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Tibial plateau fracture is a rare complication of unicompartmental knee arthroplasty. The fracture almost always occurs during surgery, and it is likely to be the result of a technical error, usually an unnecessarily deep vertical saw cut into the proximal tibia. However, anything that weakens or overloads the proximal tibia may contribute to fracture, such as damage to the posterior cortex, excess removal of bone particularly in small patients with osteopenic bones, inadequate preparation of the keel slot, or use of excessive force with a heavy hammer. This series of eight case reports presents our experience with this complication after medial Oxford unicompartmental knee arthroplasty and outlines a treatment protocol.

About one-third of osteoarthritic patients requiring knee replacement have focal lesions limited mainly to the medial compartment and can achieve excellent postoperative function after medial unicompartmental replacement. However, late failures of many unicompartmental prostheses require revision at a rate about twice that of total knee replacement. The use of a fully conforming mobile-bearing meniscal unicompartmental prosthesis in the hands of experienced surgeons can reduce revision rates to levels equivalent to the best results achieved with total knee replacement. The paper argues the case for such a prosthesis and demonstrates that the usual modes of failure of unicompartmental arthroplasty, most of them biomechanical, can thereby be avoided.

Purpose: To report the prevalence of intraocular lens (IOL) opacification and related clinical features in patients implanted with Hydroview IOL., Setting: Gloucestershire Eye Unit, Gloucestershire, United Kingdom., Methods: A total of 1330 eyes of 1265 patients who had cataract surgery with Hydroview IOL implantation between September 2000 and April 2001 were reviewed between April and October 2004. The visual acuity, visual symptoms, IOL status, and associated ocular comorbidity were recorded., Results: One hundred ninety-three (14.5%) of 1330 eyes had evidence of IOL opacification. A total of 56 (4.2%) had visually significant opacification and had IOL exchange. The prevalence of IOL opacification ranged from 1.1% in patients who had surgery in September 2000 to 36.3% in the December 2000 group. In eyes with IOL opacification, the visual symptoms were decreased vision (57%), glare (32%), and mistiness of vision (27%). One hundred forty-four eyes (75%) with IOL opacification had visual acuity of 6/12 or better; 21.5% of diabetic eyes had IOL opacification compared with 14.3% of nondiabetic eyes (P =.06); 20.5% of glaucomatous eyes had IOL opacification compared with 14.0% of nonglaucomatous eyes (P = .033)., Conclusions: This is the first large sample recall of patients implanted with the Hydroview H60M IOL. The overall prevalence of IOL opacification was 14.5%, with peak prevalence in patients who had surgery in December 2000.

Aims: To test whether measuring hyperaemic changes in pulse wave velocity (PWV) could be used as a new method of assessing endothelial function for use in clinical practice., Methods and Results: Flow-mediated changes in vascular tone may be used to assess endothelial function and may be induced by distal hyperaemia, while endothelium-mediated changes in vascular tone can influence PWV. These three known principles were combined to provide and test a novel method of measuring endothelial function by the acute effects of distal hyperaemia on upper and lower limb PWV (measured by a recently developed method). Flow-mediated changes in upper and lower limb PWV were compared in 17 healthy subjects and seven patients with stable chronic heart failure (CHF), as a condition where endothelial function is impaired but endothelium-independent dilator responses are retained. Corroborative measurements of PWV and brachial artery diameter responses to endothelium-dependent and -independent pharmacological stimuli were performed in a further eight healthy subjects. Flow-mediated reduction of PWV (by 14% with no change in blood pressure) was found in normal subjects but was almost abolished in patients with CHF. PWV responses appear to be inversely related to and relatively greater than brachial artery diameter responses., Conclusion: The method may offer potential advantages of practical use and sensitivity over conduit artery diameter responses to measure endothelial dysfunction.

We conducted this pilot cadaver study to investigate whether the use of a navigation system during minimally invasive unicompartmental knee arthroplasty leads to more consistent results than the conventional hand-guided technique. We describe the accuracy of implant positioning in using standard instrumentation and computer navigation. Radiographic assessment showed that accurate component placement was achieved using both methods. These results were not statistically significant. The computer navigated femoral component placement without intramedullary (IM) rod was as accurate as the conventional method with IM rod. The study showed that computer navigation can produce accurate results even without an intramedullary rod. Image guidance can maintain the accuracy of the standard instrumentation and enhance 3D vision and the intraoperative orientation of the surgeon.

Experimental hyperhomocysteinemia after an oral methionine or homocysteine load is associated with impaired nitric oxide-dependent vasodilatation in healthy human beings. However, it remains unproven that this effect is mediated by elevations in plasma homocysteine. There is evidence that an increase in plasma homocysteine may increase the formation of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase. The methyl groups within ADMA are derived from the conversion of S -adenosylmethionine to S -adenosylhomocysteine intermediates in the methionine/homocysteine pathway. No previous study has assessed the role of methylation status, its impact on ADMA formation, and their association with endothelial function in healthy human beings. In a randomized, placebo-controlled, crossover study, 10 healthy subjects (mean age, 29.1 +/- 3.9 years) were administered an oral dose of methionine (0.1 g/kg), l -homocysteine (0.01 g/kg), N-acetylcysteine (NAC) (0.1 g/kg), or placebo. Endothelial function as assessed by flow-mediated dilatation (FMD) of the brachial artery was impaired after both the methionine and homocysteine load compared with placebo at 4 hours (36 +/- 15, 67 +/- 23 vs 219 +/- 26 microm, respectively, P < .001). N-Acetylcysteine had no effect on flow-mediated dilatation. Plasma total homocysteine was significantly elevated at 4 hours after methionine (23.1 +/- 6.2) and homocysteine (41.5 +/- 8.9) loading, but significantly reduced after NAC 2.4 +/- 0.6 vs 7.1 +/- 2.1 micromol/L in the placebo (P < .001). Plasma S-adenosylmethionine/S-adenosylhomocysteine ratio was significantly (P < .001) increased at 4 hours after methionine (10.9 +/- 0.7) compared with homocysteine (5.4 +/- 0.4), NAC (5.0 +/- 0.3), and placebo (6.0 +/- 0.5). Plasma ADMA concentrations were not altered by any intervention. Our results suggest that endothelial dysfunction due to methionine or homocysteine loading is not associated with an increase in plasma ADMA or a disruption in methylation status.

