Haemodynamic findings in experimental right ventricular ischaemia after right coronary arterial ligation

Acute ischaemia limited to the free wall of the right ventriclewas produced by right coronary arterial ligation (RCAL) in 20dogs. Contrast M-mode and cross-sectional echocardiography wasperformed in 7 cases to investigate the presence of tricuspidinsufficiency. The haemodynamic findings obtained with an openpericardium at 15 to 30 min showed increases in right (l.20.5to 2.70.7 mmHg, P0.01) andleft (5.0 0.8 to 6.60.9 mmHg, P005)ventricular end-diastolic pressures, and decreases in heartrate (1394.9 to 1195.1 bpm, P0.01), cardiac index (1066.6 to817.3 ml min^–1 kg^–1, P001), stroke index (79 6 to72 8 ml x 100 beat^–1 kg^–1, P0.02), right (23.8l.5to 19.41.5 mmHg, P0.01) and left (1097.2 to 958.2 mmHg, P005)ventricular systolic pressures and right ventricular strokework index (18.32.4 to 11.41.8 g m kg^–1, P0.01). In 6of 15 cases the 'y' descent became deeper than the 'x' descentin right atrial pressure (RAP). Tricuspid insufficiency gradeI–II/IV was present in 3 of 7 cases, 2 of them with a'y'>'x' in RAP. Right ventricular mechanical alternans, probablysecondary to a decrease in contractility, appeared in 10 of20 cases after RCAL. Closure of the pericardium exaggeratedthe haemodynamic alterations and a dip-plateau appeared in 2cases on the right ventricular pressure curve. We conclude thatsignificant aemodynamic alterations in right ventricular functionare produced by RCAL in dogs, and they are exaggerated afterclosing the pericardium.     

T-CELL RECEPTOR GAMMA-DELTA POSITIVE LYMPHOCYTES IN SYNOVIAL MEMBRANE

The distribution of T-lymphocytes expressing CD3 and T-cellreceptor gamma-delta (T/) has been examined by immunocytochemistryin the synovial membrane of eight patients with inflammatoryarthritis (six rheumatoid arthritis, two spondyloarthritis)and eight with non-inflammatory arthritis (four osteoarthritis,four post-traumatic arthritis). T/ cells were present in eightout of eight inflammatory arthritis synovial membranes, butin only one out of eight noninflammatory membranes (P<0.005).The mean T/ percentage (of total T-cells) in inflammatory arthritiswas 14% (range 7–25%). T/ cells were found mainly in thetransitional area of the synovial membrane with a scattereddistribution as single cells or couplets. No relation was foundbetween the presence and percentage of T/ cells and diseaseduration or steroid treatment. KEY WORDS: Rheumatoid arthritis, Inflammatory arthritis, Degenerative joint disease, Synovium, Lymphocytes     

Combined tumour necrosis factor-alpha and tumour necrosis factor receptor genotypes could predict rheumatoid arthritis patients' response to anti-TNF-alpha therapy and explain controversies of studies based on a single polymorphism

SIR, Tumour necrosis factor- (TNF-) blocker therapies are widelyused in the treatment of chronic inflammatory diseases. However,patients show large heterogeneity in their response to anti-TNF-therapy. The genotypic background of TNF- and TNF receptor (TNFR)genes could account for patients’ resistance to TNF- blockers[1, 2]. HLA-DR haplotypes have been related with rheumatoidarthritis (RA) susceptibility, severity and course [3], butTNF and TNFR polymorphisms seem to have independent predictivevalue of patients’ response to anti-TNF- therapy [2, 4,5     

Successful treatment of refractory lupus-associated haemophagocytic lymphohistiocytosis with infliximab

SIR, Tolerance of tumor necrosis factor- (TNF-) inhibitors isusually excellent, but a number of recent publications callattention to some potentially paradoxical reactions to TNF-inhibitor therapy, worsening or new-onset palmoplantar pustulosisor psoriasis [1], as well as lupus-like syndrome and inflammatorybowel disease. It is puzzling that medications used to treatone disease may induce the same disease, suggesting a complexrole of TNF- inhibitors. Recently, some case reports of haemophagocyticlymphohistiocytosis (HLH) after treatment with TNF- inhibitors     

