Gender differences in management and outcome in non-ST-elevation acute coronary syndrome

Objective

To study gender differences in management and outcome in patients with non‐ST‐elevation acute coronary syndrome.

Design, setting and patients

Cohort study of 53 781 consecutive patients (37% women) from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS‐HIA), with a diagnosis of either unstable angina pectoris or non‐ST‐elevation myocardial infarction. All patients were admitted to intensive coronary care units in Sweden, between 1998 and 2002, and followed for 1 year.

Main outcome measures

Treatment intensity and in‐hospital, 30‐day and 1‐year mortality.

Results

Women were older (73 vs 69 years, p<0.001) and more likely to have a history of hypertension and diabetes, but less likely to have a history of myocardial infarction or revascularisation. After adjustment, there were no major differences in acute pharmacological treatment or prophylactic medication at discharge.Revascularisation was, however, even after adjustment, performed more often in men (OR 1.15; 95% CI, 1.09 to 1.21). After adjustment, there was no significant difference in in‐hospital (OR 1.03; 95% CI, 0.94 to 1.13) or 30‐days (OR 1.07; 95% CI, 0.99 to 1.15) mortality, but at 1 year being male was associated with higher mortality (OR 1.12; 95% CI, 1.06 to 1.19).

Conclusion

Although women are somewhat less intensively treated, especially regarding invasive procedures, after adjustment for differences in background characteristics, they have better long‐term outcomes than men.Since the beginning of the 1990s there have been numerous studies on gender differences in management of acute coronary syndromes (ACS). Many earlier studies,^{1,2,3,4,5,6,7,8} but not all,⁹ found that women were treated less intensively in the acute phase. In some of the studies, after adjustment for age, comorbidity and severity of the disease, most of the differences disappeared.^6,7 There is also conflicting evidence on gender differences in evidence‐based treatment at discharge.^{1,3,5,6,8,10,11}After acute myocardial infarction (AMI), a higher short‐term mortality in women is documented in several studies.^{2,5,6,7,12,13,14} After adjustment for age and comorbidity some difference has usually,^2,5,12,13 but not always,^11,14 remained. On the other hand, most studies assessing long‐term outcome have found no difference between the genders, or a better outcome in women, at least after adjustment.^7,10,13,14 Earlier studies focusing on gender differences in outcome after an acute coronary syndrome have usually studied patients with AMI, including both ST‐elevation myocardial infarction and non‐ST‐elevation myocardial infarction (NSTEMI).^{2,5,6,7,12,13,14} However, the pathophysiology and initial management differs between these two conditions,¹⁵ as does outcome according to gender.^11,16 In patients with NSTEMI or unstable angina pectoris (UAP), women seem to have an equal or better outcome, after adjustment for age and comorbidity.^{1,4,8,11,16,17} Studies on differences between genders, in treatment and outcome, in real life, contemporary, non‐ST‐elevation acute coronary syndrome (NSTE ACS) populations, large enough to make necessary adjustments for confounders, are lacking.The aim of this study was to assess gender differences in background characteristics, management and outcome in a real‐life intensive coronary care unit (ICCU) population, with NSTE ACS.     

Microscopic measurement of inflammation in synovial tissue: inter-observer agreement for manual quantitative, semiquantitative and computerised digital image analysis

Objectives

To evaluate inter‐observer agreement for microscopic measurement of inflammation in synovial tissue using manual quantitative, semiquantitative and computerised digital image analysis.

Methods

Paired serial sections of synovial tissue, obtained at arthroscopic biopsy of the knee from patients with rheumatoid arthritis (RA), were stained immunohistochemically for T lymphocyte (CD3) and macrophage (CD68) markers. Manual quantitative and semiquantitative scores for sub‐lining layer CD3+ and CD68+ cell infiltration were independently derived in 6 international centres. Three centres derived scores using computerised digital image analysis. Inter‐observer agreement was evaluated using Spearman''s Rho and intraclass correlation coefficients (ICCs).

Results

Paired tissue sections from 12 patients were selected for evaluation. Satisfactory inter‐observer agreement was demonstrated for all 3 methods of analysis. Using manual methods, ICCs for measurement of CD3+ and CD68+ cell infiltration were 0.73 and 0.73 for quantitative analysis and 0.83 and 0.78 for semiquantitative analysis, respectively. Corresponding ICCs of 0.79 and 0.58 were observed for the use of digital image analysis. All ICCs were significant at levels of p<0.0001. At each participating centre, use of computerised image analysis produced results that correlated strongly and significantly with those obtained using manual measurement.

Conclusion

Strong inter‐observer agreement was demonstrated for microscopic measurement of synovial inflammation in RA using manual quantitative, semiquantitative and computerised digital methods of analysis. This further supports the development of these methods as outcome measures in RA.Microscopic measurement of inflammation in synovial tissue is employed globally by centres working in the field of arthritis research.¹ Adequate and comparable synovial tissue can be safely obtained using blind‐needle biopsy or rheumatological arthroscopy.^2,3,4 In the acquired samples, various parameters may be examined, including cell populations, vascularity, cytokines and adhesion molecules. In rheumatoid arthritis (RA), many of these have been found to relate to disease activity, severity, outcome, and to exhibit a change after treatment with corticosteroids, disease‐modifying antirheumatic drugs (DMARDs) and biological therapy.^{5,6,7,8,9,10,11,12,13,14,15}Several analysis techniques have been employed to measure these parameters. Semiquantitative analysis is a relatively quick method and therefore may facilitate examining large quantities of tissue.⁷ Quantitative analysis is time‐consuming but more sensitive than semiquantitative scoring to change in individual patients.¹⁶ It has been shown in previous studies that these methods can reflect overall joint inflammation when applied to relatively limited amounts of synovial tissue, even though inflammation may differ widely between individual sites in a single joint.^17,18,19 Computerised digital image analysis has been applied more recently in this area and has been shown to correlate well with conventional methods of measurement.^20,21,22This multi‐centre study was undertaken to standardise and validate the methods mentioned previously by evaluating inter‐observer agreement between multiple examiners in the measurement of selected parameters of inflammation in RA synovial tissue by manual quantitative, semiquantitative and computerised image analysis.     

Socioeconomic status, pathogen burden and cardiovascular disease risk

Objective

Socioeconomic status (SES) is inversely associated with coronary heart disease (CHD) risk. Cumulative pathogen burden may also predict future CHD. The hypothesis was tested that lower SES is associated with a greater pathogen burden, and that pathogen burden accounts in part for SES differences in cardiovascular risk factors.

Methods

This was a cross‐sectional observational study involving the clinical examination of 451 men and women aged 51–72 without CHD, recruited from the Whitehall II epidemiological cohort. SES was defined by grade of employment, and pathogen burden by summing positive serostatus for Chlamydia pneumoniae, cytomegalovirus and herpes simplex virus 1. Cardiovascular risk factors were also assessed.

Results

Pathogen burden averaged 1.94 (SD) 0.93 in the lower grade group, compared with 1.64 (0.97) and 1.64 (0.93) in the intermediate and higher grade groups (p = 0.011). Pathogen burden was associated with a higher body mass index, waist/hip ratio, blood pressure and incidence of diabetes. There were SES differences in waist/hip ratio, high‐density lipoprotein‐cholesterol, fasting glucose, glycated haemoglobin, lung function, smoking and diabetes. The SES gradient in these cardiovascular risk factors was unchanged when pathogen burden was taken into account statistically.