Medial unicompartmental knee replacement (UKR) has many advantages over total replacement (TKR) including better function and reduced morbidity. However, the long-term failure rates of fixed-bearing UKR are high, especially because of polyethylene wear. The fully congruent mobile bearing of the Oxford UKR exhibits minimal polyethylene wear, failure from this cause does not seem to occur before 10 years. The instrumentation allows precise implantation to restore isometric function of the ligaments. During its 20 years development, the limits of usefulness of the implant have been established and found to include about one in four knees requiring replacement for osteoarthritis. In an independent series, using these criteria, the 15 year survival was 94%. Since 1998, the phase 3 implant has been used with modified instruments through a small incision, avoiding damage to the extensor mechanism. Patients now recover about three times faster than after TKR, and regain much better flexion (mean 135 degrees ). The current evidence supports that the minimally invasive Oxford UKR should be seriously considered as primary treatment for anteromedial compartment osteoarthritis-provided the appropriate surgical expertise is available.

Background and Objective: Endothelial dysfunction is an early, pre-clinical manifestation of coronary heart disease and is associated with increased plasma levels of von Willebrand factor (vWF), soluble E-selectin, and thrombomodulin, markers of endothelial cell damage/activation and reduced nitric oxide bioavailability. Homocysteine is associated with an increased risk of cardiovascular disease and mortality. High-dose folic acid treatment lowers plasma homocysteine by 25% and improves nitric oxide bioavailability; however, the effects on other indices of endothelial cell activation/damage has not been examined in patients with coronary heart disease and normal renal function., Design and Methods: In a randomised, double-blind, cross-over study in 50 patients with coronary heart disease and normal serum creatinine, folic acid (5 mg/daily) was administered for 6 weeks and blood was analysed for von Willebrand factor, soluble E-selectin, and thrombomodulin. Endothelial nitric oxide bioavailability was assessed by flow-mediated dilatation., Results: Plasma folate levels increased (9.1+/-3.4 vs. 310+/-235 microg/l; p<0.001) and nitric oxide bioavailability improved (47+/-35 vs. 110+/-43 microm; p<0.001) following active treatment. However, markers of endothelial cell injury were not significantly influenced (von Willebrand factor 118+/-33 vs. 119+/-34%; E-selectin 52+/-17 vs. 51+/-16 microg/l; thrombomodulin 3.94+/-1.81 vs. 3.94+/-1.51 microg/l; p=NS comparing post-placebo with post-folate). No correlation was observed between improvement in flow-mediated dilatation and change in endothelial marker proteins., Interpretation and Conclusion: These data suggest that endothelial markers are not useful surrogates of endothelial nitric oxide bioavailability in coronary heart disease and may be a less sensitive marker of endothelial function than nitric oxide.

Evidence reported from numerous clinical studies over the past decade has revealed an association between increased plasma total homocysteine (tHcy) concentrations and cardiovascular disease (CVD). In addition, epidemiological studies have identified an inverse association between blood folate concentrations, folate intake and cardiovascular endpoints, that are independent of homocysteine. Folic acid supplementation can lower plasma tHcy concentrations safely and inexpensively. Furthermore, folic acid can reverse endothelial dysfunction observed in patients with CVD. This reversal in endothelial dysfunction with folic acid has been shown to be independent of plasma tHcy lowering, suggesting that folate has pleiotropic effects on the vasculature other than homocysteine lowering. In vitro evidence demonstrates that 5-methyltetrahydrofolate (5MeTHF) the main circulating metabolite of folate, can increase nitric oxide production and can directly scavenge superoxide radicals. The potential beneficial role of folic acid supplements on vascular disease are currently being tested in randomized placebo controlled studies.

Elevated plasma homocysteine is associated with increased cardiovascular risk but it remains unproven that the effect is directly causal. Folate and homocysteine metabolism are closely linked such that administration of folic acid in doses ranging from 0.2-10 mg/day lowers plasma total homocysteine (tHcy) by up to 25%. Folic acid has been widely advocated as a therapy which may reduce cardiovascular risk, but the clinical benefit remains as yet unproven and the choice of dose remains unclear. The effect of folic acid on endothelial function has been investigated in patients with proven coronary heart disease (CHD) by measuring flow-mediated dilatation (FMD) in the brachial artery. Oral folic acid (5 mg/day) markedly enhances endothelial function (FMD) and lowers homocysteine. Studies of the acute effects of folic acid have shown that this improvement occurs within the first 2-4 hours following the first dose, at which times there was no significant reduction in plasma tHcy. Administration of 5-methyltetrahydrofolate directly into the brachial artery markedly enhances FMD, an effect that is blocked by monomethyl arginine (LNMMA), suggesting that the effects of folate are mediated by nitric oxide. This Review summarises studies which show that pharmacological doses of folate markedly enhance endothelial function in patients with CHD. The discordance with changes in plasma homocysteine suggests that these effects may occur by mechanisms distinct from homocysteine lowering.

Plant ns-LTPs display an original structure with four helices and a flexible C-terminus, maintained together by four disulphide bridges and delineating an elongated central hydrophobic cavity. In order to relate these structural features to the protein stability and plasticity, combined molecular mechanics and simulated annealing calculations were undertaken on a wheat ns-LTP "mutant" with Cys-Ala replacement and with the application of core inter-residue restraints up to 2 A, reducing the cross-section size of the hydrophobic cavity. Analysis of the energy-minimized structures shows that removal of the disulphide bridges results in structures with a lower total energy and a smaller cavity volume. A 1-ns MD simulation at 300K in water, underlines that, despite the absence of a well-packed hydrophobic core, the native structure is extremely stable at room temperature and the cavity is not hydrated. This confirms that the disulphide bridges are essential for the existence of the cavity, whereas its plasticity depends both on the hydrophobic chain lining the cavity and on the C-terminal flexibility. A high temperature (500K) MD simulation confirms the stability of the secondary structure elements and the flexibility of the loops and of the C-terminal segment. Two important structural transitions during this simulation are discussed and possible routes for the insertion and release of hydrophobic ligands are suggested.

