A longitudinal study of MARS MRI scanning of soft-tissue lesions around metal-on-metal total hip arthroplasties and disease progression.

We investigated the changes seen on serial metal artefact reduction magnetic resonance imaging scans (MARS-MRI) of metal-on-metal total hip arthroplasties (MoM THAs). In total 155 THAs, in 35 male and 100 female patients (mean age 70.4 years, 42 to 91), underwent at least two MRI scans at a mean interval of 14.6 months (2.6 to 57.1), at a mean of 48.2 months (3.5 to 93.3) after primary hip surgery. Scans were graded using a modification of the Oxford classification. Progression of disease was defined as an increase in grade or a minimum 10% increase in fluid lesion volume at second scan. A total of 16 hips (30%) initially classified as 'normal' developed an abnormality on the second scan. Of those with 'isolated trochanteric fluid' 9 (47%) underwent disease progression, as did 7 (58%) of 'effusions'. A total of 54 (77%) of hips initially classified as showing adverse reactions to metal debris (ARMD) progressed, with higher rates of progression in higher grades. Disease progression was associated with high blood cobalt levels or an irregular pseudocapsule lining at the initial scan. There was no association with changes in functional scores. Adverse reactions to metal debris in MoM THAs may not be as benign as previous reports have suggested. Close radiological follow-up is recommended, particularly in high-risk groups.

Report of a Royal College of Physicians and National Institute for Health Research workshop - developing research capacity to ensure successful study development and delivery.

The landscape and opportunities for clinical research have changed significantly following the creation of the National Institute for Health Research (NIHR) in 2006. This article describes the scale and impact of the NIHR network infrastructure for clinical research and identifies areas for future development in partnership with the National Health Service (NHS), clinicians and research funders.

Extracorporeal carbon dioxide removal to "protect" the lung.

The case histories are presented of three adults who had severe hypercapnic acidosis despite mechanical ventilation with what were considered to be injurious tidal volumes and airway pressures. The use of a percutaneously inserted arteriovenous extracorporeal carbon dioxide removal (AV-ECCO(2)R) device facilitated a dramatic reduction in the amount of ventilatory support required, achieving a "lung-protective" level. Two patients survived to hospital discharge. One patient died after it became apparent that her late-stage interstitial lung disease was unresponsive to immunosuppression. AV-ECCO(2)R may be a useful strategy in facilitating lung-protective ventilation.

PMX464, a thiol-reactive quinol and putative thioredoxin inhibitor, inhibits NF-kappaB-dependent proinflammatory activation of alveolar epithelial cells.

BACKGROUND AND PURPOSE: Subtle changes in the intracellular reduction-oxidation (redox) state can modulate nuclear factor-kappaB (NF-kappaB) activity. Thioredoxin-1 (Trx) is a small, ubiquitous, redox-active thiol (-SH) protein that, with thioredoxin reductase-1 (TrxR), modifies the redox status of NF-kappaB pathway components. PMX464 is a novel thiol-reactive quinol thought to inhibit the Trx/TrxR system. The aim of this work was to investigate whether PMX464 inhibited NF-kappaB-mediated proinflammatory activation of human type II alveolar epithelial cells (A549). EXPERIMENTAL APPROACH: Intercellular adhesion molecule-1 (ICAM-1), granulocyte-macrophage colony-stimulating factor (GM-CSF) and CXCL8, NF-kappaB DNA binding, nuclear translocation of NF-kappaB p65 subunit, IkappaBalpha degradation, IkappaB phosphorylation and IkappaB kinase (IKK) activity were assessed in A549 cells stimulated with IL-1beta with or without PMX464 pretreatment. Effects of PMX464 on ICAM-1 expression in human lung microvascular endothelial cells (HLMVEC) were also investigated. For comparison, selected measurements (ICAM-1 and IkappaB-alpha phospho-IkappaB-alpha) were made on A549 cells after RNA interference-mediated silencing (siRNA) of Trx. KEY RESULTS: PMX464 reduced ICAM-1, GM-CSF and CXCL8 expression in IL-1beta-stimulated A549 cells and ICAM-1 in HLMVEC. PMX464 inhibited IL-1beta-induced NF-kappaB DNA binding, nuclear translocation of NF-kappaB p65 subunit and factors involved in NF-kappaB activation; specifically, IkappaBalpha degradation, IkappaB phosphorylation and IkappaB kinase (IKK) activity in A549. By contrast, Trx siRNA did not alter ICAM-1 expression or IkappaBalpha degradation/phosphorylation in IL-1beta-stimulated A549 cells. CONCLUSION AND IMPLICATIONS: PMX464 inhibits a proinflammatory response in A549 cells targeting the NFkappaB pathway above IKK. The lack of effect with Trx siRNA suggests that PMX464 acts on thiol proteins, in addition to Trx, to elicit anti-inflammatory responses in lung epithelial cells.