Conclusions

Although serological signs of infection with common pathogens are more frequent in lower SES groups, their distribution across the social gradient does not match the linear increases in CHD risk present across higher, intermediate and lower SES groups. Additionally, pathogen burden does not appear to mediate SES differences in cardiovascular risk profiles.There is a socioeconomic gradient in coronary heart disease (CHD) mortality and cardiovascular disease risk in the USA, UK and many other countries.^1,2 Lower socioeconomic status (SES) is associated with a range of cardiovascular risk factors including smoking, adverse lipid profiles, abdominal adiposity, glucose intolerance and inflammatory markers.^3,4,5,6,7 Both early life SES and adult socioeconomic position appear to contribute to the social gradient.^5,8A history of infection may contribute to cardiovascular disease risk by stimulating sustained vascular inflammation. Evidence concerning the relevance of individual pathogens is mixed, but the cumulative pathogen burden, defined by positive serostatus for a range of pathogens, has been associated with coronary artery disease and carotid atherosclerosis in case–control^9,10,11 and longitudinal cohort studies.^12,13,14 Pathogen burden is also related to cardiovascular risk markers such as endothelial dysfunction,¹⁵ low high‐density lipoprotein (HDL)‐cholesterol¹⁶ and insulin resistance,¹⁷ in some but not all studies.^9,18It is plausible that pathogen burden could contribute to SES differences in cardiovascular disease risk. Exposure to infection is greater in lower SES groups, particularly in early life,¹⁹ and childhood infection is associated with endothelial dysfunction.²⁰ We therefore tested the hypothesis that lower SES is associated with greater cumulative pathogen burden in healthy middle‐aged and older adults. Seropositivity was measured for three pathogens, Chlamydia pneumoniae, cytomegalovirus (CMV) and herpes simplex virus 1 (HSV‐1), that have been associated with cardiovascular disease risk,^21,22,23 and have contributed to studies of cumulative pathogen burden.^10,12,14,15 We also determined whether variations in pathogen burden accounted for SES differences in cardiovascular risk factors.     

Tissue chimerism in systemic lupus erythematosus is related to injury

Background

Chimerism indicates the presence of cells from one individual in another individual, and has been associated with several autoimmune diseases. Although this finding may point towards a role for chimerism in the induction of SLE, it could also indicate that chimerism is the result of repair mechanisms after injury.

Objective

To perform a post‐mortem investigation for the presence of chimerism in 48 organs from seven women with SLE and establish whether there was a relationship between chimerism and injury.

Methods

Chimeric male cells in female tissue specimens were identified by in situ hybridisation of the Y‐chromosome. Organs were categorised into four different groups according to injury experienced. Results were compared with those for unaffected control organs.

Results

Chimerism was found in all seven patients with SLE. Y‐chromosome‐positive cells were present in 24 of 48 organs from women with SLE, which was significantly more than in control organs (p<0.001). Chimerism occurred more often in organs from patients with SLE who had experienced injury than in normal control organs, irrespective of whether the injury experienced was SLE‐related, non‐SLE‐related or both.

Conclusions

This is the first report of the distribution of chimerism in a large number of organs from women with SLE. It shows that the occurrence of chimerism is related to injury. The data support the hypothesis that tissue chimerism is the result of a repair process.Chimerism is the presence of cells from one individual in another individual. The involvement of chimerism in the pathogenesis of autoimmune diseases has been addressed in several studies.^1,2,3 We recently investigated the occurrence of chimerism in kidneys of women with the autoimmune disease systemic lupus erythematosus (SLE) and found that chimerism occurs twice as often in lupus nephritis as in normal kidneys.⁴ SLE is an immune‐mediated disease that affects several organs and has a variety of clinical symptoms.⁵ This disease is characterised by the presence of autoantibodies, particularly autoantibodies against nuclear components.⁶ Despite extensive research, the aetiology of SLE is still unknown, but is probably multifactorial. Chimerism is a candidate factor that may be responsible for the development of SLE.SLE occurs in women and men at a ratio of approximately 10:1. In women, the first symptoms most often occur during their fertile years.⁷ This is interesting in terms of whether chimerism plays a role in SLE, because pregnancy is thought to be the most likely source of chimeric cells. During pregnancy, fetal cells enter the maternal circulation, making the mother chimeric. These circulating fetal cells have been reported to be haematopoietic progenitor cells, trophoblast cells, nucleated erythrocytes and leucocytes.^8,9,10,11 We have shown that, in kidneys with lupus nephritis, both CD3 and CD34 positive chimeric cells are present.⁴The presence of chimeric cells in tissues affected by SLE may indicate the pathogenic potential of chimeric cells. For example, their presence could be interpreted as a graft‐versus‐host or a host‐versus‐graft reaction.¹² In these scenarios, chimeric cells are involved in the initiation of disease. However, recent publications have stressed the importance of chimeric cells in repair, showing in experimental designs that fetal cells migrate to sites of injury in the mother.¹³Organ injury in autoimmune diseases such as SLE can be extensive. If chimeric cells indeed have repair capabilities, the amount of tissue chimerism would be expected to be high in organs from women with SLE, especially in those that show histological signs of injury. Moreover, it is possible that specifically SLE‐related injury leads to the presence of chimerism, in contrast with other forms of injury. In an autopsy case study of one patient with SLE, Johnson et al¹⁴ showed that chimerism was present in the heart, lung, kidney, intestines and skin. However, Khosrotehrani et al¹⁵ found no chimerism in skin specimens from seven patients with mild SLE. Apart from the 57 kidney specimens with lupus nephritis that we previously studied, there have been no other data gathered on either the occurrence of chimerism in organs from women with SLE or the relationship between tissue chimerism and injury.Therefore, we investigated the association of chimerism and injury in a large number of tissue samples from patients with SLE, categorising whether these tissues had an SLE‐related injury, a non‐SLE‐related injury, a combination of the two, or were histologically normal.     

Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome

Objective

S100A12 is a pro‐inflammatory protein that is secreted by granulocytes. S100A12 serum levels increase during inflammatory bowel disease (IBD). We performed the first study analysing faecal S100A12 in adults with signs of intestinal inflammation.

Methods

Faecal S100A12 was determined by ELISA in faecal specimens of 171 consecutive patients and 24 healthy controls. Patients either suffered from infectious gastroenteritis confirmed by stool analysis (65 bacterial, 23 viral) or underwent endoscopic and histological investigation (32 with Crohn''s disease, 27 with ulcerative colitis, and 24 with irritable bowel syndrome; IBS). Intestinal S100A12 expression was analysed in biopsies obtained from all patients. Faecal calprotectin was used as an additional non‐invasive surrogate marker.

Results

Faecal S100A12 was significantly higher in patients with active IBD (2.45 ± 1.15 mg/kg) compared with healthy controls (0.006 ± 0.03 mg/kg; p<0.001) or patients with IBS (0.05 ± 0.11 mg/kg; p<0.001). Faecal S100A12 distinguished active IBD from healthy controls with a sensitivity of 86% and a specificity of 100%. We also found excellent sensitivity of 86% and specificity of 96% for distinguishing IBD from IBS. Faecal S100A12 was also elevated in bacterial enteritis but not in viral gastroenteritis. Faecal S100A12 correlated better with intestinal inflammation than faecal calprotectin or other biomarkers.

