Imbalance of the interleukin 1 system in colonic mucosa—association with intestinal inflammation and interleukin 1 receptor agonist genotype 2

Background—Interleukin 1 (IL-1) α and β arepotent cytokines which play key roles in inflammation. They arecontrolled by IL-1 receptor antagonist (IL-1ra).
Aims—To investigate the influence of mucosalinflammation and IL-1ra genotype on the IL-1ra:IL-1 balance.
Patients and methods—IL-1α, IL-1β, and IL-1rawere measured by enzyme linked immunosorbent assay (ELISA) in biopsyspecimens taken from inflamed and non-inflamed colon of 60 patientswith Crohn's disease (CD), 34 with ulcerative colitis (UC), 15 inflammatory controls, and 103 non-inflamed controls. IL-1ra genotypewas determined by polymerase chain reaction and gel electrophoresis.
Results—IL-1α and IL-1β were significantlyincreased in inflamed mucosa in inflammatory bowel disease (IBD) (CD:53.5 (22.4) and 409.9 (118.7) pg/mg protein, respectively; UC: 18.9 (6.8) and 214.5 (78.2) pg/mg, respectively) and non-IBD patients (19.2(7.4) and 281.4 (121.0) pg/mg, respectively; p<0.0001) compared withnormal controls (2.8 (0.6) and 30.6 (5.6) pg/mg, respectively). In CDIL-1α and β were also significantly increased in non-inflamed mucosa (6.1 (1.3) pg/mg and 88.7 (17.4) pg/mg, respectively;p<0.0012). IL-1ra:(IL-1α+β) ratios were significantly decreased ininflamed mucosa of patients with CD (182 (45); p<0.0001), UC (425 (136); p=0.0018) and without IBD (221 (76); p<0.0001), and innon-inflamed mucosa in CD (369 (149); p<0.0001) compared with normalcontrols (1307 (245); p<0.0001). Patients with IL-1ra genotype 2 hadslightly but significantly reduced mucosal IL-1ra concentrations(p=0.003). The greatest difference was seen in colonic biopsy specimensfrom patients with inflamed Crohn's disease.
Conclusion—Mucosal inflammation can modulate thebalance of the IL-1:IL-1ra system in colonic mucosa.

Keywords:interleukin 1; interleukin 1 receptor antagonist; inflammatory bowel disease; Crohn's disease; mucosal inflammation; genotype

     

Prophylactic effect of dietary glutamine supplementation on interleukin 8 and tumour necrosis factor α production in trinitrobenzene sulphonic acid induced colitis

Background—It is well established that glutaminesupplemented elemental diets result in less severe intestinal damage inexperimental colitis. However, few studies have examined the mode ofaction of glutamine in reducing intestinal damage.
Aims—To examine the effects of glutaminesupplemented elemental diets on the potent inflammatory cytokinesinterleukin 8 (IL-8) and tumour necrosis factor α (TNF-α) intrinitrobenzene sulphonic acid (TNBS) induced colitis which presentswith both acute and chronic features of ulcerative colitis.
Methods—Sprague-Dawley rats were randomised intothree dietary groups and fed 20% casein (controls), or 20% caseinsupplemented with either 2% glutamine (2% Gln) or 4% glutamine (4%Gln). After two weeks they received intracolonic TNBS to inducecolitis.
Results—Both Gln groups of rats gained more weight thanthe control group (p<0.05) which had progressive weight loss. Colon weight, macroscopic, and microscopic damage scores for the Gln groupswere lower than in the control group (p<0.05). IL-8 and TNF-αconcentrations in inflamed colonic tissues were lower in the Gln groupsthan in the control group (p<0.05), and correlated well with diseaseseverity. Bacterial translocation was lower both in incidence (p<0.05)and in the number of colony forming units (p<0.05) for the Gln groups,than in the control group. With respect to all indices studied, the 4%Gln group performed better than did the 2% Gln group.
Conclusion—Prophylactic glutamine supplementationmodulates the inflammatory activities of IL-8 and TNF-α in TNBSinduced colitis.