Fractures of Corin 'Taper-Fit' CDH stems used in 'cement-in-cement' revision total hip replacement.

We describe two cases of fracture of Corin Taper-Fit stems used for cement-in-cement revision of congenital dysplasia of the hip. Both prostheses were implanted in patients in their 50s, with high offsets (+7.5 mm and +3.5 mm), one with a large diameter (48 mm) head and one with a constrained acetabular component. Fracture of the stems took place at nine months and three years post-operatively following low-demand activity. Both fractures occurred at the most medial of the two stem introducer holes in the neck of the prosthesis, a design feature that is unique to the Taper-Fit stem. We would urge caution in the use of these particular stems for cement-in-cement revisions.

Extracellular thioredoxin levels are increased in patients with acute lung injury.

BACKGROUND: Acute lung injury (ALI) and its extreme manifestation the acute respiratory distress syndrome (ARDS) complicate a wide variety of serious medical and surgical conditions. Thioredoxin is a small ubiquitous thiol protein with redox/inflammation modulatory properties relevant to the pathogenesis of ALI. We therefore investigated whether thioredoxin is raised extracellulary in patients with ALI and whether the extent of any increase is dependent upon the nature of the precipitating insult. METHODS: Bronchoalveolar lavage (BAL) fluid and plasma samples were collected from patients with ALI (n=30) and healthy controls (n=18, plasma; n=14, BAL fluid). Lung tissue was harvested from a separate group of patients and controls (n=10). Thioredoxin was measured by ELISA in fluids and by immunohistochemistry in tissue. Interleukin (IL)-8 levels were determined by ELISA. Disease severity was assessed as APACHE II and SOFA scores. RESULTS: BAL fluid levels of thioredoxin were higher in patients with ALI than in controls (median 61.6 ng/ml (IQR 34.9-132.9) v 16.0 ng/ml (IQR 8.9-25.1), p<0.0001); plasma levels were also significantly higher. When compared with controls, sections of wax embedded lung tissue from patients with ALI showed greater positive staining for thioredoxin in alveolar macrophages and type II epithelial cells. BAL fluid levels of thioredoxin correlated with IL-8 levels in BAL fluid but not with severity of illness scores or mortality. BAL fluid levels of thioredoxin, IL-8, and neutrophils were significantly greater in patients with ALI of pulmonary origin. CONCLUSIONS: Extracellular thioredoxin levels are raised in patients with ALI, particularly of pulmonary origin, and have a significant positive association with IL-8. Extracellular thioredoxin levels could provide a useful indication of inflammation in ALI.

Echocardiography in the critically ill: current and potential roles.

BACKGROUND: The use of echocardiography in the critically ill presents specific challenges. However, information of direct relevance to clinical management can be obtained relating to abnormalities of structure and function and can be used to estimate pulmonary arterial and venous pressures. DISCUSSION: Investigation of the consequences of myocardial ischaemia, valvular dysfunction and pericardial disease can be facilitated, and changes characteristic of specific conditions (e.g. sepsis, pulmonary thromboembolism) detected. Echocardiography can also be used to monitor the effects of therapeutic interventions. CONCLUSIONS: The applications of echocardiography in the critical care setting (excluding standard peri-operative echocardiography for cardiac surgery) are reviewed, with particular emphasis on the assessment of cardiac physiology.

Quantifying pulmonary perfusion in primary pulmonary hypertension using electron-beam computed tomography.