Conclusions

Faecal S100A12 is a novel non‐invasive marker distinguishing IBD from IBS or healthy individuals with a high sensitivity and specificity. Furthermore, S100A12 reflects inflammatory activity of chronic IBD. As a marker for neutrophil activation, faecal S100A12 may significantly improve our arsenal of non‐invasive biomarkers of intestinal inflammation.The etiology of inflammatory bowel disease (IBD) consisting of ulcerative colitis and Crohn''s disease involves complex interactions among susceptibility genes, the environment, and the immune system. These interactions lead to a cascade of events that involve the activation of neutrophils, production of proinflammatory mediators, and tissue damage.¹ As intestinal symptoms are a frequent cause of referrals to gastroenterologists, it is crucial to differentiate between non‐inflammatory irritable bowel syndrome (IBS) and IBD. To date, there is a lack of biological markers to determine intestinal inflammation.^2,3 Therefore, invasive procedures are required to confirm the diagnosis of IBD. Furthermore, the natural history of chronic IBD is characterised by an unpredictable variation in the degree of inflammation. Biological markers are needed to confirm remission, detect early relapses or local reactivation, and to monitor anti‐inflammatory therapies reliably. Whereas serum markers of inflammation are still not very helpful,^3,4,5 assays that determine intestinal inflammation by detecting neutrophil‐derived products in stool show great potential.⁶An important mechanism in the initiation and perturbation of inflammation in IBD is the activation of innate immune mechanisms.^7,8 Among the factors released by infiltrating neutrophils are proteins of the S100 family.^9,10 One example is calprotectin, which is detectable in the serum and stool during intestinal inflammation.¹¹ Calprotectin was initially described as a protein of 36 kDa, but was later characterised as a complex of two distinct S100 proteins, S100A8 and S100A9.^12,13,14 In recent years, calprotectin has been proposed as a faecal marker of gut inflammation reflecting the degree of phagocyte activation.^{6,15,16,17,18,19,20} Unfortunately, variation in faecal calprotectin assays still impedes the routine use of this marker as a sole parameter in clinical practice. The observed variation may be caused by the broad expression pattern of calprotectin, which is found in granulocytes as well as monocytes and is also inducible in epithelial cells.^21,22 In this context, the elevation in lactose intolerance is notable.^16,17,23S100A12 is more restricted to granulocytes. It is secreted by activated neutrophils and is abundant in the intestinal mucosa of patients with IBD.^9,24 Overexpression at the site of inflammation and correlation with disease activity in a variety of inflammatory disorders underscore the role of this granulocytic protein as a proinflammatory molecule.²⁵ The binding of S100A12 to the receptor for advanced glycation endproducts (RAGE) leads to the long‐term activation of nuclear factor kappa B, which promotes inflammation.²⁶ In mouse models of colitis, blocking the interaction of S100A12 with RAGE has been proved to attenuate inflammation. Data on murine models of colitis as well as human IBD point to an important role for S100A12 during the pathogenesis of these disorders.^9,26,27In a previous study, we demonstrated that S100A12 is overexpressed during chronic active IBD and serves as a useful serum marker for disease activity in patients with IBD.⁹ De Jong et al.²⁸ recently reported that S100A12 can be detected in the stool of children with Crohn''s disease. The aim of our present study was thus to analyse S100A12 in stool samples as well as its expression in the intestinal tissue of patients with confirmed IBD or IBS and in the stool of a normal control group. We correlated faecal S100A12 levels with endoscopic and histological findings in the same patients and investigated the diagnostic accuracy of S100A12 to detect intestinal inflammation.     

Clinical value of multidetector CT coronary angiography as a preoperative screening test before non-coronary cardiac surgery

Objective

Myocardial scintigraphy and/or conventional angiography (CA) are often performed before cardiac surgery in an attempt to identify unsuspected coronary artery disease which might result in significant cardiac morbidity and mortality. Multidetector CT coronary angiography (MDCTCA) has a recognised high negative predictive value and may provide a non‐invasive alternative in this subset of patients. The aim of this study was to evaluate the clinical value of MDCTCA as a preoperative screening test in candidates for non‐coronary cardiac surgery.

Methods

132 patients underwent MDCTCA (Somatom Sensation 16 Cardiac, Siemens) in the assessment of the cardiac risk profile before surgery. Coronary arteries were screened for ⩾50% stenosis. Patients without significant stenosis (Group 1) underwent surgery without any adjunctive screening tests while all patients with coronary lesions ⩾50% at MDCTCA (Group 2) underwent CA.

Results

16 patients (12.1%) were excluded due to poor image quality. 72 patients without significant coronary stenosis at MDCTCA were submitted to surgery. 30 out of 36 patients with significant (⩾50%) coronary stenosis at MDCTCA and CA underwent adjunctive bypass surgery or coronary angioplasty. In 8 patients, MDCTCA overestimated the severity of the coronary lesions (>50% MDCTCA, <50% CA).No severe cardiovascular perioperative events such as myocardial ischaemia, myocardial infarction or cardiac failure occurred in any patient in Group 1.

Conclusions

MDCTCA seems to be effective as a preoperative screening test prior to non‐coronary cardiac surgery. In this era of cost containment and optimal care of patients, MDCTCA is able to provide coronary vessel and ventricular function evaluation and may become the method of choice for the assessment of a cardiovascular risk profile prior to major surgery.Since its introduction in the 1960s,¹ conventional coronary angiography (CA) has been considered the gold standard for the diagnosis of coronary artery disease because of its high contrast, temporal and spatial resolution.^2,3,4 In the past few years, we have witnessed a considerable increase in diagnostic and interventional procedures. Despite the high degree of accuracy (73–89%) of non‐invasive diagnostic tests such as exercise ECG, myocardial scintigraphy and stress‐echocardiography in detecting myocardial ischaemia,⁵ about 20% of patients undergoing CA due to a positive result of these non‐invasive tests, had no evidence of coronary lesions.^6,7Multidetector CT (MDCT), introduced into clinical practice in 2000, has demonstrated excellent technical characteristics for coronary artery evaluation. Results in the literature show a high degree of diagnostic accuracy in detecting significant coronary lesions and, particularly, an excellent capability of excluding them, due to negative predictive values ranging from 96 to 99%.^{8,9,10,11,12,13,14,15,16,17,18}Patients who are candidates for major non‐coronary cardiac or vascular surgery, such as heart valve replacement, aortic aneurysm and aortic dissection, require a complete assessment of potentially dangerous co‐morbidities. There is a 5 to 10% perioperative cardiac morbidity rate during vascular surgery, even in patients at low risk for coronary disease.¹⁹ According to Paul et al.²⁰ there is a 17% risk of severe multivessel disease in low clinical risk asymptomatic patients undergoing vascular surgery. American College of Cardiology/American Heart Association (ACC/AHA) guidelines for preoperative evaluation before major surgery recommend stratification of ischaemic heart disease with clinical and non‐invasive tests.^19,20,21,22 The diagnostic accuracy is 68 to 77% for exercise ECG and 73 to 85% for stress‐echocardiography. Myocardial scintigraphy provides an accuracy of 87–89% in patients with normal resting ECG, with a radiation exposure ranging from 4.6 to 20 mSv,²³ almost equivalent to MDCT coronary angiography (MDCTCA). However, for certain high‐risk patients, ACC guidelines suggest proceeding directly with coronary angiography rather than performing a non‐invasive test. Therefore, in clinical practice, CA is often performed before major vascular or cardiac surgery. Considering that millions of surgical procedures are probably performed every year worldwide (eg, 95 000 heart valve replacements/year in the USA),^6,7 several hundred thousand negative CAs are still performed.After some years of validation studies comparing MDCTCA with CA, studies on clinical utility are now warranted to demonstrate whether and how this technique can change and improve the current management of patients. The purpose of this study is to evaluate the clinical impact of MDCTCA as a preoperative screening test for cardiac risk assessment in patients who are candidates for major non‐coronary cardiac surgery and who are asymptomatic for ischaemic heart disease.     