Although GH deficiency may underlie the increased cardiovascular risk in adult hypopituitarism, other coexisting hormonal deficiencies and/or unphysiological hormone replacement may contribute. L-Deamino-8-D-arginine (DDAVP), when administered parenterally, potentiates hemostasis by increasing plasma procoagulant factors. We investigated whether chronic intranasal DDAVP therapy influences clotting factors (plasma fibrinogen, factor VIII, and von Willebrand factor antigen) and endothelial function (flow-mediated dilation of the brachial artery) in 30 GH-treated hypopituitary subjects, including both DDAVP-treated subjects (group A) (mean age, 46 +/- 11 yr) and vasopressin-sufficient subjects (group B) (mean age, 47 +/- 16 yr). Fifteen healthy controls (group C) (mean age, 48 +/- 12 yr) were also studied. All hypopituitary patients were receiving stable GH replacement (median duration, 19 months). Comparing the three groups, concentrations of fibrinogen (mean +/- SD) (A, 3.3 +/- 1.0 g/liter vs. B, 3.5 +/- 0.9 vs. C, 2.6 +/- 0.8, P < 0.05), factor VIII (A, 130% +/- 30% vs. B, 128% +/- 30% vs. C, 104% +/- 35%, P < 0.05) and von Willebrand factor antigen (A, 124% +/- 35% vs. B, 134% +/- 45% vs. C, 93% +/- 36%, P < 0.05) were higher in hypopituitary subjects, compared with controls. However, there were no differences in clotting factors between groups A and B. Flow-mediated dilation did not differ significantly between the two hypopituitary groups (A, 5.9% +/- 2.0% vs. B, 4.7% +/- 1.6%) and was similar to that in the control group (C, 5.7% +/- 2.1%). In conclusion, although endothelium-dependent vasodilation is intact in GH-treated hypopituitary adults, elevated concentrations of hemostatic markers suggest the persistence of a prothrombotic tendency and endothelial dysfunction. Intranasal DDAVP does not appear to influence this proatherogenic profile in hypopituitary adults with vasopressin deficiency.

A reduction in pH is known to induce the disassociation of the tetrameric form of transthyretin and favor the formation of amyloid fibers. Using continuum electrostatic techniques, we calculate the titration curves and the stability of dimer and tetramer formation of transthyretin as a function of pH. We find that the tetramer and the dimer become less stable than the monomer as the pH is lowered. The free energy difference is 13.8 kcal/mol for dimer formation and 27 kcal/mol for tetramer formation, from the monomers, when the pH is lowered from 7 to 3.9. Similar behavior is observed for both the wild-type and the mutant protein. Certain residues (namely Glu-72, His-88, His-90, Glu-92, and Tyr-116), play an important role in the binding process, as seen by the considerable pK(1/2) change of these residues upon dimer formation.

The time course of acute changes in large artery distensibility immediately and for 60 min following maximum treadmill exercise in normal subjects was characterized by simultaneously measuring upper and lower limb pulse wave velocity (PWV). A new oscillometric technique was used, which has proven to be sensitive to changes in distensibility induced by acute changes in vascular tone independently of blood pressure. The observed changes in PWV are attributable to changes in vascular tone corresponding to recovery from a systemic net constrictor response and a local net dilator response to exercise with persisting postexercise vasodilatation. They are inadequately explained by associated changes in blood pressure and cannot be attributed to changes in heart rate or viscosity. Modeled as a system of n coupled linear differential equations, the minimum (and adequate) order required to reproduce these patterns was n = 1 for the upper and n = 2 for the exercising lower limb. The economy of the solution suggests entrainment among the multiple interactive mechanisms governing vasomotor control.

Before proceeding to longer-term studies, we have studied the early clinical results of a new mobile-bearing total knee prosthesis in comparison with an established fixed-bearing device. Patients requiring bilateral knee replacement consented to have their operations under one anaesthetic using one of each prosthesis. They also agreed to accept the random choice of knee (right or left) and to remain ignorant as to which side had which implant. Outcomes were measured using the American Knee Society Score (AKSS), the Oxford Knee Score (OKS), and determination of the range of movement and pain scores before and at one year after operation. Preoperatively, there was no systematic difference between the right and left knees. One patient died in the perioperative period and one mobile-bearing prosthesis required early revision for dislocation of the meniscal component. At one year the mean AKSS, OKS and pain scores for the new device were slightly better (p < 0.025) than those for the fixed-bearing device. There was no difference in the range of movement. We believe that this is the first controlled, blinded trial to compare early function of a new knee prosthesis with that of a standard implant. It demonstrates a small but significant clinical advantage for the mobile-bearing design.

Aims/hypothesis: Reduced bioavailability of endothelium-derived nitric oxide is implicated in diabetic macrovascular and microvascular disease. In patients with diabetes, we hypothesised that protein glycosylation can alter nitric oxide binding affinity of haemoglobin and plasma proteins, hence reducing nitric oxide availability and causing an alteration in nitric oxide metabolism., Methods: Binding of nitric oxide to haemoglobin was studied across a range of glycosylation levels in vitro (HbA(1c) 5.9 to 9.8%). In clinical studies nitrate, nitrite, nitrosyl haemoglobin and plasma nitrosothiols were measured in venous blood from 23 patients with uncomplicated Type I (insulin-dependent) diabetes mellitus and 17 non-diabetic control subjects. Samples were analysed at baseline and after nitric oxide was added ex vivo., Results: Nitric oxide-haemoglobin binding was increased at a HbA(1c) greater than 8.5% compared with 5.9% (p<0.01). Basal nitrosyl haemoglobin was higher in diabetic patients compared with the control subjects (0.59+/-0.12 micro mol/l vs 0.24+/-0.12 micro mol/l, p<0.05). Plasma nitrosothiols, and nitrite and nitrate (NOx) concentrations were similar in diabetic patients compared with the control subjects (7.64+/-0.79 micro mol/l vs 5.93+/-0.75 micro mol/l, 13.98+/-2.44 micro mol/l vs 12.44+/-2.15 micro mol/l, respectively). In blood from diabetic patients, added nitric oxide was metabolised preferentially to nitrosyl haemoglobin and plasma nitrosothiols, with a twofold increase in nitrosyl haemoglobin observed across all concentrations of nitric oxide (p<0.05). These preferential increases correlated positively with HbA(1c)., Conclusion/interpretation: Nitrosyl haemoglobin is increased in patients with Type I diabetes. Preferential metabolism to nitrosyl haemoglobin and nitrosothiols occurs after increases in nitric oxide. Our results show an accentuated association between nitric oxide and glycosylated proteins, especially deoxygenated haem. An altered metabolic fate of nitric oxide could influence microvascular regulation and tissue perfusion.