Signalling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation

In the synovial cells of patients with RA, activation of thenuclear factor-B (NF-B) pathway results in the transactivationof a multitude of responsive genes that contribute to the inflammatoryphenotype, including TNF- from macrophages, matrix metalloproteinasesfrom synovial fibroblasts and chemokines that recruit immunecells to the inflamed pannus. This is largely a consequenceof activation of the ‘canonical’ NF-B pathway thatinvolves heterodimers of p50/p65. Whilst much information onthe role of NF-B in inflammation has been gleaned from geneticdeficiency of the respective genes in mice, important differencesexist in the signalling networks between human and murine immunecells and immortalized cell lines. Despite these differencesat the molecular level, the importance of NF-B in inflammationis undisputed and inhibition of the pathway is widely believedto have great potential as a therapeutic target in RA. Commercialeffort has gone into developing inhibitors of NF-B activation.However, inhibition of the NF-B activation can result in anexacerbation of inflammation if TNF- production by macrophagesis not controlled. It will be important that such inhibitorsare carefully monitored before their long-term use in chronicinflammatory conditions such as RA. KEY WORDS: NF-B, Signalling pathways, Review Submitted 13 July 2007; revised version accepted 4 October 2007.     

Unstable diabetes in a patient receiving anti-TNF-alpha for rheumatoid arthritis

SIR, Tumour necrosis factor- (TNF-) is a cytokine well-recognizedas having a significant role in the inflammatory process. Recentadvances have led to the production of drugs that inhibit theaction of TNF-, producing significant improvement in the controlof rheumatic diseases [1]. TNF- may also play a role in otherphysiological     

Right and left ventricular ejection fraction and left ventricular volume changes at rest and during exercise in normal subjects

The effect of exercise upon right and left ventricular ejectionfractions (RVEF and LVEF) as well as the changes upon left ventricularend-diastolic and end-systolic volume indices (LVEDVI and LVESVI)were investigated. Twenty-two normal subjects were studied atrest and during upright submaximal exercise. RVEF was determinedusing a first-pass method. LVEF was measured using multiplegated blood pool imaging. During the exercise test ECGs remained normal. HR and BP increasedsignificantly (P<0.01). RVEF increased from 44%±4(mean±SD) to 60%±6 (P<0.001). LVEF increasedfrom 62%±6 to 76±5 (P<0.001). A wider scatterwas observed in RVEF than in LVEF. There was a 14% increasein LVEDV-index and a 14% decrease in LVESV-index (P<0.001).A multiple regression analysis with RVEF as the dependent variableand HR, systolic BP, LVEF, LVEDV-index and LVESV-index as independentvariables showed a significant correlation between RVEF andLVEF and systolic BP (P<0.05). Our data provide insight intothe mechanisms by which the pump performance is increased innormal subjects. The central mechanisms observed are the Starlingeffect and an increase in contractility of the myocardium. Thisis connected in the general circulation to an increase in afterload,indicating a redistribution of blood from the vascular bedsto the muscles and to the heart.     

Visceral leishmaniasis infection in a rheumatoid arthritis patient treated with adalimumab

SIR, Anti-tumour necrosis factor- (TNF-)-based therapies representan important innovation in rheumatoid arthritis (RA) treatment,demonstrating efficacy in reducing disease activity and in retardingradiographic progression. Three different TNF- blockers havebeen approved for the treatment of these conditions: infliximab,adalimumab and etanercept. TNF- is essential for granuloma formationand maintenance, which are key components of host defences againstintracellular pathogens [1]. The clinical use of TNF- blockershas been associated with an increased risk of reactivation ofgranulomatous infectious diseases     

Tumour necrosis factor inhibitors: maximizing patient safety

SIR, The tumour necrosis factor (TNF-)-inhibiting drugs infliximaband etanercept have revolutionized the management of severerheumatoid arthritis and other inflammatory arthropathies. Byblocking TNF- they exert potent immunosuppressive effects ina group of patients already at increased risk     

Suppression of tumour necrosis factor production from mononuclear cells by a novel synthetic compound, CLX-090717