Bone mineral density in patients with hand osteoarthritis compared to population controls and patients with rheumatoid arthritis

Objectives

Several studies have revealed increased bone mineral density (BMD) in patients with knee or hip osteoarthritis, but few studies have addressed this issue in hand osteoarthritis (HOA). The aims of this study were to compare BMD levels and frequency of osteoporosis between female patients with HOA, rheumatoid arthritis (RA) and controls aged 50–70 years, and to explore possible relationships between BMD and disease characteristics in patients with HOA.

Methods

190 HOA and 194 RA patients were recruited from the respective disease registers in Oslo, and 122 controls were selected from the population register of Oslo. All participants underwent BMD measurements of femoral neck, total hip and lumbar spine (dual‐energy x ray absorptiometry), interview, clinical joint examination and completed self‐reported questionnaires.

Results

Age‐, weight‐ and height‐adjusted BMD values were significantly higher in HOA versus RA and controls, the latter only significant for femoral neck and lumbar spine. The frequency of osteoporosis was not significantly different between HOA and controls, but significantly lower in HOA versus RA. Adjusted BMD values did not differ between HOA patients with and without knee OA, and significant associations between BMD levels and symptom duration or disease measures were not observed.

Conclusion

HOA patients have a higher BMD than population‐based controls, and this seems not to be limited to patients with involvement of larger joints. The lack of correlation between BMD and disease duration or severity does not support the hypothesis that higher BMD is a consequence of the disease itself.Osteoporosis is recognised as a frequent complication to rheumatoid arthritis (RA).¹ Osteoarthritis (OA) is the most frequent rheumatic joint disease, and contrary to the situation in RA, several studies have revealed increased bone mineral density (BMD) in patients with knee or hip OA, even if the results have not been consistent in all studies.^{2,3,4,5,6,7,8,9,10} The hand is a frequent site of peripheral joint involvement in OA. However, a limited number of studies have addressed the issue of osteoporosis in hand osteoarthritis (HOA), and the results from these few studies have been inconsistent regarding levels of BMD compared with controls.^{8,9,10,11,12,13,14,15}OA has generally been considered as a cartilage disease characterised by slow progressive degeneration of articular cartilage due to “wear and tear” mechanisms. However, there is increasing evidence that abnormalities in the subchondral bone and systemic factors may contribute to the pathophysiological process. Studies of subchondral bone have revealed alterations in microstructure including increased BMD. This local increase in BMD in OA joints may be a consequence of reduced shock absorption in joints with degenerated cartilage,⁵ or on the contrary, thickening and stiffening of the subchondral bone with increased BMD may lead to development of OA.¹⁶ However, elevated BMD levels at sites remote from the arthritic process cannot be explained by local biomechanical factors, and the question of whether primary OA rather is a systemic bone disease has been raised.¹⁷ Systemic changes in subchondral bone could be explained by genetic factors, hormonal influences, vitamin D concentrations, growth factors or activity of bone‐forming cells.^{15,18,19,20,21} Better knowledge about the relationship between BMD and HOA may contribute to the understanding of the pathogenesis of OA.Disease registers of patients with RA²² and HOA²³ have been established in the city of Oslo. We have previously compared BMD levels in a cohort of RA patients from the Oslo RA Register (ORAR) and healthy controls.²⁴ The current study was designed to compare levels of BMD and the frequency of osteoporosis between patients with HOA, RA and controls. A second aim was to explore possible relationships between BMD levels and disease characteristics in patients with HOA.     

Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission

Objective

The aim of the study was to compare time‐trends in mortality rates and treatment patterns between patients with and without diabetes based on the Swedish register of coronary care (Register of Information and Knowledge about Swedish Heart Intensive Care Admission [RIKS‐HIA]).

Methods

Post myocardial infarction mortality rate is high in diabetic patients, who seem to receive less evidence‐based treatment. Mortality rates and treatment in 1995–1998 and 1999–2002 were studied in 70 882 patients (age <80 years), 14 873 of whom had diabetes (the first registry recorded acute myocardial infarction), following adjustments for differences in clinical and other parameters.

Results

One‐year mortality rates decreased from 1995 to 2002 from 16.6% to 12.1% in patients without diabetes and from 29.7% to 19.7%, respectively, in those with diabetes. Patients with diabetes had an adjusted relative 1‐year mortality risk of 1.44 (95% CI 1.36 to 1.52) in 1995–1998 and 1.31 (95% CI 1.24 to 1.38) in 1999–2002. Despite improved pre‐admission and in‐hospital treatment, diabetic patients were less often offered acute reperfusion therapy (adjusted OR 0.85, 95% CI 0.80 to 0.90), acute revascularisation (adjusted OR 0.78, 95% CI 0.69 to 0.87) or revascularisation within 14 days (OR 0.80, 95% CI 0.75 to 0.85), aspirin (OR 0.90, 95% CI 0.84 to 0.98) and lipid‐lowering treatment at discharge (OR 0.81, 95% CI 0.77 to 0.86).

Conclusion

Despite a clear improvement in the treatment and myocardial infarction survival rate in patients with diabetes, mortality rate remains higher than in patients without diabetes. Part of the excess mortality may be explained by co‐morbidities and diabetes itself, but a lack of application of evidence‐based treatment also contributes, underlining the importance of the improved management of diabetic patients.Patients with diabetes have higher short‐ and long‐term mortality rates after acute myocardial infarction (MI) than those without diabetes.^1,2,3,4 This pattern has remained even after the introduction of modern therapeutic principles.^5,6,7 According to US mortality rate trends diabetic patients have not experienced a similar mortality rate reduction as that seen in non‐diabetic patients.^8,9,10 Less use of evidence‐based treatment has been suggested as an important explanation.^{4,10,11,12,13,14} The systematic use of such therapy should decrease hospital mortality rate in diabetic patients so that it approaches that in those without diabetes.¹⁵The Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS‐HIA), covering almost all Swedish patients with MI, offers detailed information on treatment patterns and prognosis in unselected patients with and without diabetes. The aim of this study is to analyse time trends in treatment patterns and prognosis in order to see whether management has improved.     

Disease management programme for secondary prevention of coronary heart disease and heart failure in primary care: a cluster randomised controlled trial

Aims

To evaluate the effect of a disease management programme for patients with coronary heart disease (CHD) and chronic heart failure (CHF) in primary care.

Methods

A cluster randomised controlled trial of 1316 patients with CHD and CHF from 20 primary care practices in the UK was carried out. Care in the intervention practices was delivered by specialist nurses trained in the management of patients with CHD and CHF. Usual care was delivered by the primary healthcare team in the control practices.

Results

At follow up, significantly more patients with a history of myocardial infarction in the intervention group were prescribed a beta‐blocker compared to the control group (adjusted OR 1.43, 95% CI 1.19 to 1.99). Significantly more patients with CHD in the intervention group had adequate management of their blood pressure (<140/85 mm Hg) (OR 1.61, 95% CI 1.22 to 2.13) and their cholesterol (<5 mmol/l) (OR 1.58, 95% CI 1.05 to 2.37) compared to those in the control group. Significantly more patients with an unconfirmed diagnosis of CHF had a diagnosis of left ventricular systolic dysfunction confirmed (OR 4.69, 95% CI 1.88 to 11.66) or excluded (OR 3.80, 95% CI 1.50 to 9.64) in the intervention group compared to the control group. There were significant improvements in some quality‐of‐life measures in patients with CHD in the intervention group.

