The shape of the distal femur: a geometrical study using MRI.

We scanned 25 left knees in healthy human subjects using MRI. Multiplanar reconstruction software was used to take measurements of the inferior and posterior facets of the femoral condyles and the trochlea. A 'basic circle' can be defined which, in the sagittal plane, fits the posterior and inferior facets of the lateral condyle, the posterior facet of the medial condyle and the floor of the groove of the trochlea. It also approximately fits both condyles in the coronal plane (inferior facets) and the axial plane (posterior facets). The circle fitting the inferior facet of the medial condyle in the sagittal plane was consistently 35% larger than the other circles and was termed the 'medial inferior circle'. There were strong correlations between the radii of the circles, the relative positions of the centres of the condyles, the width of the condyles, the total knee width and skeletal measurements including height. There was poor correlation between the radii of the circles and the position of the trochlea relative to the condyles. In summary, the condyles are approximately spherical except for the inferior facet medially, which has a larger radius in the sagittal plane. The size and position of the condyles are consistent and change with the size of the person. However, the position of the trochlea is variable even though its radius is similar to that of the condyles. This information has implications for understanding anterior knee pain and for the design of knee replacements.

Below gap optical absorption in GaAs driven by intense, single-cycle coherent transition radiation.

Single-cycle terahertz fields generated by coherent transition radiation from a relativistic electron beam are used to study the high field optical response of single crystal GaAs. Large amplitude changes in the sub-band-gap optical absorption are induced and probed dynamically by measuring the absorption of a broad-band optical beam generated by transition radiation from the same electron bunch, providing an absolutely synchronized pump and probe geometry. This modification of the optical properties is consistent with strong-field-induced electroabsorption. These processes are pertinent to a wide range of nonlinear terahertz-driven light-matter interactions anticipated at accelerator-based sources.

Antiviral treatment following penetrating keratoplasty for herpetic keratitis.

PURPOSE: To assess the effect of antiviral treatment on corneal graft survival following penetrating keratoplasty for herpetic keratitis. METHODS: Retrospective cohort study of 454 patients receiving primary penetrating keratoplasties (PKs) for viral infection reported to NHS Blood and Transplant (NHSBT) between April 1999 and June 2005. Follow-up data were available on 403 PKs. Kaplan-Meier survival estimates were used to determine graft survival for the three treatment groups: no medication, topical antiviral, and oral antiviral medication. A Cox regression model was used to investigate the combined effects of all additional factors on graft failure. The model was fitted using all pre-operative factors first and then post-operative factors including type of antiviral medication were included. RESULTS: Patients who received oral antiviral medication post-operatively had consistently better graft survival than those receiving no medication or only topical medication. Patients receiving oral antivirals were less than a third as likely to have a failed graft at 5 years compared with those on no antiviral medication (relative risk (RR) 0.3, CI: 0.2-0.7, P=0.002). Other factors that were found to influence the risk of graft failure were the presence of deep corneal vascularisation (P=0.009), PK performed for therapeutic reasons (P=0.03), large diameter grafts (P=0.04), and experiencing a rejection episode (P=0.003). CONCLUSION: Oral antiviral treatment reduces the risk of graft failure in patients undergoing primary PK for herpetic keratitis and should be routinely used in this group of patients post-operatively unless contra-indicated.

A critique of revision rate as an outcome measure: re-interpretation of knee joint registry data.

National registers compare implants by their revision rates, but the validity of the method has never been assessed. The New Zealand Joint Registry publishes clinical outcomes (Oxford knee scores, OKS) alongside revision rates, allowing comparison of the two measurements. In the two types of knee replacement, unicompartmental (UKR) had a better knee score than total replacement (TKR), but the revision rate of the former was nearly three times higher than that of the latter. This was because the sensitivity of the revision rate to clinical failure was different for the two implants. For example, of knees with a very poor outcome (OKS < 20 points), only about 12% of TKRs were revised compared with about 63% of UKRs with similar scores. Revision therefore is not an objective measurement and should not be used to compare these two types of implant. Furthermore, revision is much less sensitive than the OKS to clinical failure in both types and therefore exaggerates the success of knee replacements, particularly of TKR.

Cementless Oxford unicompartmental knee replacement shows reduced radiolucency at one year.

We randomised 62 knees to receive either cemented or cementless versions of the Oxford unicompartmental knee replacement. The implants used in both arms of the study were similar, except that the cementless components were coated with porous titanium and hydroxyapatite. The tibial interfaces were studied with fluoroscopically-aligned radiographs. At one year there was no difference in clinical outcome between the two groups. Narrow radiolucent lines were seen at the bone-implant interfaces in 75% of cemented tibial components. These were partial in 43%, and complete in 32%. In the cementless implants, partial radiolucencies were seen in 7% and complete radiolucencies in none. These differences are statistically significant (p < 0.0001) and imply satisfactory bone ingrowth into the cementless implants.

Approach to critical illness polyneuropathy and myopathy.