Rapid detection and accurate identification of methicillin-resistant staphylococci are critical for the effective management of infections caused by these organisms. We describe a multiplex PCR-based assay for the direct detection of methicillin-resistant staphylococci from blood culture bottles (BacT/Alert; Organon-Teknika, Durham, N.C.). A simple lysis method followed by a multiplex PCR assay designed to detect the nuc, mecA, and bacterial 16S rRNA genes was performed. A total of 306 blood culture specimens were collected over a period of 10 months from June 1998 to April 1999, consisting of 236 blood cultures growing staphylococci (including 124 methicillin-resistant Staphylococcus spp.), 50 positive blood cultures which grew organisms other than staphylococci, and 20 blood cultures that were negative for bacterial and fungal pathogens after 5 days of incubation and terminal subculture. DNA extraction, PCR, and detection could be completed in 2.5 h. Of the positive blood cultures with staphylococci, the multiplex PCR assay had a sensitivity and specificity of 99.2% and 100%, respectively. Our results show that rapid, direct detection of methicillin-resistant staphylococci is possible, allowing clinicians to make prompt and effective decisions for the management of patients with staphylococcal bacteremia.

An increased incidence of dislocation is the most important potential disadvantage introduced by the use of meniscal-bearing prostheses. The aim of this in vitro study was to measure the resistance to dislocation of a meniscal-bearing total knee arthroplasty in various circumstances and to establish which anatomic structures contribute to bearing stability. The prosthesis was implanted into cadaver knee specimens mounted in a 6 df rig. Dislocation was provoked by applying anteriorly or posteriorly directed forces (20-100N) to the tibia in the plane of the tibial plateau. Dislocation was defined as any stable displacement of the bearing (relative to the tibia or the femur) that persisted after release of the load applied to provoke it. The specimens were tested in an arc of knee flexion between 30 degrees and 90 degrees, with and without simulated quadriceps loads, with and without abducting and adducting loads, and before and after division of the posterior cruciate ligament and the lateral retinaculum. In the presence of quadriceps load, dislocation could not be provoked. In the absence of quadriceps load, dislocation was not provoked by posteriorly directed force but sometimes was caused by anteriorly directed force. All but 1 of the dislocations were unicompartmental, the lateral compartment proving much less stable than the medial. The tendency toward dislocation increased from 30 degrees to 60 degrees and from 60 degrees to 90 degrees of knee flexion. Adducting moments applied to the knee caused lift-off of the lateral femoral condyle from the bearing and increased the tendency toward dislocation. Abducting moments had the opposite effect. Division of the posterior cruciate ligament had no significant effect. Division of the lateral retinaculum increased the tendency toward dislocation. A femoral component that can be implanted without lateral release is desirable., (Copyright 2002, Elsevier Science (USA).)

Background: Homocysteine is a risk factor for coronary artery disease (CAD), although a causal relation remains to be proven. The importance of determining direct causality rests in the fact that plasma homocysteine can be safely and inexpensively reduced by 25% with folic acid. This reduction is maximally achieved by doses of 0.4 mg/d. High-dose folic acid (5 mg/d) improves endothelial function in CAD, although the mechanism is controversial. It has been proposed that improvement occurs through reduction in total (tHcy) or free (non-protein bound) homocysteine (fHcy). We investigated the effects of folic acid on endothelial function before a change in homocysteine in patients with CAD., Methods and Results: A randomized, placebo-controlled study of folic acid (5 mg/d) for 6 weeks was undertaken in 33 patients. Endothelial function, assessed by flow-mediated dilatation (FMD), was measured before, at 2 and 4 hours after the first dose of folic acid, and after 6 weeks of treatment. Plasma folate increased markedly by 1 hour (200 compared with 25.8 nmol/L; P<0.001). FMD improved at 2 hours (83 compared with 47 microm; P<0.001) and was largely complete by 4 hours (101 compared with 51 microm; P<0.001). tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79 micromol/L; P=NS). fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55 compared with 1.78 micromol/L; P=0.02). FMD improvement did not correlate with reductions in either fHcy or tHcy at any time., Conclusions: These data suggest that folic acid improves endothelial function in CAD acutely by a mechanism largely independent of homocysteine.

Flow-mediated dilatation (FMD) of the brachial artery assessed by high-resolution ultrasound is widely used to measure endothelial function. However, the technique is not standardized, with different groups using occlusion of either the wrist or the upper arm to induce increased blood flow. The validity of the test as a marker of endothelial function rests on the assumption that the dilatation observed is endothelium-dependent and mediated by nitric oxide (NO). We sought to compare the NO component of brachial artery dilatation observed following wrist or upper arm occlusion. Dilatation was assessed before and during intra-arterial infusion of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) following occlusion of (i) the wrist (distal to ultrasound probe) and (ii) the upper arm (proximal to ultrasound probe) for 5 min in ten healthy males. Dilatation was significantly greater after upper arm occlusion (upper arm, 11.62+/-3.17%; wrist, 7.25+/-2.49%; P=0.003). During L-NMMA infusion, dilatation after wrist occlusion was abolished (from 7.25+/-2.49% to 0.16+/-2.24%; P<0.001), whereas dilatation after upper arm occlusion was only partially attenuated (from 11.62+/-3.17% to 7.51+/-2.34%; P=0.006). The peak flow stimulus was similar after wrist and upper arm occlusion. We conclude that dilatation following upper arm occlusion is greater than that observed after wrist occlusion, despite a similar peak flow stimulus. L-NMMA infusion revealed that FMD following wrist occlusion is mediated exclusively by NO, while dilatation following upper arm occlusion comprises a substantial component not mediated by NO, most probably related to tissue ischaemia around the brachial artery. FMD following wrist occlusion may be a more valid marker of endothelial function than dilatation following upper arm occlusion.