Conclusions

Disease management programmes can lead to improvements in the care of patients with CHD and presumed CHF in primary care.Cardiovascular diseases including coronary heart disease (CHD) and chronic heart failure (CHF) are the main cause of morbidity and mortality in most European countries.¹ Mortality from cardiovascular disease has declined over the last 30 years, a trend which has been attributed to secondary prevention therapies.^2,3 However, European surveys have shown considerable potential for improved levels of secondary prevention in people with established CHD.⁴ Studies in primary care, where most of these patients are managed, have also reported considerable potential to further increase secondary prevention through medical and lifestyle interventions.^5,6 “Medical” measures include aspirin therapy and blood pressure and lipid control, while “lifestyle” measures include increased exercise, dietary modification and smoking cessation.⁵ CHF is also a highly prevalent, chronic condition with high mortality and morbidity. It is increasing in prevalence and the public health burden from CHF is therefore likely to rise substantially over the next 10 years.⁷ The quality of life of patients with CHF is worse than for most chronic conditions managed in primary care and five‐year survival is worse than for many malignant conditions.⁸ However, appropriate treatment, including inhibitors of the renin‐angiotensin‐aldosterone system and beta‐blockers, has the potential to reduce hospitalisation and mortality in these patients.^9,10 The task of implementing a comprehensive package of effective measures for large numbers of patients has been described as daunting.⁵ It is therefore important to develop implementation strategies that are practical and effective. Many patients with CHF are incorrectly diagnosed and inadequately treated in primary care¹¹ and obstacles to appropriate primary care management include lack of knowledge, fear of complications with pharmacological treatments, lack of time and limited facilities for investigations.^12,13Systematic reviews indicate that secondary prevention programmes improve the process of care, reduce admissions to hospital and enhance quality of life or functional status in patients with CHD.¹⁴ Similarly, systematic reviews of disease management programmes in CHF suggest that specialised, multidisciplinary follow‐up can reduce hospitalisation and may lead to cost saving.^15,16,17 However, all the CHF trials included in these systematic reviews were conducted in highly specialised centres and recruited patients following discharge after hospitalisation. The applicability of the available CHF management programmes to countries with a primary care‐based healthcare system has therefore recently been questioned.¹⁸To achieve improved secondary prevention of CHD and CHF, primary care will need to adopt a systematic approach. Although disease management clinics for the management of CHD in primary care can improve patients'' outcomes,⁵ there are no such studies in the management of patients with CHF. Since the majority of patients with CHF will also have CHD,¹⁹ we investigated the effect of a disease management programme for patients with either or both conditions in primary care.     

Comparison of in vitro-specific blood tests with tuberculin skin test for diagnosis of latent tuberculosis before anti-TNF therapy

Introduction

Latent tuberculosis infection (LTBI) is detected with the tuberculin skin test (TST) before anti‐TNF therapy. We aimed to investigate in vitro blood assays with TB‐specific antigens (CFP‐10, ESAT‐6), in immune‐mediated inflammatory diseases (IMID) for LTBI screening.

Patients and methods

Sixty‐eight IMID patients with (n = 35) or without (n = 33) LTBI according to clinico‐radiographic findings or TST results (10 mm cutoff value) underwent cell proliferation assessed by thymidine incorporation and PKH‐26 dilution assays, and IFNγ‐release enzyme‐linked immunosorbent spot (ELISPOT) assays with TB‐specific antigens.

Results

In vitro blood assays gave higher positive results in patients with LTBI than without (p<0.05), with some variations between tests. Among the 13 patients with LTBI diagnosed independently of TST results, 5 had a negative TST (38.5%) and only 2 a negative blood assays result (15.4%). The 5 LTBI patients with negative TST results all had positive blood assays results. Ten patients without LTBI but with intermediate TST results (6–10 mm) had no different result than patients with TST result ⩽5 mm (p>0.3) and lower results than those with LTBI (p<0.05) on CFP‐10+ESAT‐6 ELISPOT and CFP‐10 proliferation assays.

Conclusion

Anti‐TB blood assays are beneficial for LTBI diagnosis in IMID. Compared with TST, they show a better sensitivity, as seen by positive results in 5 patients with certain LTBI and negative TST, and better specificity, as seen by negative results in most patients with intermediate TST as the only criteria of LTBI. In the absence of clinico‐radiographic findings for LTBI, blood assays could replace TST for antibiotherapy decision before anti‐TNF.TNFα blocker agents are approved for the treatment of immune‐mediated inflammatory diseases (IMID) and provide marked clinical benefit. However, they can reactivate tuberculosis (TB) infection in patients previously exposed to TB bacilli.^1,2 The presence of quiescent mycobacteria defines latent TB infection (LTBI).^3,4 Thus, screening for LTBI is necessary before initiating therapy with TNF blockers.⁵ However, to date, no perfect gold standard exists for detecting LTBI, and tuberculin skin test (TST) remains largely used. The recommendations for detecting LTBI differ worldwide.^3,6,7 In France, recommendations were established in 2002 by the RATIO (Research Axed on Tolerance of Biotherapies) study group for the Agence Française de Sécurité Sanitaire des Produits de Santé.^8,9 Patients are considered to have LTBI requiring treatment with prophylactic antibiotics before starting anti‐TNFα therapy if they had previous TB with no adequate treatment, tuberculosis primo‐infection, residual nodular tuberculous lesions larger than 1 cm³ or old lesions suggesting TB diagnosis (parenchymatous abnormalities or pleural thickening) as seen on chest radiography or weals larger than 10 mm in diameter in response to the TST. Adequate anti‐TB treatment was defined as treatment initiated after 1970, lasting at least 6 months and including at least 2 months with the combination rifampicin–pyrazinamide. The choice of the threshold of 10 mm for the TST result was established in 2002 in France since the programme of vaccination with bacille Calmette–Guérin (BCG) was mandated in France, and nearly 100% of the population has been vaccinated. Nevertheless, after July 2005, the threshold was decreased to 5 mm as in most of all other countries.¹⁰The TST is the current method to detect LTBI but has numerous drawbacks. Indeed, the TST requires a return visit for reading the test result. It has a poor specificity, since previous BCG vaccination and environmental mycobacterial exposure can result in false‐positive results in all subjects.^6,11,12 This poor specificity can lead to unnecessary treatment with antibiotics, with a significant risk of drug toxicity.^13,14,15 On the other hand, TST in IMID may often give a more negative reaction than in the general population, mainly because of the disease or immunosuppressive drug use.^16,17 This poor sensitivity can lead to false‐negative results, with a subsequent risk of TB reactivation with anti‐TNF therapy.The identification of genes in the mycobacterium TB genome that are absent in BCG and most environmental mycobacteria offers an opportunity to develop more specific tests to investigate Mycobacterium tuberculosis (M. tuberculosis) infection, particularly LTBI.¹⁸ Culture fibrate protein‐10 (CFP‐10) and early secretory antigen target‐6 (ESAT‐6) are two such gene products that are strong targets of the cellular immune response in TB patients. In vivo‐specific T‐cell based assay investigating interferon gamma (IFNγ) release or T‐cell proliferation in the presence of these specific mycobacterial antigens could be useful in screening for LTBI before anti‐TNF therapy. New IFNγ‐based ex vivo assays involving CFP‐10 and ESAT‐6 (T‐SPOT TB, Oxford Immunotec, Abingdon, UK) and QuantiFERON TB Gold (QFT‐G; Cellestis, Carnegie, Australia) allow for diagnosis of active TB, recent primo‐infection or LTBI.¹² These tests seem to be more accurate than the TST for this purpose in the general population.¹² To date, the performance of the commercial assays in detecting LTBI in patients with IMID receiving immunosuppressive drugs has not been demonstrated, and the frequency of indeterminate results is still debated.^19,20,21We aimed to investigate the performance of homemade anti‐CFP‐10 and anti‐ESAT‐6 proliferative and enzyme‐linked immunosorbent spot (ELISPOT) assays in detecting LTBI in patients with IMID before anti‐TNFα therapy. We analysed two subgroups of patients: those with confirmed LTBI independent of TST result, and those with LTBI based exclusively on a positive TST result between 6 and 10 mm.     