Objectives. To evaluate the clinical efficacy of a novel syntheticperoxisome proliferator-activated receptor gamma (PPAR-) agonist,CLX-090717, in several in vitro cell culture systems and murineCIA, an experimental model of RA. Methods. Peripheral blood monocytes purified by elutriation,and rheumatoid synovial cells isolated from clinical tissuewere cultured with CLX-090717 and TNF- release was measured.Molecular mechanism of action was analysed by western blottingand electrophoretic mobility shift assay. Thioglycollate-elicitedmurine peritoneal macrophages were cultured with CLX-090717and lipopolysaccharide (LPS)-induced TNF- release was assayed.Therapeutic studies were done in mice with established arthritisby evaluating clinical parameters and histology. In addition,type II collagen response of lymphocytes from mice with CIAwas examined. Results. CLX-090717 significantly inhibited spontaneous TNF-release by RA synovial membrane cells, as well as LPS-inducedTNF- release from human and murine monocytic cells. Inhibitionof TNF- in monocytes was mediated partially through a nuclearfactor-B (NF-B)-dependent pathway, as judged by sustained levelsof IB in cytosolic extracts and a reduced level of LPS-inducedNF-B activity in nuclear extracts. CLX-090717 reduced clinicalsigns of arthritis and damage to joint architecture when administeredtherapeutically to arthritic mice. Mechanisms of action in CIAinvolved the reduction in proliferation of arthritic lymphocytesto antigen in vitro as well as reduced TNF- release. Conclusions. Our data suggest that the synthetic compound CLX-090717has potential as a small molecular weight anti-inflammatorytherapeutic for chronic inflammatory conditions. KEY WORDS: Arthritis, Collagen, Cytokines, Monocytes, Synovium, Inflammation     

Is TNFalpha really a good therapeutic target in motoneuronal degeneration? A case of amyotrophic lateral sclerosis in a patient with RA receiving infliximab

SIR, Tumour necrosis factor- (TNF-) has been implicated in thepathogenesis of various inflammatory conditions such as rheumatoidarthritis (RA), Crohn's disease and psoriasis. In these diseases,TNF- blockade is a successful and safe treatment option [1].TNF- can be neurotoxic and has also been implicated in the pathogenesisof some central nervous system diseases where inflammation hasrecently emerged as a significant contributor to motor neurondamage [2]. TNF- acts as the main driver for neuroinflammationin amyotrophic lateral sclerosis (ALS). Animal studies [3–5]as well as phase II     

IL-1 SECRETING CELL ASSAY AND ITS APPLICATION TO CELLS FROM PATIENTS WITH RHEUMATOID ARTHRITIS

The cells within a population that were secreting interleukin-1(IL-1) were enumerated and visualized by an ELISA-SPOT assay.Initial experiments designed to validate the assay revealedthat the number of IL-1ß spot forming cells was increasedby exposing normal blood monocytes to LPS and that spot formationwas prevented by incubating the cells with cycloheximide. Normalblood polymorphonuclear leucocytes (PMNs) produced IL-1 andIL-1ß in response to recombinant granulocyte monocytecolony stimulating factor (rhGMCSF) but not to cytochalasinB, calcium ionophore or LPS. Monocytes and PMN were isolatedfrom the synovial fluid (SF) and blood of patients with rheumatoidarthritis (RA) and the ability of these cells to secrete IL-1and IL-1ß compared. A higher proportion of SF derivedmonocytes were found to secrete IL-1 spontaneously comparedto the corresponding blood cells. IL-1 secreting monocytes werenot detected although high numbers of IL-1 secreting cells werefound among cells isolated from rheumatoid synovium. By contrastSF PMNs did not produce IL-1 or IL-1ß whereas bloodPMNs from some (3/8) RA patients produced IL-1 and/or IL-1ß.It is considered that the IL-1 ELISA-SPOT is a highly sensitivetechnique for detecting IL-1 secreting cells. KEY WORDS: Synovial cells, Interleukin-i1, Interleukin-1ß, Rheumatoid arthritis     

{alpha}1-ANTICHYMOTRYPSIN, C-REACTIVE PROTEIN AND ERYTHROCYTE SEDIMENTATION RATE IN POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS

Forty-four patients with polymyalgia rheumatica and/or giantcell arteritis (PMR/GCA) were followed from presentation, throughremissions and relapses for a median duration of 36 months.Clinical disease activity, ESR, CRP and 1-antichymotrypsin (1-ACT)were measured. Before treatment ESR, CRP and 1-ACT were all significantly raised,compared with age- and sex-matched controls. On clinical remission with prednisolone treatment, ESR and CRPfell to control levels but 1-ACT behaved quite differently,remaining raised for 18 months or until prednisolone treatmentcould be withdrawn. At 18 month follow-up of PMR/GCA, an 1-ACTlevel of 0.7 g/1 was associated with a reduced risk of subsequentrelapse (P = 0.006). At clinical relapse during treatment, ESR was not raised comparedwith controls, and CRP, although significantly higher than controls(P = 0.015), remained less than 6 mg/1 in the majority of patients. The three laboratory investigations were, therefore, of limitedvalue in confirming relapses of PMR/GCA during prednisolonetreatment, but 1-ACT may be useful as an indicator of underlyingdisease activity and hence as a guide to the speed that theprednisolone dosage should be reduced. KEY WORDS: 1-Antichymotrypsin, Erythrocyte sedimentation rate, C-Reactive protein, Polymyalgia rheumatica, Giant cell arteritis     

Polymorphism of the tumour necrosis factor-alpha gene at position -308 and renal manifestations of primary Sjögren's syndrome

SIR, Tumour necrosis factor- (TNF-) is a pro-inflammatory cytokinewhich plays an important role in the pathogenesis of many inflammatoryand infectious diseases, including primary Sjögren's syndrome(pSS). TNF- is expressed in minor salivary gland duct cellsin patients with pSS [1]. It promotes the influx of mononuclearcells not only into the salivary glands but also, for example,to the renal epithelia [2], and has been shown to be involvedin the pathogenesis of experimental tubulointerstitial nephritis.The roles of TNF- in the     

PLASMA LEVELS OF INTERLEUKIN-1-ALPHA IN RHEUMATOID ARTHRITIS

Interleukin-1-beta (IL-1ß has been implicated as aninflammatory mediator in rheumatoid arthritis (RA) but littleis known about the related cytokine, IL-1, in this disease.IL-1 has biological properties similar to IL-1ß but,unlike IL-1ß remains mostly cell-associated. In thisstudy plasma IL- was measured by radioimmunoassay in patientswith RA and in healthy controls. Plasma levels were comparedwith conventional measures of disease activity. The mean levelsin the two groups were not significantly different and, withinthe patient group (n = 53), the only significant cross-sectionalcorrelation was between plasma IL-1 and ESR. In longitudinalstudies, some individual patients had plasma IL-1 levels thatcorrelated with different measures of disease activity. We concludethat while IL- may be involved in the immunopathogenesis ofRA, its measurement in plasma seems to offer little of clinicalvalue. KEY WORDS: Interleukin-1-alpha, Plasma, Rheumatoid arthritis, Prospective longitudinal study     

ROLE OF TNF{alpha}, IN RELATION TO IL-1 AND IL-6 IN THE PROTEOGLYCAN TURNOVER OF HUMAN ARTICULAR CARTILAGE

In both young and old human articular cartilage explants, TNFinduced a concentration-dependent, reversible suppression ofthe proteoglycan (PG) synthesis. Young cartilage was more sensitiveto TNF than old cartilage: 50% suppression of PG synthesis wasreached at a TNF concentration of 5 U/ml for young and 30 U/mlfor old cartilage, whereas at 10³ U/ml the PG synthesis of youngcartilage was blocked and that of old cartilage suppressed by80%. These inhibition levels of PG synthesis resulted in 25%PG depletion of the explants after 8 days of culture. The releaseof cartilage PG not enhanced. TNF induced no detectable amountsof IL-1 (<0.01 U) in young or old cartilage but did induceIL-6 production. The induced amounts of IL-6 were higher inyoung than in old cartilage but no dose-dependency was evident.Antibodies to neither IL-1 nor IL-6 had any influence on theTNF-induced suppression of PG synthesis. The combination ofTNF and IL-1 led to an additive inhibition of PG synthesis whichhad no relationship to induced IL-6. TNF was about 100-foldless active than IL-1. KEY WORDS: Explant culture, Cytokines, Bioassay     