Forty Oxford medial unicompartmental arthroplasties (UCAs) were performed through a short incision medial to the patellar tendon, without dislocation of the patella, using updated instruments (Oxford Knee Phase III, Biomet Ltd., Bridgend, UK). The rate of recovery of these knees (measured by the time taken to achieve straight-leg raising, 70 degrees of flexion, and independent stair climbing) was compared with that of 20 Oxford UCAs performed through an open approach with dislocation of the patella. Both groups were compared with 40 AGC (Biomet) total knee arthroplasties performed for osteoarthritis during the same time period. The average rate of recovery after the short-incision UCA was twice as fast as after open UCA and 3 times as fast as after total knee arthroplasty. Accuracy of implantation, assessed from 11 variables seen on fluoroscopically centered postoperative radiographs, was the same after UCA by the short-incision approach as after the open approach, suggesting that the short-term advantage of increased speed of recovery was gained without affecting the long-term results. We now employ the short incision with the phase III instruments for all UCAs.

This hypothesis paper aims to illustrate the role of fatty meal ingestion has on the vascular endothelium and coagulation system. In particular highlighting the potential risk of fatty meal ingestion both as a trigger to an adverse factor in patients with acute coronary syndromes. We propose that as a result of ingesting fatty meals as a part of daily living, there occurs a constellation of changes in the vasculature that results in both a hypercoagulable and a provasoconstrictor state. These acute changes in response to a fatty meal on endothelial function, prothrombosis, and platelet activation can potentially trigger, facilitate and propagate the forces that drive acute coronary syndromes. In type 2 diabetes, adverse postprandial phenomena are exaggerated and prolonged and may therefore be expected to contribute significantly to the excess risk of acute coronary syndromes and atherosclerotic development in these subjects.

The MRSA-Screen (Denka-Seiken, Tokyo, Japan) latex agglutination test was evaluated for its ability to detect PBP 2a from 200 clinical isolates of coagulase-negative staphylococci (CoNS; 84 mecA-positive strains and 116 mecA-negative strains) consisting of 108 Staphylococcus epidermidis, 37 S. saprophyticus, 15 S. haemolyticus, 11 S. hominis, 10 S. capitis, 10 S. warneri, and 3 S. lugdunensis species as well as 6 other species of CoNS. The assay was compared with susceptibility testing with an agar screen plate with oxacillin at 6 microg/ml (OXA6), by oxacillin disk diffusion (DD), by broth microdilution (BMDIL), by the E test, and with Vitek GPS-SV and Vitek GPS-107 susceptibility cards. PCR for the detection of the mecA gene was used as the "gold standard." The sensitivities and specificities for the methods evaluated were as follows: MRSA-Screen, 100 and 100%, respectively; OXA6, 100 and 99%, respectively; DD, 98 and 62%, respectively; BMDIL, 100 and 60%, respectively; E test, 100 and 51%, respectively; Vitek GPS-SV susceptibility card, 98 and 87%, respectively; and Vitek GPS-107 susceptibility card, 100 and 61%, respectively. The MRSA-Screen test accurately and rapidly detected oxacillin resistance in CoNS.

Homocysteine is a risk factor for coronary artery disease (CAD). Folic acid lowers homocysteine and may improve endothelial function in CAD, although the mechanism is unclear. We investigated the effect of folic acid on endothelial function, homocysteine, and oxidative stress in patients with CAD. We also examined the acute effect of 5-methyltetrahydrofolate (5-MTHF), the principal circulating folate, on endothelial function in vivo and on intracellular superoxide in cultured endothelial cells. A randomized crossover study of folic acid (5 mg daily) for 6 weeks was undertaken in 52 patients with CAD. Ten further patients were given intra-arterial 5-MTHF. Endothelial function was assessed by flow-mediated dilatation (FMD). Folic acid increased plasma folate (P<0.001), lowered homocysteine by 19% (P<0.001), and improved FMD (P<0.001). FMD improvement did not correlate with homocysteine reduction. Malondialdehyde and total plasma antioxidant capacity, markers of oxidative stress, were unchanged. 5-MTHF acutely improved FMD (P<0.001) without altering homocysteine (P=0.47). In vitro, 5-MTHF abolished homocysteine-induced intracellular superoxide increase (P<0.001); this effect was also observed with folic acid and tetrahydrobiopterin. Our data support the beneficial effect of folic acid on endothelial function in CAD but suggest that the mechanism is independent of homocysteine. Reduction of intracellular endothelial superoxide may have contributed to the effect.

Objective: This work was undertaken to determine whether dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia., Background: Marine omega-3 fatty acids improve vascular function, but the underlying mechanism(s) are unclear. We studied the effects of marine omega-3 fatty acids on large artery endothelial function in subjects with hypercholesterolemia., Methods: Hypercholesterolemic subjects with no other known cause for endothelial dysfunction were recruited to a prospective, placebo-controlled, randomized, double-blind, parallel-group study. Treatment with omega-3 fatty acids at a dose of 4 g/day (n = 15/group) was compared with placebo, at the beginning (day 0) and end (day 120) of a four-month treatment period. Endothelial function was assessed pre- and posttreatment by noninvasive ultrasonic vessel wall tracking of brachial artery flow-mediated dilation (FMD)., Results: Treatment with marine omega-3 fatty acids resulted in a significant improvement in FMD (0.05 +/- 0.12 to 0.12 +/- 0.07 mm, p < 0.05) and a significant reduction in triglycerides (2.07 +/- 1.13 to 1.73 +/- 0.95 mmol/liter, p < 0.05), whereas treatment with placebo resulted in no change in FMD (0.03 +/- 0.10 to 0.04 +/- 0.10 mm) or triglycerides (2.29 +/- 2.09 to 2.05 +/- 1.36 mmol/liter) (both p < 0.05 treated compared with control). Responses to sublingual glyceryl trinitrate were unchanged., Conclusions: Marine omega-3 fatty acids improve large artery endothelium-dependent dilation in subjects with hypercholesterolemia without affecting endothelium-independent dilation.