Keywords:glutamine; trinitrobenzene sulphonic acid; inflammatory bowel disease; rats; interleukin 8; tumour necrosis factorα

     

Different microcirculatory and interstitial matrix patterns in idiopathic dilated cardiomyopathy and Chagas' disease: a three dimensional confocal microscopy study

OBJECTIVE—To analyse the morphological aspects of the extracellular matrix and microcirculation to clarify whether chronic Chagas' cardiopathy (CCC) is an accurate model to study the pathogenesis of idiopathic dilated cardiomyopathy (IDCM).
DESIGN—Thick histological myocardial sections were prepared to analyse collagen, and microcirculation was examined during confocal laser and light microscopy.
SETTING—The specimens were prepared at the pathology service of the Heart Institute of São Paulo, Brazil.
PATIENTS—Nine control hearts, eight IDCM hearts, and 10 CCC hearts were studied after necropsy.
MAIN OUTCOME MEASURES—The number of collagen struts per 100× field, the area of fibrosis (%), and the diameters of arterioles and capillaries were measured in each heart to establish outcome.
RESULTS—A smaller number (mean (SD)) of collagen struts was seen in the hearts in the IDCM group (9.1 (4.1)) than in the control (22.4 (3.2)) (p < 0.05) or CCC (15.7 (7.4)) (p > 0.05) groups. Fibrosis was greater in the CCC hearts (13.8 (10.5)%) than in the IDCM hearts (5.9 (6.6)%) (p > 0.05). Major increases in arteriole (65.4 (9.9) µm) and capillary (9.9 (1.7) µm) diameters were seen in the CCC hearts but not in the IDCM hearts (arteriole diameter 40.3 (7.9) µm; capillary diameter 7.9 (1.3) µm).
CONCLUSIONS—Hearts demonstrating CCC and IDCM present different extracellular and microvessel alterations. This suggests that distinct pathogenic mechanisms are responsible for each condition and that CCC is not an effective model to study IDCM.


Keywords: microcirculation; Chagas' disease; dilated cardiomyopathy; extracellular matrix     

T cell derived cytokines in psoriatic arthritis synovial fluids

OBJECTIVE—The aim of this study was to investigate the concentrations of T cell derived cytokines in the synovial fluids (SFs) of patients with psoriatic arthritis (PsA) in comparison with rheumatoid arthritis (RA) and osteoarthritis (OA).
METHODS—Th1 type cytokines (interleukin 2 (IL2), tumour necrosis factor β (TNFβ), and interferon γ (INFγ)) and Th2 type cytokines (IL4, IL10) were measured by means of enzyme linked immunosorbent assays.
RESULTS—IL2 was usually not detectable in any of the disease groups. TNFβ was found in 3 of 31 PsA SFs (mean (SEM) 11.1 (2.3) pg/ml) and in a significantly lower concentration than in 20 of the 40 RA SFs (42.2 (15.6) pg/ml; p < 0.002). INFγ was measurable in 2 of 10 PsA and 6 of 16 RA SFs (p > 0.05). IL4 was present at low concentrations in 4 of 22 PsA SFs (0.41 (0.8) pg/ml), and in 15 of 20 RA SFs (0.63 (0.09) pg/ml; p < 0.01). IL10 was found in 4 of 27 PsA SFs (12.3 (0.9) pg/ml) and in 27 of 32 RA SFs (37.3 (4.9) pg/ml; p < 0.0001). In all OA SFs cytokine concentrations were below the limit of detection.
CONCLUSION—The pattern of T cell derived cytokines in PsA SFs was similar to that of RA SFs. However, both the frequency and the concentrations of cytokines were lower in PsA SFs than in RA SFs, while OA SFs generally lacked any detectable T cell cytokines altogether. The presence of Th1 and Th2 cell derived cytokines in PsA SFs suggests the presence of activated T cells in the inflamed joint tissues and their participation in the immunoinflammatory events.

Keywords: psoriatic arthritis; rheumatoid arthritis; cytokines; T cells; synovial fluids     

Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophils and regulation by interleukin 10 during intestinal inflammation

Background—Concentrations of pro-inflammatorycytokines are increased in the intestinal mucosa of patients withactive inflammatory bowel disease (IBD). Polymorphonuclear neutrophilgranulocytes (PMN) are the most abundant cell type in intestinallesions in IBD. Interleukin 10 (IL-10) is an importantcontra-inflammatory cytokine which induces downregulation ofpro-inflammatory cytokines.
Aims—To investigate whether PMN from patients withIBD or infectious colitis, respectively, secrete increased amounts ofpro-inflammatory cytokines and can be regulated by IL-10.
Methods—Secretion (ELISA) as well as correspondingmRNA levels (semiquantitative RT-PCR) of pro-inflammatory cytokines(IL-1β, TNF-α) and of IL-1 receptor antagonist were assessed inperipheral PMN.
Results—PMN from patients with IBD are primed tosecrete enhanced amounts of pro-inflammatory cytokines accompanied bydetection of corresponding mRNAs in comparison with normal controls.This finding is not specific for IBD but rather reflects intestinal inflammation in general. IL-10 markedly inhibited pro-inflammatory cytokine secretion as well as corresponding mRNA concentrations.
Conclusions—PMN are an important source ofpro-inflammatory cytokines in patients with intestinal inflammation andcan be downregulated by IL-10.