A newly acquired neuromuscular cause of weakness has been found in 25-85% of critically ill patients. Three distinct entities have been identified: (1) critical illness polyneuropathy (CIP); (2) acute myopathy of intensive care (itself with three subtypes); and (3) a syndrome with features of both 1 and 2 (called critical illness myopathy and/or neuropathy or CRIMYNE). CIP is primarily a distal axonopathy involving both sensory and motor nerves. Electroneurography and electromyography (ENG-EMG) is the gold standard for diagnosis. CIM is a proximal as well as distal muscle weakness affecting both types of muscle fibres. It is associated with high use of non-depolarising muscle blockers and corticosteroids. Avoidance of systemic inflammatory response syndrome (SIRS) is the most effective way to reduce the likelihood of developing CIP or CIM. Outcome is variable and depends largely on the underlying illness. Detailed history, careful physical examination, review of medication chart and analysis of initial investigations provides invaluable clues towards the diagnosis.

Introduction of a new mobile-bearing total knee prosthesis: minimum three year follow-up of an RCT comparing it with a fixed-bearing device.

As part of the step-wise validation of a new prosthesis (TMK), we previously published the 1 year results of a randomised controlled trial in patients undergoing bilateral knee replacement [Price A., Rees J., Beard D., Juszczak E. et al. A mobile-bearing total knee prosthesis compared with a fixed-bearing prosthesis. JBJS B 2003;85-B-1:62-7.]. Forty patients had the new mobile-bearing prosthesis implanted in one knee and an established fixed-bearing device in the other (AGC). We now report the 3 year status of these patients and, in addition, review a separate multi-centre cohort of 172 patients who had undergone unilateral arthroplasty with the TMK. No significant differences were found in outcome (American Knee Society Score and Oxford Knee Score) between the two prostheses. The greater incidence of "clicking" in the mobile-bearing knee, reported in the previous review, persisted (TMK=48%, AGC=30%). The presence of this mechanical noise was found to have no relationship with outcome in either of the prostheses. The unilateral cohort study showed an acceptable complication rate for the new prosthesis, although some patients reported subjective instability. The method of controlled introduction of the TMK, of which this constitutes a further step, has allowed us to assess the significance of a reported problem (clicking) and to provide scientific data from which other surgeons can decide about use of the implant.

Development and clinical application of meniscal unicompartmental arthroplasty.

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.

High- but not low-dose folic acid improves endothelial function in coronary artery disease.

BACKGROUND: While folic acid (FA) reduces plasma homocysteine (Hcy), whether the simultaneous improvement in endothelial function is dependent on Hcy lowering per se is questionable. In the present study the relationship between FA dose, Hcy lowering and endothelial function in patients with coronary artery disease (CAD) was investigated. MATERIALS AND METHODS: Eighty-four patients with CAD received either 400 microg FA or 5 mg placebo daily for a 6-week treatment period. A further 44 patients with CAD received either 100 mg kg(-1) day(-1) of betaine or placebo for a 6-week treatment period. Flow-mediated dilatation (FMD), a measure of endothelial function, was assessed before and after the 6-week periods. Isometric tension and Western blotting were used to investigate the effect of FA on endothelial function and endothelial nitric oxide synthase (eNOS) dimerization in isolated rabbit aortic rings and cultured porcine aortic endothelial cells (PAEC), respectively. RESULTS: Both 400 micro g day(-1) and 5 mg day(-1) FA significantly increased plasma folate and decreased plasma Hcy. The FMD improved significantly after 6 weeks' treatment of 5 mg day(-1) FA but did not correlate with the reduction in Hcy. There was no change in FMD in either the 400 micro g FA or placebo group. In a subgroup analysis of 11 patients in the betaine group, despite a reduced Hcy, a significant impairment in FMD was observed. In the in vitro studies FA, but not betaine, reversed methionine-induced endothelial dysfunction. Moreover, the FA promoted eNOS dimerization in cultured PAEC. CONCLUSIONS: These data suggest that FA dose-dependently improves endothelial function in CAD via a mechanism independently of Hcy lowering. It may involve promotion of eNOS dimerization.

Evaluation of survival and ischaemic and thromboembolic event rates in patients with non-valvar atrial fibrillation in the general population when treated and untreated with warfarin.

OBJECTIVE: To compare survival and adverse outcome of patients with non-valvar atrial fibrillation (NVAF) treated with or without warfarin. DESIGN: Record linkage method to identify patients with a previous hospital diagnosis of atrial fibrillation and to link these patients to international normalised ratio (INR) test results and mortality data. SETTING: Cardiff and the Vale of Glamorgan, Wales. MAIN OUTCOME MEASURES: Mortality, specifically from ischaemic and thromboembolic events. RESULTS: 6108 patients were identified with NVAF, of whom 36.4% received warfarin. Mean survival in the warfarin and non-warfarin groups was 52.0 months and 38.2 months, respectively (p < 0.001), and 14.4 months (p < 0.001) after adjustment for confounding factors. Warfarin treated patients in the upper quartile of INR control had significantly longer survival (57.5 months) than did those in the lowest quartile of control (38.1 months, p < 0.001). The risk of stroke in the warfarin group when treated was lower than that in the non-warfarin group (relative rate (RR) 0.74, p < 0.001). The risk of death from ischaemic stroke was lower in the warfarin group (RR 0.43, p < 0.001). The risk of all ischaemic and embolic events in the warfarin group was lower when they were taking warfarin (RR 0.74, p < 0.001). The risk of bleeding in the warfarin group when treated was greater (RR 1.78, p = 0.001). CONCLUSIONS: Patients with NVAF within the recommended target INR range of 2.0-3.0 survive longer and have reduced morbidity. Probably too few people are anticoagulated with warfarin in NVAF.