The relationship between somatotype and somatotype components with coronary artery disease (CAD) and regional adiposity was considered in 58 males (age 60.2 +/- 9.4 years) undergoing investigative coronary angiography for suspected atherosclerotic CAD. Severity of CAD was determined in terms of both the degree of stenosis and the anatomical position of the lesions on the coronary arteries (myocardial score). Six patients had negative angiographic findings but three of these had impaired left ventricular function as determined by left ventriculography. The mean (+/-SD) somatotype of the group was 5.7 / 5.6 / 1.2 (1.7 / 1.4 / 1.0), illustrating a clear dominance of the first two somatotype components. Canonical correlation analysis showed that somatotype was not significantly related to the angiography results (P > 0.05). However, correlations between the somatotype components and the angiography results with their respective first canonical variates showed that the somatotype variate was one of high mesomorphy and low ectomorphy and the angiography variate was essentially one of a high myocardial score. After adjustment for the confounding interrelationship among the somatotype components, endomorphy was significantly correlated with abdominal circumference (r = 0.65, P < 0.001), the abdomen-to-hip ratio (r = 0.53, P < 0.001) and the abdominal sagittal diameter (r = 0.60, P < 0.001). Mesomorphy was not related to these indicators of android or abdominal adiposity following partial adjustment. Ectomorphy was inversely related to the indices of general and regional adiposity. This study suggests that adiposity and muscularity are important features in terms of increased CAD risk, whereas linearity is beneficial. Am. J. Hum. Biol. 12:128-138, 2000. Copyright 2000 Wiley-Liss, Inc.

Objective: To evaluate the safety, efficacy, and feasibility of the technician run open access exercise electrocardiography service at Freeman Hospital., Design: Questionnaire analysis of the responses of the general practitioners of randomly selected patients who used the service., Setting: A tertiary care cardiac centre, providing an open access service to general practitioners in the community., Patients: 269 patients randomly selected from 552 who underwent open access exercise electrocardiography over a 2.5 year period., Outcome Measures: Utilisation of service: the reasons for referral, whether the service was optimally used by the general practitioners, and its effect on their management practice; effect on number of cardiology referrals; benefit to the patients; safety, efficacy, and feasibility of a technician run service; general practitioners' assessment of the service., Results: 147 of 178 general practitioners (82.6%) responded to the questionnaire, on 247 of 269 patients (91. 8%). General practitioners used the service for diagnosing ischaemic heart disease in 72.5% of cases, for prognostic purposes in 17.8%, or both in 5.3%. In 197 cases (79.8%), the general practitioners felt that the service had changed the way they managed their patients. The exercise test was positive in 90 patients (36.5%) and identified 38 as at high risk. The service was effective in optimising the cardiology service by reducing referrals by 47%., Conclusions: The service was used by general practitioners primarily for diagnosing ischaemic heart disease and not so often for prognosis. The utilisation of the service was optimal as assessed by the high positivity rate. The service meets its primary objective of assisting general practitioners in the management of patients with suspected ischaemic heart disease, and may have helped to optimise resources by reducing the number of referrals to cardiologists. It has helped prioritize patient management and may have benefited high risk patients by facilitating rapid identification and referral. It can be run safely and effectively by trained technicians.

We determined the outcome of 56 'Oxford' unicompartmental replacements performed for anteromedial osteoarthritis of the knee between 1982 and 1987. Of these, 24 were in patients who had died without revision, one was lost to follow-up and two had been revised. Of the remaining 29 knees, 26 were examined clinically and radiologically, two were only examined clinically and one patient was contacted by telephone. The mean age of the patients was 80.3 years. At a mean follow-up of 11.4 years (10 to 14) the measurements of the knee score, range of movement and degree of deformity were not significantly different from those made one to two years after operation, except that the range of flexion had improved. Comparison of fluoroscopically-controlled radiographs at a similar interval of time showed no change in the appearance of the lateral compartments. The retained articular cartilage continued to function for ten or more years which suggests that anteromedial osteoarthritis may be considered as a focal disorder of the knee. This justifies continued efforts to develop methods of treatment which preserve intact joint structures.

Aims: The need for intravenous urography (IVU) in upper tract surveillance for primary transitional cell carcinoma (TCC) of the bladder is contentious. We reviewed our intensive screening policy in the follow-up of these patients to ascertain if such a policy is required and if specific groups could be identified to rationalise this protocol., Methods: Review of the clinical and radiological data on 174 patients with a diagnosis of primary TCC of the bladder attending a teaching hospital urology department., Results: Eight upper tract 'lesions' were identified: six TCC and two false-positive examinations using IVU. No link was demonstrable between upper tract recurrence and tumour stage, grade or multiplicity at diagnosis. All had recurrent bladder tumour but four of the six upper tract tumours occurred at 72 months or later. Twenty-nine patients over the study period developed either a dilated pelvi-calyceal system or a non-functioning kidney detected on IVU., Conclusions: Upper tract TCC can present late and patients with early bladder recurrence and those who do not show a reduction in bladder tumour number at follow-up cystoscopy are most at risk. IVU can probably be safely abandoned in those without local recurrence at 24 months. IVU is sensitive but not specific for upper tract tumour but also yields other relevant clinical information concerning the renal tract. Screening for upper tract metachronous disease should therefore be confined to those with recurrent transitional cell carcinoma of the bladder.

Nucleotide conformation and dynamics are important for the study of radiation damage to DNA at the atomic level. It is necessary to study not only normal oligonucleotide structure but also those containing modified bases which result from interaction with OH-radicals. There are now over 8000 atomic coordinate entries in the Brookhaven Protein Data Bank, of which over 900 relate to experimentally determined structures of nucleic acids and nucleic acid/protein complexes. We review some of these data which have led to the elucidation of novel DNA conformations, insight into DNA sequence specificity and knowledge of protein/DNA interactions. Further understanding of the conformation, stability and dynamics of nucleic acids has come from molecular modelling. We have used such techniques to study chemical modifications to bases such as alkylation of thymine and guanine and the effects of curvature in longer sequences. Recent improvements in this area include the inclusions of explicit counter-ions and solvent molecules, the use of Particle Mesh Ewald methods to incorporate the long-range electrostatic interactions and the use of longer time scale simulations. We have employed these methods to analyse the effects of incorporation of 8-oxodeoxyguanosine into duplex DNA. This lesion is a common result of radiation damage and is known to have important effects in mutagenesis, cancer and ageing.