Keywords:granulocytes; interleukin 1β; interleukin 10; inflammatory bowel disease; intestinal immunity; inflammation; neutrophils; tumour necrosis factor α

     

S-Nitrosoglutathione inhibits platelet activation and deposition in coronary artery saphenous vein grafts in vitro and in vivo

Objective—To investigate platelet activation and deposition in human saphenous vein and internal mammary artery grafts following coronary artery bypass in vitro and in vivo, as well as inhibition of activation by the platelet selective nitric oxide donor S-nitrosoglutathione (GSNO).
Design—Controlled in vitro and in vivo studies.
Setting—Tertiary cardiac centre.
Patients—24 patients undergoing coronary artery bypass surgery requiring vein and artery grafts.
Interventions—In vitro: human platelet rich plasma was perfused through segments of vein and artery, with or without GSNO 10^-6 M, and the platelet count was measured in the effluent. In vivo: indium-111 labelled antibody against the platelet α granule protein GMP-140 was injected at the end of coronary bypass grafting and γ counts were compared between vein and artery grafts with or without systemic infusion of GSNO (40 nmol/min).
Results—In vitro: platelet count in perfused vein (< 70% of baseline) decreased more than in artery segments (89-94% of baseline) (p < 0.001). The platelet count was unchanged with GSNO in vein and artery segments. In vivo: γ counts were greater at all time points over vein than artery grafts (p < 0.05), and were reduced by infusion of GSNO (p < 0.05).
Conclusions—Platelet activation is greater in vein than in artery grafts in vitro and in vivo. Activation, which contributes to early vein graft failure, was inhibited by GSNO.

Keywords: coronary artery bypass surgery;  platelet activation;  S-nitrosoglutathione;  ischaemic heart disease     

Malalignment of the sarcomeric filaments in hypertrophic cardiomyopathy with cardiac myosin heavy chain gene mutation

OBJECTIVE—To investigate changes in the alignment of the sarcomeric filaments in hypertrophic cardiomyopathy and the effects of cardiac β myosin heavy chain (β-MHC) mutation on the sarcomeric ultrastructure.
DESIGN—A retrospective analysis.
PATIENTS—Endomyocardial biopsy samples were examined by transmission electron microscopy in seven patients with hypertrophic cardiomyopathy and β-MHC mutation, six with hypertrophic cardiomyopathy but without the mutation, and five controls (with chest pain syndromes).
MAIN OUTCOME MEASURE—Alignment of the sarcomeric filaments and the distance between neighbouring thick myosin filaments.
RESULTS—In controls, cross sections of the sarcomere at the A band showed a highly organised orthohexagonal array with 6 thin actin filaments surrounding one thick myosin filament, whereas in hypertrophic cardiomyopathy the alignment of the sarcomeric filaments was sparse and disrupted. In hypertrophic cardiomyopathy with a mutation, the distance between neighbouring thick myosin filaments was greater than in controls (mean (SD) 45.3 (4.7) v 38.5 (3.5) nm, p < 0.05), and the variance of the distance was greater than in controls (8.0 (0.7) v 4.8 (1.0) nm, p < 0.001) or in patients with hypertrophic cardiomyopathy without a mutation (6.7 (0.6) nm, p < 0.05). In the latter, the variance of the distance was also greater than in the controls (p < 0.01). A significant correlation was found between the grade of the myocyte hypertrophy and the variance of the distance (r = 0.654; p < 0.01).
CONCLUSIONS—The alignment of the sarcomeric filaments is disrupted in hypertrophic cardiomyopathy, particularly when there is β-MHC mutation.


Keywords: hypertrophic cardiomyopathy; β myosin heavy chain; myosin filament; sarcomere     

Five genetic markers in the interleukin 1 family in relation to inflammatory bowel disease