Traditionally, a gravitational distribution of pulmonary perfusion has been described in normal subjects. How this may vary in patients with primary pulmonary hypertension (PPH), which is characterised by vascular obstruction due to intimal thickening, smooth muscle cell proliferation and episodes of thrombosis in small and medium sized pulmonary arteries, is unclear. In this study the potential of electron-beam computed tomography in quantifying the distribution of pulmonary perfusion in patients with PPH was investigated. Contrast-enhanced sections were obtained during inspiration in the supine position at baseline and during administration of the vasodilator adenosine in five healthy subjects and five patients with PPH. Under each experimental condition, regions of interest were placed along the nondependent-to-dependent axis and values for relative perfusion derived. In healthy individuals, a marked nondependent-to-dependent gradient in perfusion was observed. By contrast, in PPH, perfusion values were significantly lower and were uniform across the lung section, although the administration of adenosine resulted in increased perfusion in all regions of interest. Electron-beam computed tomography provides physiological and structural information about the pulmonary circulation in subjects with pulmonary vascular disease.

KL-6 levels are elevated in plasma from patients with acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) is an extreme form of lung injury characterised by disruption to the alveolar epithelium. KL-6 is a mucin-like glycoprotein expressed on type II pneumocytes. Circulating levels of KL-6 have diagnostic and prognostic significance in a number of interstitial lung diseases, and when elevated are thought to indicate disruption of the alveolar epithelial lining. In this study, the authors sought to determine whether plasma KL-6 levels were elevated in patients with ARDS and whether these were associated with aetiology, disease severity, outcome or ventilatory strategy. Plasma samples were collected from 28 patients with ARDS, nine ventilated controls of matched illness severity and 10 healthy individuals. KL-6 concentrations were measured by enzyme-linked immunosorbent assay. Patients with ARDS had higher plasma levels of KL-6 (median 537 U x mL(-1), interquartile range (IQR) 383-1,119), as compared to ventilated controls (median 255 U x mL(-1), IQR 83-338) and normal individuals (median 215 U x mL(-1), IQR 149-307). In patients with ARDS, plasma KL-6 levels were higher in nonsurvivors than survivors, and correlated positively with oxygenation index and negatively with arterial oxygen tension:inspiratory oxygen fraction ratio. There were also significant positive correlations with mean and peak airway pressures. Elevated levels of plasma KL-6 may provide a useful marker for acute respiratory distress syndrome in ventilated patients and have possible prognostic significance. Alveolar epithelial cell damage may be influenced by the nature of mechanical ventilatory support.

Variable tissue expression of transferrin receptors: relevance to acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is associated with altered plasma and lung iron chemistry. Iron can promote microbial virulence and catalyse pro-oxidant reactions, thereby contributing to the oxidative stress that characterises the syndrome. Therefore, the expression of ferritin and transferrin receptors (TfR) were sought in the lungs and hearts of rodents treated with lipopolysaccharide (LPS), and measurements of TfR and ferritin protein expression were taken from lung biopsy specimens from patients with ARDS and appropriate controls. TfR messenger ribonucleic acid (mRNA) was significantly upregulated in the lungs and significantly downregulated in the hearts of rats 4 h after LPS. Ferritin mRNA levels (light and heavy chains) remained unaltered. Protein TfR levels were significantly upregulated in lungs and downregulated in hearts 4 h post-LPS. Ferritin protein levels were significantly downregulated in lungs compared to baseline values but were unaltered in hearts. Nonhaem iron levels were increased in lungs and decreased in hearts, and iron-regulatory-protein activity increased in hearts but not lungs. TfR protein levels were significantly increased in lung biopsies from patients with ARDS compared to controls. Transferrin receptors are upregulated in rodent lungs during inflammation but are downregulated in the heart. Transferrin receptor protein levels were significantly increased in the lungs in clinical acute respiratory distress syndrome. These findings have implications for the pathogenesis of acute respiratory distress syndrome, especially in relation to the role of iron as a mediator of oxidative stress.

Pulmonary perfusion quantified by electron-beam computed tomography: effects of hypoxia and inhaled NO.