Objectives: Adult hypopituitarism with growth hormone deficiency (GHD) results in reduced exercise capacity, detrimental changes in body composition and lipid profiles and may be associated with an excess cardiovascular mortality. Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and predisposes to the deposition of unstable atherosclerotic plaques. We have used a noninvasive method to assess endothelial function in the brachial arteries of a group of treated hypopituitary adults with GHD, and a group of healthy age- and sex-matched controls., Patients: Seventeen hypopituitary adults with GHD (13 male, 4 female) aged 26-54 years were studied. Each patient was receiving standard replacement therapy for all other hormonal deficiencies such that all target hormones were maintained in the normal reference range. All observations obtained were compared with those made in age- and sex-matched control subjects. All study subjects had no identifiable risk factors for endothelial dysfunction., Measurements: Using an ultrasound vessel wall tracking system, the diameter of the left brachial artery was measured at rest, in response to reactive hyperaemia (endothelium-dependent dilation) and following sublingual glyceryl trinitrate (GTN) (endothelium-independent vasodilatation). We also measured fasting lipids, insulin, plasma glucose, glycated haemoglobin (HbA1c) and IGF-1, and studied the relationship of these parameters to endothelial function., Results: Flow mediated endothelium-dependent dilatation (FMD), expressed as a percentage change from resting base-line diameter, was significantly impaired in the GHD group (3.70 +/- 2.36% vs. 7.30 +/- 2.42%, P < 0.001). In contrast, GTN-mediated dilatation was similar in both groups. There were no differences in total cholesterol, HDL cholesterol, LDL cholesterol or plasma triglyceride between the groups. Both fasting insulin (27.1 +/- 18.1 vs. 15.89 +/- 6.65 mU/l, P < 0.05) and glycated haemoglobin (HbA1c) levels (5.29 +/- 0.43 vs. 4.91 +/- 0.43%, P < 0.05) were significantly higher in the GHD group. FMD in both groups showed an inverse relationship with total cholesterol (r = -0.58, P < 0.05, GHD and r = -0.55, P < 0.05 controls). However, in the GHD subjects, there was a strong inverse relationship between FMD and LDL-cholesterol (r = -0.81, P < 0.0001). No other relationships were noted between FMD and any other metabolic parameters, or characteristics of GHD., Conclusions: Endothelial dysfunction is present in GH deficient adults prior to the onset of overt atherosclerotic disease. The similar glucose yet elevated fasting insulin levels imply a state of relative insulin insensitivity. The strong inverse correlation between endothelial dysfunction and LDL-cholesterol suggests a possible aetiological role for LDL-cholesterol in the pathogenesis of any excess cardiovascular risk associated with adult hypopituitarism.

Background: The cardiovascular complications of Marfan syndrome arise due to alterations in the structural and functional properties of fibrillin, a constituent of vascular connective tissues. Fibrillin-containing microfibrils are closely associated with arterial endothelial cells, indicating a possible functional role for fibrillin in the endothelium. Plasma concentrations of endothelial cell products are elevated in Marfan subjects, which indirectly indicates endothelial dysfunction. This study directly assessed flow- and agonist-mediated endothelium-dependent brachial artery reactivity in Marfan subjects., Methods and Results: In 20 Marfan and 20 control subjects, brachial artery diameter, blood flow, and blood pressure were measured by ultrasonic wall tracking, Doppler ultrasound, and photoplethysmography, respectively. Measurements were taken during hand hyperemia (a stimulus for endothelium-derived nitric oxide [NO] release in the upstream brachial artery) and after sublingual administration of the endothelium-independent vasodilator nitroglycerin. In 9 Marfan and 6 control subjects, the above parameters were also assessed during intra-arterial infusions of acetylcholine and bradykinin (agonists that stimulate NO production) and NG-monomethyl-L-arginine (L-NMMA, an inhibitor of NO production). Flow-mediated responses differed markedly between Marfan and control subjects (-1.6+/-3.5% versus 6. 50+/-4.1%, respectively; P<0.0001), whereas nitroglycerin produced similar vasodilation (14.2+/-5.7% versus 15.2+/-7.8%; P=NS). Agonist-induced vasodilation to incremental intra-arterial infusions of acetylcholine and bradykinin were not significantly different between Marfan and control subjects, and intra-arterial L-NMMA produced similar reductions in brachial artery diameter in both groups., Conclusions: These data demonstrate impaired flow-mediated but preserved agonist-mediated endothelium-dependent vasodilation in Marfan subjects and suggest preservation of basal NO release. Selective loss of flow-mediated dilation suggests a role for fibrillin in endothelial cell mechanotransduction.

DNA damage produced by free radicals is probably the most frequent lesion encountered by cells (Wallace, S.S., Environmental and Molecular Mutagenesis 12, 431-477, 1988 (1)). One of the most common effects is the formation of 7-hydro-8-oxodeoxyguanine due to oxygen radicals interacting with the normal guanine base. Such chemical changes appear to be important in mutagenesis, cancer and aging. We have used computer simulation techniques to model the effect of inclusion of such a modified base within a duplex strand of DNA. We find that such modifications can be stabilized within a normal sequence. The conformation of the modified base relative to the sugar residue depends on many local interactions not accessible to the isolated nucleoside. We have also studied the essential dynamics of both normal and modified sequences and show that there are only subtle changes to the dynamics on inclusion of such a modification.

Retrieval studies have shown that the use of fully congruent meniscal bearings reduces wear in knee replacements. We report the outcome of 143 knees with anteromedial osteoarthritis and normal anterior cruciate ligaments treated by unicompartmental arthroplasty using fully congruous mobile polyethylene bearings. At review, 34 knees were in patients who had died and 109 were in those who were still living. The mean elapsed time since operation was 7.6 years (maximum 13.8). We established the status of all but one knee. There had been five revision operations giving a cumulative prosthetic survival rate at ten years (33 knees at risk) of 98% (95% CI 93% to 100%). Considering the knee lost to follow-up as a failure, the 'worst-case' survival rate was 97%. No failures were due to polyethylene wear or aseptic loosening of the tibial component. One bearing which dislocated at four years was reduced by closed manipulation. The ten-year survival rate is the best of those reported for unicompartmental arthroplasty and not significantly different from the best rates for total knee replacement.