Background—An imbalance between theproinflammatory cytokine interleukin 1β (IL-1β) and theanti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra) has beenpostulated as a pathogenic factor in inflammatory bowel disease (IBD).
Aims—To study allelic frequenciesof novel polymorphisms in the genes for IL-1β and IL-1ra in patientswith IBD and to assess the relation between ex vivo cytokine productionand allelic variants of the IL-1β and IL-1ra genes.
Subjects—Two hundred and seventyhealthy controls, 74 patients with ulcerative colitis (UC), 72 withCrohn's disease (CD), 40 with primary sclerosing cholangitis for theallelic frequencies, and 60 healthy individuals for the ex vivostimulation test.
Methods—Genotyping was performed bypolymerase chain reaction and subsequent cleavage with specificendonucleases (Mwo1, MspAI1, Alu1, Taq1, BsoF1) for five novelrestriction fragment length polymorphisms (RFLPs) in the genes forIL-1ra and IL-1β.
Results—No significant differences were found inthe allelic frequencies or allele carriage rates of the markers in theIL-1β and IL-1ra genes between CD, UC, and healthy controls. Noassociation between the genetic markers and cytokine production levelswas observed. Patients with UC carried the combination of both the infrequent allele of the Taq1 RFLP and the Mwo1 RFLP significantly morefrequently (35.2% in UC versus 71.1% in controls).
Conclusions—UC is associatedwith carriage of both infrequent alleles of the Taq1 and Mwo1 RFLPs.However, it could not be confirmed whether the association reflects apathogenic mechanism underlying UC.

     

Induction of various cytokines and development of severe mucosal inflammation by cagA gene positive Helicobacter pylori strains

Background—Helicobacter pyloristrains possessing the cagA gene are thought to induceinterleukin 8 (IL-8) in gastric mucosa. However, it is still unclearwhether a relation exists between the cagA gene and theexpression patterns of cytokines other than IL-8.
Aims—To investigate therelation between the cagA gene and the productionof various cytokine proteins using an enzyme linked immunosorbentassay (ELISA).
Patients and methods—In 184 patients,the cagA gene was detected by polymerase chain reaction(PCR), and levels of production of IL-1β, IL-6, IL-7, IL-8, IL-10,and tumour necrosis factor α (TNF-α) in antral biopsy specimenswere measured by ELISA.
Results—Mucosal levels of IL-1β, IL-6,IL-8, and TNF-α were significantly higher in H pyloripositive than in H pylori negative patients.Furthermore, the mucosal levels of IL-1β and IL-8 were significantly higher in specimens infected with cagApositive strains than in those infected with cagAnegative strains. In H pylori positivepatients, the mucosal level of IL-8 was closely correlated withthat of IL-1β (p<0.0001), and the mucosal level of IL-6was closely correlated with that of TNF-α (p<0.0001).
Conclusion—These findings suggest that theability to induce cytokines differs among the strains;cagA⁺ strains induce various kinds ofcytokines and may cause severe inflammation, whereascagA strains induce IL-8 and IL-1β onlyweakly and may cause only mild inflammation. However, as most patientsinfected with the cagA⁺ strains havegastritis, these strains may not be equivalent to ulcerogenic strains.

Keywords:cytokines; Helicobacter pylori; cagA gene; interleukin 8; interleukin 1β

     

β Blockade in congestive heart failure: persistent adverse haemodynamic effects during chronic treatment with subsequent doses

Objective—To determine whether the acute adverse haemodynamic effects of β blockade in patients with congestive heart failure persist during chronic treatment.
Design—Sequential haemodynamic evaluation of heart failure patients at baseline and after three months of continuous treatment with the β₁ selective antagonist metoprolol.
Setting—Cardiac care unit in university hospital.
Patients—26 patients with moderate to severe congestive heart failure (New York Heart Association grade II to IV) and background treatment with digoxin, diuretics, and angiotensin converting enzyme inhibitors, and with a left ventricular ejection fraction < 25%.
Methods—Baseline variables included a six minute walk, maximum oxygen consumption, and right heart catheterisation. All patients received metoprolol 6.25 mg orally twice daily initially and the dose was gradually increased to a target of 50 mg twice daily. Haemodynamic measurements were repeated after three months of treatment, both before (trough) and after drug readministration.
Results—Long term metoprolol had functional, exercise, and haemodynamic benefits. It produced decreases in heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance, and increases in cardiac index, stroke volume index, and stroke work index. However, when full dose metoprolol was readministered during chronic treatment, there was a reduction in cardiac index (from 2.8 (SD 0.46) to 2.3 (0.38) l/min/m², p << 0.001) and stroke work index (from 31.4 (11.1) to 26.6 (10.0) g.m/m², p < 0.001) and an increase in systemic vascular resistance (from 943 (192) to 1160 (219) dyn.s.cm⁻⁵, p << 0.001).
Conclusions—Adverse haemodynamic effects of β blockers in heart failure persist during chronic treatment, as shown by worsening haemodynamic indices with subsequent doses.