[Is computer navigation a useful tool in unicompartmental knee arthroplasty? A pilot cadaver study]. / Ist die Navigation bei der Schlittenprothese sinnvoll? Eine Pilotstudie am Leichenknie.

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.

Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population.

OBJECTIVE: To evaluate how well patients with non-valvar atrial fibrillation (NVAF) were maintained within the recommended international normalised ratio (INR) target of 2.0-3.0 and to explore the relation between achieved INR control and clinical outcomes. DESIGN: Record linkage study of routine activity records and INR measurements. SETTING: Cardiff and the Vale of Glamorgan, South Wales, UK. PARTICIPANTS: 2223 patients with NVAF, no history of heart valve replacement, and with at least five INR measurements. MAIN OUTCOME MEASURES: Mortality, ischaemic stroke, all thromboembolic events, bleeding events, hospitalisation, and patterns of INR monitoring. RESULTS: Patients treated with warfarin were outside the INR target range 32.1% of the time, with 15.4% INR values > 3.0 and 16.7% INR values < 2.0. However, the quartile with worst control spent 71.6% of their time out of target range compared with only 16.3% out of range in the best controlled quartile. The median period between INR tests was 16 days. Time spent outside the target range decreased as the duration of INR monitoring increased, from 52% in the first three months of monitoring to 30% after two years. A multivariate logistic regression model showed that a 10% increase in time out of range was associated with an increased risk of mortality (odds ratio (OR) 1.29, p < 0.001) and of an ischaemic stroke (OR 1.10, p = 0.006) and other thromboembolic events (OR 1.12, p < 0.001). The rate of hospitalisation was higher when INR was outside the target range. CONCLUSIONS: Suboptimal anticoagulation was associated with poor clinical outcomes, even in a well controlled population. However, good control was difficult to achieve and maintain. New measures are needed to improve maintenance anticoagulation in patients with NVAF.

[Medial unicompartmental knee replacement using the "Oxford Uni" meniscal bearing knee]. / Die mediale Schlittenprothese mit mobilem Polyethylenmeniskus "Oxford Uni".

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.

Endothelial function and coagulant factors in growth hormone-treated hypopituitary adults receiving desmopressin.

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.

The pH-dependent stability of wild-type and mutant transthyretin oligomers.

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.

A mobile-bearing total knee prosthesis compared with a fixed-bearing prosthesis. A multicentre single-blind randomised controlled trial.

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.

Abnormal metabolic fate of nitric oxide in Type I diabetes mellitus.

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 of methicillin-resistant staphylococci from blood culture bottles by using a multiplex PCR assay.

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.

In vitro evaluation of the resistance to dislocation of a meniscal-bearing total knee prosthesis between 30 degrees and 90 degrees of knee flexion.

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.

Effects of GH replacement on endothelial function and large-artery stiffness in GH-deficient adults: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening. DESIGN AND PATIENTS: In a randomized, double-blind, placebo-controlled study, we investigated the effects of GH replacement on endothelial function and large-artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19-64 years) over a 6-month period. Thirty-two age- and sex-matched healthy controls were also studied. MEASUREMENTS: Endothelial function was assessed using ultrasonic wall tracking to measure flow-mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured. RESULTS: At baseline, FMD (mean +/- SD) was impaired in GH-deficient subjects vs. controls (3.4 +/- 2.3 vs. 5.7 +/- 2.0%, P < 0.0001), although endothelium-independent dilatation was similar. The augmentation index was higher in GH-deficient subjects vs. controls (23 +/- 12 vs. 14 +/- 14%, P < 0.01). GH-deficient subjects had higher LDL cholesterol (4.1 +/- 0.8 vs. 3.5 +/- 0.8 mmol/l, P < 0.01) and lower HDL cholesterol (1.1 +/- 0.3 vs. 1.4 +/- 0.4 mmol/l, P < 0.01). In GH-deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = -0.40, P < 0.05) and between FMD and the augmentation index (r = - 0.58, P < 0.01). Regression analysis identified FMD as an independent predictor of the augmentation index (P < 0.0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5.0 +/- 2.6 vs. 2.8 +/- 1.9%, P < 0.01). There were decreases in central aortic systolic pressure (117 +/- 15 vs. 123 +/- 17 mmHg, P < 0.01), diastolic pressure (82 +/- 10 vs. 86 +/- 8 mmHg, P < 0.01) and the augmentation index (22 +/- 8% vs. 26 +/- 10%, P < 0.05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3.5 +/- 0.8 vs. 4.2 +/- 0.8 mmol/l, P < 0.01). There were no significant changes in the placebo group. CONCLUSIONS: Adult GHD is associated with endothelial dysfunction and increased large-artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.