adhesion molecule protein and mRNA expression in cultured human endothelial cells. Gold sodium thiomalate inhibited cytokine (TNF, IL-1, IL-4)-stimulated expression of vascular cell adhesion molecule-1 and E-selectin but not intercellular adhesion molecule-1 on endothelial cells. Gold sodium thiomalate also suppressed TNF-stimulated increases in vascular cell adhesion molecule-1 and E-selectin mRNA levels but had no effect on intercellular adhesion molecule-1 mRNA. Thiomalate (mercaptosuccinate), but not gold thioglucose or D-penicillamine, mimics the effect of gold sodium thiomalate at equimolar concentrations. We propose that the inhibition of vascular cell adhesion molecule-1 and E-selectin expression by gold sodium thiomalate is due to its thiomalate and not its gold component. Gold sodium thiomalate has a direct effect on endothelial adhesion molecule expression, and this may contribute to its antiinflammatory activity.

Endotoxaemia in multiple organ failure due to sepsis.

Patients with multiple organ failure secondary to intraabdominal sepsis are often blood culture negative despite exhibiting the features of septic shock. This study examined the possible central role of endotoxin in such patients. In 15 consecutive intensive care patients with the above clinical picture endotoxin was measured by a chromogenic limulus (LAL) assay; on admission and thereafter 4 hourly. Regular blood cultures and cultures of any primary septic focus were also performed and liver function was assessed by measurement of indocyanine-green clearance from plasma (ICGC). All 15 patients had significant endotoxaemia at least intermittently. No significant difference was observed between survivors (n = 5) and non-survivors (n = 10) in either initial or peak endotoxin levels, although the pattern of endotoxaemia differed with non-survivors exhibiting consistently high or steadily increasing levels. Of 5 patients with an intra-abdominal (I/A) septic focus only one had a positive blood culture while 5 of 10 patients with extra-abdominal (E/A) infection had positive cultures. Despite this the I/A group had higher initial and peak endotoxin levels. 3 patients with Gram-positive septicaemia had significant endotoxaemia in the absence of any gram-negative infection. Changes in ICGC appeared to be of useful prognostic significance. ICGC was significantly lower in the I/A group and in both groups there was a significant negative correlation between ICGC and the level of endotoxaemia. These results suggest that endotoxin may play a central role in the syndrome of multiple organ failure and further suggest that the endotoxin is endogenous (gut-derived) secondary to failure of hepatic filtration.

Sedation in intensive care: morphine and renal function.

Intravenous morphine infusions have been administered to 12 critically-ill patients during controlled ventilation. Acute oliguric renal failure was present in 4 patients, who were treated with a combination of haemofiltration and haemodialysis. Severity of physiological disturbance was assessed using a modified APACHE Score, level of sedation by a linear-analogue scale, and blood morphine levels by high-pressure liquid chromatography. Morphine clearance was impaired in renal failure, and was dependent on haemofiltration volumes; accumulation of morphine did not occur during this form of treatment. Conscious level was clearly more closely related to the degree of physiological disturbance than blood morphine levels; and for a given blood morphine level, depression of consciousness was more pronounced the greater the degree of physiological disturbance. Use of a physiological sickness score may help to clarify some of the factors influencing cerebral function during critical illness. Careful clinical monitoring of level of sedation is important in patients with oliguric renal failure receiving morphine, and haemofiltration appears to reduce the risk of morphine accumulation in these patients.

Tizanidine in the treatment of spasticity.

A double-blind crossover trial compared tizanidine with baclofen in 36 patients with spasticity. Tizanidine appeared to reduce lower limb spasticity more effectively and to have fewer side effects, but no statistically significant differences emerged when the two drugs were compared. An additional open study of tizanidine confirmed the beneficial action in a selected minority of patients with spasticity. This drug may have an important role in the management of spasticity, but further studies are required.