Keywords: heart failure;  β blockers;  adverse effects     

Increased concentrations of inflammatory mediators in unstable angina: correlation with serum troponin T

OBJECTIVE—To measure plasma interferon γ, monocyte chemotactic protein-1 (MCP-1), and interleukin 6 and to assess their correlation with cardiac troponin T in unstable angina.
DESIGN—Blood sampling in patients undergoing coronary arteriography for known or suspected ischaemic heart disease.
PATIENTS—76 patients divided in three groups: 29 with unstable angina (group 1), 28 with stable angina (group 2), and 19 without ischaemic heart disease and with angiographically normal coronary arteries (group 3).
MAIN OUTCOME MEASURES—Plasma interleukin 6, interferon γ, MCP-1, and troponin T in the three groups of patients.
RESULTS—Interleukin 6 was increased in group 1 (median 2.19 (range 0.53-50.84) pg/ml) compared with the control group (1.62 (0.79-3.98) pg/ml) (p < 0.005), whereas interferon γ was higher in group 1 (range 0-5.51 pg/ml) than in the other two groups (range 0-0.74 pg/ml and 0-0.37 pg/ml; p < 0.005 and p < 0.001, respectively). Patients with unstable angina (group 1) and positive troponin T had higher concentrations of interferon γ than those with negative troponin T (0-5.51 pg/ml v 0-0.60 pg/ml, p < 0.001). Plasma MCP-1 was also higher in group 1 (median 267 (range 6-8670) pg/ml) than in the other two groups (134 (19-890) pg/ml and 84.5 (5-325) pg/ml; p < 0.005 and p < 0.001, respectively), and among group 1 patients with a positive troponin T assay than in those with normal troponin T (531 (14.5-8670) pg/ml v 69 (6-3333) pg/ml; p < 0.01). There was no difference in plasma interleukin 6 in group 1 patients between those with and without raised troponin T.
CONCLUSIONS—The inflammatory cytokines interferon γ and MCP-1 are increased in patients with unstable angina, particularly in those with raised concentrations of troponin T, suggesting that they are probably related to myocardial cell damage or to plaque rupture and thrombus formation.


Keywords: inflammatory cytokines; troponin T; unstable angina     

Spontaneous secretion of interferon γ and interleukin 4 by human intraepithelial and lamina propria gut lymphocytes

Background—Cytokines secreted by intestinal Tlymphocytes probably play a critical role in regulation of the gutassociated immune responses.
Aims—To quantify interferon γ (IFN-γ) andinterleukin 4 (IL-4) secreting cells (SC) among human intraepithelial(IEL) and lamina propria (LPL) lymphocytes from the duodenum and rightcolon in non-pathological situations and in the absence of in vitro stimulation.
Patients—Duodenal and right colonic biopsyspecimens were obtained from patients with no inflammation of theintestinal mucosa.
Methods—Intraepithelial and lamina propria cellsuspensions were assayed for numbers of cells spontaneously secretingIFN-γ and IL-4 by a two site reverse enzyme linked immunospottechnique (ELISPOT).
Results—The relatively high proportion ofduodenal lymphocytes spontaneously secreting IFN-γ (IEL 3.6%; LPL1.9%) and IL-4 (IEL 1.3%; LPL 0.7%) contrasted with the very lownumbers of spontaneously IFN-γ SC and the absence of spontaneouslyIL-4 SC among peripheral blood mononuclear cells. In the basal state,both IFN-γ and IL-4 were mainly produced by CD4⁺ cells.Within the colon, only 0.2% of IEL and LPL secreted IFN-γ in thebasal state, and 0.1% secreted IL-4.
Conclusions—Compared with peripheral lymphocytessubstantial proportions of intestinal epithelial and lamina proprialymphocytes spontaneously secrete IFN-γ and/or IL-4. These cytokinesare probably involved in the normal homoeostasis of the humanintestinal mucosa. Disturbances in their secretion could play a role inthe pathogenesis of gastrointestinal diseases.

     