Impaired enterocyte proliferation in aquaporin-3 deficiency in mouse models of colitis

Background/Aims

Recent evidence has implicated the involvement of aquaporins (AQPs) in cellular functions that are unrelated to transepithelial water transport. Although AQPs are expressed in the gastrointestinal tract, their importance has so far been unclear. AQP3 is a water/glycerol transporter expressed at the basolateral membrane of colonic epithelial cells. The aim of this study was to investigate the involvement of AQP3 in enterocyte proliferation using mouse models of inflammatory bowel disease.

Methods

Expression and function of AQP3 in mouse colonic epithelium were established. Colitis was induced in wild‐type and AQP3 null mice by oral dextran sulphate administration or intracolonic acetic acid administration. Outcome measures included clinical disease severity, survival, pathology and cellular responses. Some mice were administered glycerol to test whether disease progression could be altered.

Results

AQP3 null mice given dextran sulphate developed severe colitis after 3 days, with colonic haemorrhage, marked epithelial cell loss and death. Wild‐type mice, which had comparable initial colonic damage as assessed by cell apoptosis, developed remarkably less severe colitis, surviving to >8 days. Cell proliferation was greatly reduced in AQP3 null mice. Oral glycerol administration significantly improved survival and reduced the severity of colitis in AQP3 null mice. Survival was also reduced in AQP3 null mice in the acetic acid model.

Conclusions

The results implicate a novel role for AQP3 in enterocyte proliferation that is probably related to its glycerol‐transporting function. AQP3 is thus a potential target for therapy of intestinal diseases associated with enterocyte destruction.The aquaporins (AQPs) are a family of water channels expressed in many epithelial, endothelial and other cell types. They facilitate transepithelial water transport in kidney tubules for urine concentration, and in glandular, choroidal and ciliary epithelia for fluid secretion.^1,2 AQPs in non‐epithelial tissues in the central nervous system and eye are also involved in the regulation of tissue hydration. Recently, analysis of transgenic mice lacking specific AQPs has revealed new cellular roles for AQPs that are unrelated to transcellular water transport.³ We found impaired angiogenesis in AQP1‐deficient mice as a consequence of reduced endothelial cell migration,⁴ which may be caused by slowed water movement into lamellipodia at the leading edge of migrating cells. A subset of AQPs (AQPs 3, 7 and 9), called ‘aquaglyceroporins'', transport water as well as glycerol, and possibly other small solutes. Mice lacking AQP3 have dry skin and delayed epidermal healing, with reduced glycerol content in epidermis and stratum corneum,^5,6 caused by impaired glycerol transport from the dermis through the normally AQP3‐expressing basal keratinocytes. Recent studies provided evidence for a new role for AQP3 in cell proliferation. Mice lacking AQP3 were found to have significantly impaired epidermal proliferation in a wound healing model,⁷ and impaired corneal epithelial cell proliferation after epithelial injury.⁸ Mice lacking AQP7 manifest age‐dependent adipocyte hypertrophy and glycerol accumulation,⁹ which we proposed is caused by reduced glycerol exit from the normally AQP7‐expressing adipocytes.AQPs are expressed strongly in gastrointestinal organs including the stomach (parietal cells), liver (hepatocytes and cholangiocytes), pancreas (acinar epithelia), gallbladder (epithelium), small intestine (lacteals, enterocytes) and colon (colonocytes).^10,11 Consequently, roles for AQPs in the secretion of bile and pancreatic fluid have been postulated, as well as in intestinal fluid absorption and secretion. However, phenotype analysis of AQP1, AQP4 and AQP8 knockout mice has revealed little or no consequence of AQP deletion on major gastrointestinal fluid‐transporting functions.^{12,13,14,15,16} The absence of overt gastrointestinal phenotypes in AQP‐deficient mice is surprising in view of the renal, central nervous system, ocular, glandular, cutaneous and other phenotypes found in these mice, particularly since the magnitude of gastrointestinal fluid transport is second only to that in kidney.The epithelium lining the intestine maintains its architecture by a balance between the continuous processes of epithelial cell generation from clonal stem cells¹⁷ at the base of intestinal crypts, and death of cells near the luminal surface. Recent evidence has suggested dysregulation of these processes in inflammatory bowel diseases (IBDs) such as ulcerative colitis, and has emphasised the importance of cell proliferation in disease progression.^18,19 There is evidence for a crucial role for Toll‐like receptor (TLR) signalling and commensal bacteria in the initiation and transduction of the inflammatory and tissue repair responses.^20,21 TLR‐4 null mice and related MyD88 null mice show significantly more severe disease progression in murine models of colitis as a result of impaired epithelial cell proliferation.²⁰Here, we present evidence for a new AQP function in the gastrointestinal tract. We found remarkably greater colonic pathology and mortality in mice lacking AQP3 than in wild‐type mice in experimental models of colitis, with impaired epithelial cell proliferation at the base of colonic crypts in the null mice. The motivations for this study included the strong expression of AQP3 in colonic epithelial cells that undergo rapid turnover,¹⁷ and, as mentioned above, the impairment of epidermal and corneal cell proliferation in AQP3 deficiency.^7,8 We used the dextran sulphate and intracolonic acetic acid models of colitis^21,22,23,24 to induce epithelial damage and restitution in the colon. The primary model used was the dextran sulphate model, a well‐described oral model of colitis. In order to verify the findings using a direct damage, non‐oral model, we also used intracolonic instillation of acetic acid.^25,26 Enterocyte turnover is strongly stimulated in these models, which we predicted could expose defects in enterocyte proliferation and/or migration in AQP3 deficiency. Consequences of the findings here include the potential involvement of AQP3 in epithelial cell proliferation in a variety of intestinal inflammatory diseases, and the possibility of new therapies based on pharmacological modulation of AQP3 expression.     

Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation

Background

We previously showed that neonatal maternal separation (MS) of rat pups causes immediate and long‐term changes in intestinal physiology.

Aim

To examine if administration of probiotics affects MS‐induced gut dysfunction.

Methods

MS pups were separated from the dam for 3 h/day from days 4 to 19; non‐separated (NS) pups served as controls. Twice per day during the separation period, 10⁸ probiotic organisms (two strains of Lactobacillus species) were administered to MS and NS pups; vehicle‐treated pups received saline. Studies were conducted on day 20, when blood was collected for corticosterone measurement as an indication of hypothalamus–pituitary–adrenal (HPA) axis activity, and colonic function was studied in tissues mounted in Ussing chambers. Ion transport was indicated by baseline and stimulated short‐circuit current (Isc); macromolecular permeability was measured by flux of horseradish peroxidase (HRP) across colonic tissues; and bacterial adherence/penetration into the mucosa was quantified by culturing tissues in selective media. Colonic function and host defence were also evaluated at day 60.

Results

Isc and HRP flux were significantly higher in the colon of MS versus NS pups. There was increased adhesion/penetration of total bacteria in MS pups, but a significant reduction in Lactobacillus species. Probiotic administration ameliorated the MS‐induced gut functional abnormalities and bacterial adhesion/penetration at both day 20 and 60, and reduced the elevated corticosterone levels at day 20.