Objective: Syndrome X (angina, normal coronary arteriogram and positive exercise test) remains an enigma with unexplained features and apparent conflicts of evidence. The present study addressed whether (i) the Syndrome is characterised by generalised flow-related endothelial dysfunction, (ii) myocardial thallium201 defects reflect myocardial or microvascular dysfunction, (iii) endothelial dysfunction and its consequences can be improved by oral L-arginine., Methods: Flow-mediated brachial artery dilatation was measured by ultrasonic 'wall-tracking' in 7 Syndrome X patients, further characterised as having thallium201 defects and no known cause of endothelial dysfunction, and a normal control group. Syndrome X patients entered a 4-week randomised double-blind placebo-controlled cross-over trial of oral L-arginine (7 g twice daily), with brachial artery studies, exercise tests and technetium99 tetrafosmin scans., Results: Flow-mediated dilatation was absent in Syndrome X vs. normal. Stress technetium99 tetrafosmin and thallium201 scans showed similar defects. Flow-mediated dilatation, symptom-limited exercise duration and peak oxygen consumption (VO2max) were increased but rate-pressure-product (RPP) and radionuclide defects were unchanged after L-arginine vs. placebo., Conclusions: The study supports coronary microvascular rather than myocardial dysfunction and shows loss of flow-mediated dilatation in systemic arteries. Oral L-arginine improved flow-mediated dilatation, exercise capacity and VO2max (by ca. 17%) despite unchanged RPP. The findings support generalised endothelial dysfunction. The arginine effects imply NO-mediated improvement of skeletal muscle perfusion suggesting improved homogeneity of microvascular distribution.

Using a new, non-invasive method, we measured the patellofemoral force (PFF) in cadaver knees mounted in a rig to simulate weight-bearing. The PFF was measured from 20 degrees to 120 degrees of flexion before and after implanting three designs of knee prosthesis. Medial unicompartmental arthroplasty with a meniscal-bearing prosthesis and with retention of both cruciate ligaments caused no significant change in the PFF. After arthroplasty with a posterior-cruciate-retaining prosthesis and division of the anterior cruciate ligament, the PFF decreased in extension and increased by 20% in flexion. Implantation of a posterior stabilised prosthesis and division of both cruciate ligaments produced a decrease in the PFF in extension but maintained normal load in flexion. There was a direct relationship between the PFF and the angle made with the patellar tendon and the long axis of the tibia. The abnormalities of the patellar tendon angle which resulted from implantation of the two total prostheses explain the observed changes in the PFF and show how the mechanics of the patellofemoral joint depend upon the kinematics of the tibiofemoral articulation.

A reduction in pH induces the release of iron from transferrin in a process that involves a conformational change in the protein from a closed to an open form. Experimental evidence suggests that there must be changes in the protonation states of certain, as yet not clearly identified, residues in the protein accompanying this conformational change. Such changes in protonation states of residues and the consequent changes in electrostatic interactions are assumed to play a large part in the mechanism of release of iron from transferrin. Using the x-ray crystal structures of human ferri- and apo-lactoferrin, we calculated the pKa values of the titratable residues in both the closed (iron-loaded) and open (iron-free) conformations with a continuum electrostatic model. With the knowledge of a residue's pKa value, its most probable protonation state at any specified pH may be determined. The preliminary results presented here are in good agreement with the experimental observation that the binding of ferric iron and the synergistic anion bicarbonate/carbonate results in the release of approximately three H+ ions. It is suggested that the release of these three H+ ions may be accounted for, in most part, by the deprotonation of the bicarbonate and residues Tyr-92, Lys-243, Lys-282, and Lys-285 together with the protonation of residues Asp-217 and Lys-277.

The pharmacokinetics, safety, and efficacy of recombinant factor IX (rFIX) have been evaluated in previously treated and untreated patients with hemophilia B. In a study of 56 previously treated patients, there was a total of 1,070 hemorrhages, which required 1,514 infusions of rFIX. Of the 1,070 episodes, 80% resolved after a single rFIX infusion. The majority of the remaining episodes requiring more than 1 infusion were either major or complicated hemorrhages. Eighty-seven percent of the 1,514 infusions were rated by the physicians or patients as providing an excellent or good response. These results are consistent with the efficacy data from other hemophilia product clinical trials. rFIX has also been administered as bolus doses or by continuous infusion in conjunction with 13 surgical procedures. Estimated blood loss during and after surgery was as expected when compared with blood loss for similar procedures in patients without hemophilia, and 97% of the clinical responses during and after surgery were rated by physicians or patients as excellent or good. Pharmacokinetic comparison of rFIX with one plasma-derived product showed a statistically significant lower recovery (28% less) of rFIX. The half-lives between the two products were comparable. Common adverse events associated with rFIX treatment have been comparable to other factor IX products. As expected, there has been no evidence of viral transmission by rFIX.

DNA intrinsic structure and curvature is a subject of debate because of the importance of these attributes in processes such as DNA packaging, transcription, and gene regulation. X-ray crystallography of DNA single crystals has provided a wealth of information about the local, short range conformational features of DNA. On the other hand, gel electrophoresis analysis of DNA has not only uncovered the macroscopic curvature of DNA but it also provides most of the available data on DNA intrinsic curvature. However, gel electrophoresis can not identify features of DNA structure at the nucleotide or atomic level. In order to address the problem of DNA intrinsic curvature in an attempt to bridge the gap between X-ray crystallography and gel electrophoresis, we use the computational method of molecular dynamics (MD). In this study, we report the results of 2.0 ns MD simulations on a 51 bp fragment of the K-DNA of Leishmania tarentolae containing several A-tracts. The K-DNA double helix is very stable and remains in an intermediate state between the canonical A and B forms of the duplex. The magnitude of global curvature (75 degrees) agrees well with the experimental estimate (72 degrees) available. Analysis of local (every base triplet) and sublocal (every helix turn) curvature shows that the 51 bp K-DNA fragment has curvature features also present in the Wedge, Junction and Calladine's models of DNA intrinsic curvature. We further characterize the flexibility of individual nucleotides in the molecule and find the sugar flexibility within the A-tracts to be strongly correlated with the pattern of A-tract cleavage by the hydroxyl radical. Differential curvature and flexibility at the 5' and 3'junctions between A-tracts and general-sequence DNA are found to modulate the global curvature of the K-DNA fragment.

We describe a consecutive series of girls with idiopathic anterior knee pain in adolescence and who were treated nonoperatively. At a mean follow-up of 16 years, 22% had no pain, 71% thought that their symptoms were better than at presentation, 88% used analgesics rarely or not at all, and 90% continued to participate regularly in sports. Nevertheless, about one in four of the patients continued to have significant symptoms for < or = 20 years after presentation. No features were identified that predicted those patients in whom symptoms would persist. We conclude that surgical treatment of idiopathic anterior knee pain in adolescents is not justified until a procedure has been shown to provide a better outcome than that reported here or until a way has been found to distinguish the few patients who will not get better spontaneously from the majority who will.