β2 Adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium

OBJECTIVE—To define the effects of β₂ adrenergic receptor stimulation on ventricular repolarisation in vivo.
DESIGN—Prospective study.
SETTING—Tertiary referral centre.
PATIENTS—85 patients with coronary artery disease and 22 normal controls.
INTERVENTIONS—Intravenous and intracoronary salbutamol (a β₂ adrenergic receptor selective agonist; 10-30 µg/min and 1-10 µg/min), and intravenous isoprenaline (a mixed β₁/β₂ adrenergic receptor agonist; 1-5 µg/min), infused during fixed atrial pacing.
MAIN OUTCOME MEASURES—QT intervals, QT dispersion, monophasic action potential duration.
RESULTS—In patients with coronary artery disease, salbutamol decreased QT_onset and QT_peak but increased QT_end duration; QT_onset-QT_peak and QT_peak-QT_end intervals increased, resulting in T wave prolongation (mean (SEM): 201 (2) ms to 233 (2) ms; p < 0.01). There was a large increase in dispersion of QT_onset, QT_peak, and QT_end which was more pronounced in patients with coronary artery disease—for example, QT_end dispersion: 50 (2) ms baseline v 98 (4) ms salbutamol (controls), and 70 (1) ms baseline v 108 (3) ms salbutamol (coronary artery disease); p < 0.001. Similar responses were obtained with isoprenaline. Monophasic action potential duration at 90% repolarisation shortened during intracoronary infusion of salbutamol, from 278 (4.1) ms to 257 (3.8) ms (p < 0.05).
CONCLUSIONS—β₂ adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium. The increase in dispersion of repolarisation provides a mechanism whereby catecholamines acting through this receptor subtype may trigger ventricular arrhythmias.


Keywords: β₂ adrenergic receptors; ventricular repolarisation; QT dispersion; salbutamol; isoprenaline     

Increased expression of transforming growth factor α precursors in acute experimental colitis in rats

Background and aim—Epidermal growth factor (EGF)and transforming growth factor α (TGF-α), members of the EGF familyof growth factors, protect rat gastric and colonic mucosa againstinjury. Having shown previously that exogenously applied EGF protects rat colonic mucosa against injury, the aim of the present study was toevaluate the endogenously expressed ligand mediating the protectiveeffect of EGF/TGF-α in vivo.
Methods—In an experimental model oftrinitrobenzene sulphonic acid (TNBS)/ ethanol induced colitis in ratsEGF and TGF-α expression was evaluated using a ribonucleaseprotection assay, northern blot analysis, western blot analysis, and immunohistochemistry.
Results—TGF-α mRNA increased 3-4 times at 4-8hours after induction of colitis and returned to control levels within24 hours. TGF-α immunoreactive protein with a molecular size of about28kDa representing TGF-α precursors increased markedly afterinduction of colitis with a peak at 8-12 hours. No fully processed 5.6 kDa TGF-α protein was detected in normal or inflamed colon tissue. Only a weak signal for EGF mRNA expression was detected in the ratcolon and no EGF protein was observed by immunohistochemistry orwestern blot analysis.
Conclusions—TGF-α precursors are the mainligands for the EGF receptor in acute colitis. It is hypothesised thatTGF-α precursors convey the biological activity of endogenous TGF-αpeptides during mucosal defence and repair.

     

Beta human chorionic gonadotropin concentrations in serum of patients with pancreatic adenocarcinoma

Background—Human chorionic gonadotropin (hCG) isnormally produced and secreted by trophoblastic cells during pregnancyand from gestational trophoblastic neoplasms. It is also detected in ovarian, stomach, and colon adenocarcinomas, as well as in squamouscell carcinoma of the oesophagus. Recently, interest in its role in thepathogenesis of tumours has been enlivened after the presence of βhCGin the cell membrane of several malignant cells was shown in vitro.
Aims—To investigate the circulatingconcentrations of βhCG in patients with exocrine pancreaticadenocarcinoma and to examine its potential prognostic value.
Patients—Thirty six patients with exocrinepancreatic adenocarcinoma, 12 patients with chronic pancreatitis, and21 healthy volunteers were studied.
Methods—βhCG serum concentrations were detectedby the application of a radioimmunoassay technique.
Results—Fifteen of 36 patients with pancreaticadenocarcinoma and only one patient with chronic pancreatitis haddetectable plasma concentrations of βhCG (p<0.01). The patients withcirculating serum titres of βhCG had a worse outcome compared withthe group of βhCG negative patients: the difference was statisticallysignificant (p=0.01).
Conclusion—More than 40% of pancreatic exocrinetumours produce βhCG and its production is correlated with an adverseeffect on outcome.