Conclusions

The results indicate that altered enteric flora are responsible for colonic pathophysiology. Probiotics improve gut dysfunction induced by MS, at least in part by normalisation of HPA axis activity.Intestinal epithelial cells are continuously exposed to noxious bacteria, antigens and toxins in the gut lumen, as well as to beneficial commensal organisms. The balance between potentially pathogenic and non‐pathogenic flora is critical for homeostasis and preventing intestinal disease. For example, in patients with inflammatory bowel disease (IBD)¹ and irritable bowel syndrome (IBS),² there are changes in spatial organisation and composition of gut organisms compared with control individuals, with reduced levels of Lactobacillus and Bifidobacterium species. Animal models indicate a role for bacteria in the development of intestinal inflammation;^3,4 disease improvement occurs following manipulation of flora with antibiotics or probiotics.^5,6 Models of spontaneous intestinal disease, including genetic deficiencies in interleukin 10 (IL10),⁷ IL2⁸ and T cell receptors,⁹ are spared from developing inflammation when the mice are housed under germ‐free conditions.The colonisation process begins at parturition, is crucial for long‐term maintenance of the microbiota, and results in the development of gut defences such as secretory immunoglobulin A (sIgA) production (which does not develop in germ‐free animals).¹⁰ Age‐dependent changes in microbiota exist, with altered levels of Enterobacteriaceae, Clostridium and Bacteroides from the suckling period through weaning in rats.¹¹ Colonisation with certain strains of bacteria may be important in preventing the development of intestinal diseases including colitis. Studies have reported that colonising IL10 gene‐deficient mice, which spontaneously develop colitis as adults, with Lactobacillus species as neonates can prevent development of disease.¹² Exposure of animals to stress during establishment of the intestinal microflora may result in altered colonisation, thereby predisposing them to the development of diseases in later life.Neonatal maternal separation (MS) is a well‐established model of early life trauma.^13,14 Studies have shown that early psychological trauma in neonates results in long‐lasting alterations in colonic physiology including increased secretory state,¹⁵ enhanced macromolecular permeability,¹⁵ increased motility¹⁶ and visceral hyperalgesia.^16,17 For these reasons, MS has been suggested to be a model of IBS,¹⁶ a condition where child abuse has often been documented.¹⁸ MS also adversely affects gut physiology at the time of separation, as reported in rat pups where the mucosal barrier was found to be defective.¹⁹ Alterations in mucosal barrier function in neonates may result in increased antigen uptake, sensitisation and susceptibility to stress‐induced dysfunction in later life. Postnatal microbial colonisation in mice has been shown to play an important role in the development of the hypothalamus–pituitary–adrenal (HPA) axis,²⁰ which is essential for the normal stress response, and has been shown to be altered in animals exposed to MS.^13,21This study was designed to determine if changes in colonic flora are present in rat pups during MS and if re‐establishing normal flora can prevent colonic barrier dysfunction. We found that probiotic administration to neonatal rats during separation restored colonic flora and repaired the gut barrier, effects which persisted until adulthood. Furthermore, probiotics reduced the elevated corticosterone in MS pups, suggesting that their effects on the gut were mediated at least in part via normalisation of HPA axis activity.     

Endothelial protein C receptor is overexpressed in rheumatoid arthritic (RA) synovium and mediates the anti-inflammatory effects of activated protein C in RA monocytes

Objectives

(1) To investigate whether inflammatory synovial tissues from patients with rheumatoid arthritis (RA) express endothelial protein C receptor (EPCR) and (2) to determine the major cell type(s) that EPCR is associated with and whether EPCR functions to mediate the effects of activated protein C (APC) on these cells.

Methods

EPCR, CD68 and PC/APC in synovial tissues were detected by immunostaining and in situ PCR. Monocytes were isolated from peripheral blood of patients with RA and treated with APC, lipopolysaccharide (LPS), and/or EPCR blocking antibody RCR252. Cells and supernatants were collected for RT‐PCR, western blotting, enzyme‐linked immuosorbent assay and chemotaxis assay.Results: EPCR was expressed by both OA and RA synovial tissues but was markedly increased in RA synovium. EPCR was colocalised with PC/APC mostly on CD68 positive cells in synovium. In RA monocytes, APC upregulated EPCR expression and reduced monocyte chemoattractant protein‐1‐induced chemotaxis of monocytes by approximately 50%. APC also completely suppressed LPS‐stimulated NF‐κB activation and attenuated TNF‐α protein by more than 40% in RA monocytes. The inhibitory effects of APC were reversed by RCR252, indicating that EPCR is required.

Conclusions

Our results demonstrate for the first time that EPCR is expressed by synovial tissues, particularly in RA, where it co‐localises with PC/APC on monocytes/macrophages. In addition, APC inhibits the migration and activation of RA monocytes via EPCR. These inhibitory effects on RA monocytes suggest that PC pathway may have a beneficial therapeutic effect in RA.Rheumatoid arthritis (RA) is a chronic autoimmune disease with persistent inflammation of multiple synovial joints, which results in progressive tissue destruction of bone and cartilage.^1,2 It is characterised by the infiltration of inflammatory cells (neutrophils, monocytes and lymphocytes) into the synovial compartment and the production of inflammatory mediators. In RA, monocytes migrate into the synovium to become activated macrophages where they secrete significant amounts of inflammatory cytokines such as interleukin (IL)‐1, tumour necrosis factor (TNF)‐α and proteases, which are important in initiating, propagating and maintaining synovial inflammation.³ Macrophages can also differentiate into dendritic cells and osteoclasts,⁴ the latter being recognised as the key cellular effectors of pathological bone erosion in arthritis.⁵ In rheumatoid synovial sections, most synovial lining cells are highly activated macrophage‐like cells functioning as antigen‐processing and antigen‐presenting cells to T lymphocytes.⁶ Macrophages are critically involved in the pathogenesis of RA, not only by producing a variety of pro‐inflammatory cytokines and chemokines, but also by contributing to the cartilage and bone destruction.Activated protein C (APC) is a 61‐kDa serine protease derived from its vitamin K‐dependent plasma precursor, protein C (PC). Activation of PC occurs on the endothelial cell surface and is triggered by a complex formed between thrombin and thrombomodulin. The conversion to APC is augmented in the presence of its specific receptor, endothelial protein C receptor (EPCR),⁷ which is expressed on the surface of endothelial cells, keratinocytes⁸ and some leucocytes, including eosinophils, neutrophils and monocytes.⁹APC acts as an anticoagulant by neutralising the procoagulant activities of factors Va and VIIIa and inhibiting thrombin generation. In addition, APC exerts significant anti‐inflammatory properties, associated with a decrease in pro‐inflammatory mediators and a reduction of leucocyte recruitment.¹⁰ Many anti‐inflammatory properties of APC are mediated through EPCR, which itself can independently exert anti‐inflammatory effects.^11,12,13 For example, severe EPCR deficiency adversely affects survival and cardiac function of mice subjected to challenge by endotoxin infusion.¹³ Baboons treated with an antibody to block PC binding to EPCR respond lethally to normally sublethal concentrations of E coli and exhibit disseminated intravascular coagulation, intense neutrophil influx into the tissues and elevation of inflammatory cytokines, indicating that EPCR provides a critical step in the host defense against E coli.¹² Over expression of EPCR protects transgenic mice from endotoxin‐induced injury.¹⁴ In addition, recent findings suggest that EPCR is required for embryo survival and development.^15,16,17PC/APC is elevated in RA synovial fluid and synovial joints, where it co‐localises with MMP‐2.¹⁸ However, whether EPCR is present in the inflammatory joint is unknown. The purpose of this study was: (1) to determine whether inflammatory (RA) synovial tissue expresses EPCR and if so whether these levels are higher than non‐inflammatory OA synovial tissue; and (2) to elucidate the major cell type(s) EPCR is associated with and whether it functions to mediate the effects of APC on these cells.     