Patients with acute lung injury may benefit from the manipulation of pulmonary blood flow using inhaled nitric oxide (iNO) to optimise ventilation/perfusion matching. Current techniques for studying changes in regional pulmonary perfusion are difficult to apply clinically. This study therefore investigated the potential of electron-beam computed tomography (EBCT) to quantify the effects of hypoxia and iNO on regional pulmonary perfusion in five healthy subjects. Contrast-enhanced sections were obtained sequentially under conditions of normoxia, hypoxia (fractional concentration of oxygen in inspired gas (FI,O2) 0.12) and hypoxia, with iNO (14.8 parts per million (ppm)) administered during inspiration in the supine position. Regions of interest were placed along the nondependent to dependent axis and values for relative perfusion derived. Under normoxic conditions a vertical gradient of perfusion existed, which became less apparent due to increased perfusion in nondependent regions after the induction of hypoxia (FI,O2 0.12). The addition of iNO (FI,O2 0.12 and NO 14.8 ppm) increased perfusion in all regions of the lung section, suggesting redistribution of pulmonary perfusion from other regions of the lung. Absolute values of perfusion were comparable to those documented with existing techniques. The use of a high spatial-resolution technique confirmed the presence of marked perfusion heterogeneity between anatomically close regions of lung.

Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome.

Pulmonary hypertension (PH) is a characteristic feature of the acute respiratory distress syndrome (ARDS). The magnitude of PH has been shown to correlate with the severity of lung injury in patients with ARDS independently of the severity of associated hypoxaemia and has an adverse prognostic significance. Early in the histopathological evolution of ARDS, pulmonary vasoconstriction, thromboembolism and interstitial oedema contribute to the development of PH, although pulmonary vascular remodelling probably occurs eventually. Intravenous vasodilator agents lead to an increase in intrapulmonary shunting and systemic hypotension, which can limit their therapeutic use, and have not been shown to improve survival. By contrast, rapidly metabolised vasodilators administered by inhalation induce selective pulmonary vasodilatation and decrease shunting, but again do not appear to confer a survival benefit. Research aimed at further understanding the mechanisms that underlie pulmonary hypertension, a characteristic feature of the acute respiratory distress syndrome, are expected to provide improvements in pharmacological interventions for the treatment of pulmonary hypertension in the acute respiratory distress syndrome.

Review article: albumin as a drug--biological effects of albumin unrelated to oncotic pressure.

Albumin is the main determinant of plasma oncotic pressure and it plays a pivotal role in modulating the distribution of fluids between compartments. Moreover, it has many other biological properties which may be important not only for its physiological actions but also for its therapeutic effects. Among the non-oncotic properties are its capacity of molecule transportation and free radical scavenging, its ability to modulate capillar permeability, neutrophil adhesion and activation and its haemostatic effects. The following article reviews these biological effects as well as its structure, synthesis, catabolism and distribution.

Iron and the redox status of the lungs.

Iron is an element essential for the survival of most aerobic organisms. However, when its availability is not adequately controlled, iron, can catalyze the formation of a range of aggressive and damaging reactive oxygen species, and act as a microbial growth promoter. Depending on the concentrations formed such species can cause molecular damage or influence redox signaling mechanisms. This review describes recent knowledge concerning iron metabolism in the lung, during both health and disease. In the lower part of the lung a small redox active pool of iron is required for reasons that are at present unclear, but may be related to antimicrobial functions. When the concentration of iron is increased in the lung (usually because of environmental exposure), iron is deleterious and contributes to a range of chronic and acute respiratory diseases. Moreover, aberrant regulation of iron metabolism, and/or deficient antioxidant protection, is also associated with acute lung diseases, such as the acute respiratory distress syndrome (ARDS). Iron, with the consequent production of reactive oxygen species (ROS), microbial growth promotion, and adverse signaling is strongly implicated as a major contributor to the pathogenesis of numerous disease processes involving the lung. Heme oxgenase, an enzyme that produces reactive iron from heme catabolism, is also briefly discussed in relation to lung disease.

The pulmonary physician in critical care - part 9: non-ventilatory strategies in ARDS.

Pharmacological approaches to the treatment of ARDS are reviewed. Future treatments should be targeted at elements of the pathological process that produce specific clinical problems.