Keywords:β-human chorionic gonadotropin; chorionicgonadotropin; pancreatic cancer; tumour marker; paraneoplasticsyndrome

     

Prediction of the effectiveness of long term β blocker treatment for dilated cardiomyopathy by signal averaged electrocardiography

Objective—To determine whether the effectiveness of long term β blocker treatment for idiopathic dilated cardiomyopathy can be predicted by signal averaged electrocardiography (ECG).
Patients—31 patients with dilated cardiomyopathy and without bundle branch block were included in a retrospective study and 16 in a prospective study.
Methods—A signal averaged ECG was recorded before β blocker treatment, and three variables were measured from the vector magnitude: QRS duration, root mean square voltage for the last 40 ms (RMS40), and duration of the terminal low amplitude signals (< 40 µV) (LAS40). In the retrospective study, these variables were compared among good responders (showing  0.10 increase in ejection fraction 12 months after start of β blocker treatment) and poor responders without such improvement. The validity of the signal averaged ECG criteria for prediction of the response to β blocker treatment was examined in the prospective study.
Results—In the retrospective study, good responders (n = 16) had a shorter QRS duration (mean (SD): 122.9 (11) v 138 (14.4) ms, p < 0.005) and LAS40 (33.1 (8.9) v 42.5 (7.8) ms, p < 0.005), and a higher RMS40 (31.6 (16.3) v 19.0 (10.3) µV, p < 0.02) than poor responders (n = 15). Signal averaged ECG criteria for good response were defined as two or more of the following: QRS duration < 130 ms, RMS40 > 20 µV, LAS40 < 40 ms (sensitivity 81%, specificity 73%). In the prospective study, six of seven patients who met these criteria showed a good response to the β blocker treatment, while eight of nine who did not showed a poor response (χ² = 6.1, p < 0.02). The signal averaged ECG criteria gave a sensitivity of 86% and a specificity of 89% for predicting the effectiveness of β blocker treatment.
Conclusions—A signal averaged ECG might be useful in predicting the effectiveness of β blocker treatment for dilated cardiomyopathy.

Keywords: signal averaged ECG;  β blockers;  dilated cardiomyopathy     

Tyrosine phosphorylation of platelet derived growth factor β receptors in coronary artery lesions: implications for vascular remodelling after directional coronary atherectomy and unstable angina pectoris

Background—Growth factors such as platelet derived growth factor (PDGF) have been postulated to be important mediators of neointimal proliferation observed in atherosclerotic plaques and restenotic lesions following coronary interventions. Binding of PDGF to its receptor results in intrinsic receptor tyrosine kinase activation and subsequent cellular migration, proliferation, and vascular contraction.
Aims—To investigate whether the concentration of PDGF β receptor tyrosine phosphorylation obtained from directional coronary atherectomy (DCA) samples correlate with atherosclerotic plaque burden, the ability of diseased vessels to remodel, coronary risk factors, and clinical events.
Methods—DCA samples from 59 patients and 15 non-atherosclerotic left internal thoracic arteries (LITA) were analysed for PDGF β receptor tyrosine phosphorylation content by receptor immunoprecipitation and antiphosphotyrosine western blot. The amount of PDGF β receptor phosphorylation was analysed in relation to angiographic follow up data and clinical variables.
Results—PDGF β receptor tyrosine phosphorylation in the 59 DCA samples was greater than in the 15 non-atherosclerotic LITA (mean (SD) 0.84 (0.67) v 0.17 (0.08) over a control standard, p < 0.0001). As evaluated by stepwise regression analysis, incorporation of both PDGF β receptor tyrosine phosphorylation and immediate gain correlated strongly (adjusted r² = 0.579) with late loss, although PDGF β receptor tyramine phosphorylation alone correlated poorly with late loss. Multivariate regression analysis of coronary risk factors and clinical events revealed unstable angina as the most significant correlate of PDGF β receptor tyrosine phosphorylation (F value 20.009, p < 0.0001).
Conclusions—PDGF β receptor tyrosine phosphorylation in atherosclerotic lesions is increased compared with non-atherosclerotic arterial tissues. The association of PDGF β receptor tyrosine phosphorylation with immediate gain strongly correlates with vascular remodelling. PDGF β receptor tyrosine phosphorylation correlates with unstable angina pectoris.

Keywords: PDGF receptors;  atherosclerosis;  directional coronary atherectomy;  restenosis     

Linkage of cytokine genes to rheumatoid arthritis. Evidence of genetic heterogeneity

OBJECTIVE—To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis (RA) in affected sibling pair families stratified for specific clinical features.
METHOD—Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from: INFα, INFγ, INFβ, IL1α, IL1β, IL1R, IL2, IL6, IL5R, IL8R, BCL2, CD40L, NOS3, NRAMP, α₁ anti-trypsin, and α₁ anti-chymotrypsin, using fluorescence based automated technology. Linkage was examined by defining allele sharing sibling pairs. This was assessed by maximum likelihood—inheritance by descent methods.
RESULTS—An increase in allele sharing was seen for IL5R in female sibling pairs (LOD 0.91, p = 0.03), for INFγ in sibling pairs with an affected male (LOD 0.96, p = 0.03) and most significantly for IL2 in sibling pairs where one or both were persistently seronegative (LOD 1.05, p = 0.02).
CONCLUSION—Weak evidence of linkage of RA to IL5R, IFNγ, and IL2 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease.