A propensity-matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age

Background

Poor prognosis in heart failure (HF) patients with diabetes is often attributed to increased co‐morbidity and advanced disease. Further, this effect may be worse in women.

Objective

To determine whether the effect of diabetes on outcomes and the sex‐related variation persisted in a propensity score‐matched HF population, and whether the sex‐related variation was a function of age.

Methods

Of the 7788 HF patients in the Digitalis Investigation Group trial, 2218 had a history of diabetes. Propensity score for diabetes was calculated for each patient using a non‐parsimonious logistic regression model incorporating all measured baseline covariates, and was used to match 2056 (93%) diabetic patients with 2056 non‐diabetic patients.

Results

All‐cause mortality occurred in 135 (25%) and 216 (39%) women without and with diabetes (adjusted HR = 1.67; 95% CI = 1.34 to 2.08; p<0.001). Among men, 535 (36%) and 609 (41%) patients without and with diabetes died from all causes (adjusted HR = 1.21; 95% CI = 1.07 to 1.36; p = 0.002). Sex–diabetes interaction (overall adjusted p<0.001) was only significant in patients ⩾65 years (15% absolute risk increase in women; multivariable p for interaction = 0.005), but not in younger patients (2% increase in women; p for interaction = 0.173). Risk‐adjusted HR (95% CI) for all‐cause hospitalisation for women and men were 1.49 (1.28 to 1.72) and 1.21 (1.11 to 1.32), respectively, also with significant sex–diabetes interaction (p = 0.011).

Conclusions

Diabetes‐associated increases in morbidity and mortality in chronic HF were more pronounced in women, and theses sex‐related differences in outcomes were primarily observed in elderly patients.Diabetes is common in heart failure (HF) and is associated with poor outcomes.^1,2 HF patients with diabetes are sicker and have a higher burden of co‐morbidity than those without diabetes.^1,2 Diabetes is also associated with activation of the renin–angiotensin–aldosterone and sympathetic nervous systems.^3,4 There is mounting evidence that diabetes adversely affects collagen production in fibroblasts and calcium homeostasis in cardiac myocytes.^5,6 However, it is not clear to what extent the diabetes‐associated poor outcomes in HF are due to the direct effects of diabetes.Although outcome‐based multivariable risk adjustment models can account for these confounding covariates to some extent, concerns for residual bias limit interpretation of these results.⁷ To address this concern, propensity score matching can be used to assemble cohorts of patients with and without an exposure who would be well balanced in all measured baseline covariates.^8,9,10 More importantly, as investigators remain blinded during the design phase of a randomised clinical trial, this process of bias reduction and study cohort assembly can be done without any knowledge or use of the outcomes data, and the magnitude of bias reduction may be objectively assessed using standardised differences.^7,9,10,11Data from patients with coronary artery disease and elderly patients hospitalised with systolic HF suggest that the effect of diabetes might be worse in women than in men.^12,13,14 However, little is known about the sex‐related variation in the effect of diabetes on outcomes in a more stable younger ambulatory patient population with mild to moderate systolic and diastolic HF. It is also unknown if this sex‐related difference in the effect of diabetes on HF is a function of age. The purpose of this study thus is to determine the effect of diabetes on mortality and hospitalisation in propensity score‐matched ambulatory HF patients and to determine if the effect varies by sex and if the sex‐related differences vary by age.     

Use of intravenous magnesium to treat acute onset atrial fibrillation: a meta-analysis

Objectives

To assess the effects of intravenous magnesium on converting acute onset atrial fibrillation to sinus rhythm, reducing ventricular response and risk of bradycardia.

Design and data sources

Randomised controlled trials evaluating intravenous magnesium to treat acute onset atrial fibrillation from MEDLINE (1966 to 2006), EMBASE (1990 to 2006) and Cochrane Controlled Trials Register without language restrictions.

Review methods

Two researchers independently performed the literature search and data extraction.

Results

10 randomised controlled trials, including a total of 515 patients with acute onset atrial fibrillation, were considered. Intravenous magnesium was not effective in converting acute onset atrial fibrillation to sinus rhythm when compared to placebo or an alternative antiarrhythmic drug. When compared to placebo, adding intravenous magnesium to digoxin increased the proportion of patients with a ventricular response <100 beats/min (58.8% vs 32.6%; OR 3.2, 95% CI 1.93 to 5.42; p<0.001). When compared to calcium antagonists or amiodarone, intravenous magnesium was less effective in reducing the ventricular response (21.4% vs 58.5%; OR 0.19, 95% CI 0.09 to 0.44; p<0.001) but also less likely to induce significant bradycardia or atrioventricular block (0% vs 9.2%; OR 0.13, 95% CI 0.02 to 0.76; p = 0.02). The use of intravenous magnesium was associated with transient minor symptoms of flushing, tingling and dizziness in about 17% of the patients (OR 14.5, 95% CI 3.7 to 56.7; p<0.001).

Conclusions

Adding intravenous magnesium to digoxin reduces fast ventricular response in acute onset atrial fibrillation. The effect of intravenous magnesium on the ventricular rate and its cardiovascular side effects are less significant than other calcium antagonists or amiodarone. Intravenous magnesium can be considered as a safe adjunct to digoxin in controlling the ventricular response in atrial fibrillation.Atrial fibrillation is the commonest cardiac arrhythmia in clinical practice. Atrial fibrillation affects an estimated 2.2 million adults in the USA and has an estimated incidence of 1.0 per 1000 person‐years in the UK.^1,2 Atrial fibrillation is associated with significant morbidity and mortality. Patients in atrial fibrillation have a fivefold increased risk of thromboembolic stroke and twofold increased risk of death when compared to the general population.^3,4 Atrial fibrillation can also cause tachycardia‐induced heart failure if the rapid ventricular response is sustained for a prolonged period of time.⁵Most patients in acute atrial fibrillation have no significant haemodynamic instability and as such, pharmacological therapy is usually the initial treatment of choice. A variety of pharmacological agents can be used, either to control the rapid ventricular response or convert the arrhythmia to sinus rhythm, with variable results. The agents evaluated include digoxin, beta‐blockers, calcium antagonists, flecainide, propafenone, ibutilide, and amiodarone.⁶ However, in patients with impaired left ventricular function, digoxin or amiodarone is the pharmacological agent of choice because of their minimal negative inotropic effects.⁶Magnesium has many significant physiological and pharmacological effects on different organ systems. The mechanisms of its action include calcium antagonism, regulation of energy transfer and membrane stabilisation.⁷ Intravenous magnesium has a high therapeutic‐to‐toxic ratio and minimal negative inotropic effects.^8,9 Intravenous magnesium can reduce automaticity,¹⁰ atrioventricular nodal conduction,^11,12 polymorphic ventricular tachycardia due to prolonged QT interval and digoxin‐induced arrhythmias.^7,8,13 Prophylactic use of intravenous magnesium can also reduce the occurrence of atrial fibrillation after cardiac surgery.¹⁴ However, there are no large randomised controlled studies or meta‐analyses that evaluate intravenous magnesium as an antiarrhythmic agent in the setting of acute onset atrial fibrillation.Rhythm control by pharmacological agents is often most effective when the drug is initiated within 10 days of onset of atrial fibrillation.¹⁵ We hypothesised that intravenous magnesium could be an effective antiarrhythmic agent in patients with acute onset atrial fibrillation. We assessed the potential beneficial and harmful effects of intravenous magnesium, when compared to placebo or an alternative arrhythmic agent, in the setting of acute onset atrial fibrillation (<7 days) in this meta‐analysis. The end‐points assessed in this study included rhythm control, ventricular response <100 beats/minute, bradycardia, hypotension, and other side effects.