LACK OF CORRELATION BETWEEN CLINICAL DISEASE ACTIVITY AND ERYTHROCYTE SEDIMENTATION RATE, ACUTE PHASE PROTEINS OR PROTEASE INHIBITORS IN ANKYLOSING SPONDYLITIS

Disease activity was assessed clinically and erythrocyte sedimentationrate (ESR), C-reactive protein (CRP), orosomucoid, ₁-antitrypsin(₁ AT) and ₂-macroglobulin (₂M) were measured in 65 patientswith ankylosing spondylitis (AS). Positive correlations werefound between ESR and the acute phase proteins (APP), CRP, orosomucoidand ₁AT, but none of these variables correlated with the clinicalassessment of activity. No relationship was demonstrated betweenthe protease inhibitor, ₂M and clinical activity, ESR or anyof the APP. While the treatment of AS remains predominantly symptomatic,routine management of patients should continue to be foundedon the clinical assessment of disease activity rather than onlaboratory indices of inflammation. KEY WORDS: Ankylosing spondylitis, Clinical assessment, Erythrocyte sedimentation rate, Acute phase proteins, Protease inhibitors     

Autonomic balance in patients with angina and a normal coronary angiogram

The pathophysiology of angina pectoris in patients with a normalcoronary angiogram is not clear. Furthermore, the pathophysiologicalimpact of ST changes in syndrome X is controversial. The purposeof this study was to investigate cardiac autonomic function,by measuring 24 h heart rate variability, in patients with andwithout electrocardiographic evidence of ischaemia during exercise. Thirty-two patients with angina pectoris, a normal coronaryangiogram, echocardiogram, hyperventilation test and gastro-oesophagealinvestigation were studied. Fourteen healthy subjects servedas controls. Fifteen patients had significant ST segment depressionduring stress testing, whereas 17 had no electrocardiographicsigns of ischaemia. Heart rate variability was calculated as(1) mean RR= mean of all normal RR intervals, (2) the differencein mean RR level between when awake and when asleep (mean RRwake-sleep)—a tentative index of sympathetic activation,(3) the standard deviation (SD)—a broad band measure ofautonomic balance, and (4) a percentage of successive RR intervaldifferences 6% (pNN6%)—an index of vagal modulation. Thecoronary vascular resistance was measured at rest and duringpacing. Mean RR and autonomic indexes did not differ between patientswith a positive exercise test and controls (831/884 m 24 h SD125/134 m pNN6% 6.715.4%, respectively). Patients with a normalexercise test had shorter mean RR (758 ms vs 844 m P<0.05)and significantly reduced 24-h SD (103 ms vs 134 m P<0.05)than controls, whereas values for vagal index (6.5% vs 5.4%)did not differ from healthy controls. Mean RR wake-sleep alsotended to be lower in patients with a normal exercise test (–125 ms vs – 173 ms) compared to controls (P<0.1). Patientswith a positive exercise test had a significantly attenuatedreduction in coronary vascular resistance during pacing in comparisonto patients with a normal exercise test (–0.131–0.26mmHg x min. ml^{– 1}; P<0.05). The findings suggest the occurrence of general elevated sympatheticactivation in angina patients with a normal exercise test. Patientswith a positive exercise test exhibited no signs of autonomicdysfunction although these patients had altered coronary vascularresistance indicating microvascular angina. This supports thesuggestion that patients with a normal exercise test constitutean independent pathophysiological entity.     

Pneumocystis carinii pneumonia following a second infusion of infliximab

SIR, Anti-tumour necrosis factor (TNF-) blockade is increasinglyused for severe rheumatoid arthritis (RA). There is an increasedrisk of infection, including atypical infection [1] associatedwith TNF- blockade. We report the development of Pneumocystiscarinii pneumonia (PCP) in a man with RA shortly after commencingtherapy with the anti-TNF- agent infliximab (Remicade). Thisoccurred in the setting of concomitant therapy with low-doseweekly methotrexate and corticosteroids. A 49-yr-old man who had had seropositive RA for 9 yr