Keywords: linkage; rheumatoid arthritis; sibling pairs; cytokine genes     

Differential contribution of HLA-DR,DQ, and TAP2 alleles to systemic lupus erythematosus susceptibility in Spanish patients: role of TAP2*01 alleles in Ro autoantibody production

OBJECTIVE—To study the influence MHC class II and TAP2 alleles exert on systemic lupus erythematosus (SLE) susceptibility and on the clinical and serological manifestations of the disease, in a cohort of Spanish patients.
METHODS—HLA-DR serological typing and HLA-DQA, DQB, and TAP2 DNA sequence specific oligotyping, were carried out in 85 unrelated Spanish SLE patients and 186 healthy controls. Autoantibodies detection was carried out by indirect immunofluorescence and counter immunoelectrophoresis.
RESULTS—Total SLE group: the frequency of HLA-DR3 and HLA-DQA1*0501 is significantly increased in this group (p_c<0.005, δ=0.34 and p_c<0.005, δ= 0.45, respectively) although the highest δ value (δ=0.87) is obtained when the TAP2*01 alleles are considered. No DQB allele shows significant deviation from the control group. Renal damage: it mainly occurs in HLA-DR3 patients (p_c<0.0005 and δ=0.72). HLA-DQA1*0501 (p_c<0.05, δ=0.57) and DQB1*0201 (p_c NS, δ=0.56) are weaker susceptibility factors. Ro+ (but not La) group: this autoantibody response is associated with TAP2*01 alleles in homozygosity (p<0.05, δ=0.81). Ro/La+ group: it has a different genetic background as HLA-DQA1*0501 (δ=1) and HLA-DQB1*0201 (δ=1) are the main susceptibility factors.
CONCLUSIONS—A differential association between HLA-DR, DQA1, and DQB1 alleles and SLE or its clinical and serological manifestations are found. Furthermore, the associations are different to the ones reported in other ethnic groups. Finally, TAP2*01 group of alleles are associated with the highest susceptibility to SLE (higher than HLA-DR3) and may influence Ro (but not La) autoantibodies production, whereas HLA-DQA1*0501 and DQB1*0201 mediates concomitant Ro and La production.

     

Full recovery of contraction late after acute myocardial infarction: determinants and early predictors

OBJECTIVES—To assess the relative value of electrocardiographic, echocardiographic, angiographic, and in-hospital therapeutic indices for predicting late functional recovery after acute myocardial infarction, and to determine the variables associated with absence of recovery, partial recovery, and full recovery.
DESIGN—Prospective observational follow up study.
SETTING—Teaching hospital.
PATIENTS—74 consecutive patients with a first uncomplicated acute myocardial infarct.
INTERVENTIONS—Dobutamine-atropine stress echocardiography was performed mean (SD) 5 (2) days after the acute event. Quantitative angiography was available in all patients before hospital discharge. A follow up resting echocardiogram was obtained 12 (2) months later.
RESULTS—Functional recovery (partial, n = 18; full, n = 27) was observed in 45 of the 74 patients. Recovery was associated with earlier thrombolytic treatment (p = 0.008), earlier peak concentration of creatine kinase (p = 0.009), greater contractile reserve (p = 0.0001), non-Q wave acute myocardial infarction (p = 0.002), and more frequent elective angioplasty of the infarct related vessel (p = 0.0004). Three independent variables were selected stepwise from multivariate analysis for predicting late recovery: contractile reserve (χ² = 24.2, p < 0.0001); non-Q wave infarction (χ² = 15.7, p = 0.0001); and the time from symptom onset to thrombolysis (χ² = 4.94, p = 0.026). Three independent variables predicted full recovery: contractile reserve (χ² = 17.2, p = 0.0001); non-Q wave infarction (χ² = 10.1, p = 0.0016); and elective angioplasty of the infarct related artery (χ² = 4.53, p = 0.033). Only contractile reserve (χ² = 17.0, p < 0.001) was selected from the multivariate analysis for its ability to distinguish between partial recovery and absence of recovery.
CONCLUSIONS—Late recovery of contraction relates to earlier treatment, which is associated with lower infarct size unmasked by a non-Q wave event and the presence of contractile reserve. Elective coronary angioplasty of the infarct related artery before hospital discharge is associated with full recovery.


Keywords: myocardial infarction; echocardiography; prognosis; angioplasty