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Tumor necrosis factor alpha (TNF alpha) and beta (TNF beta) appear to play an important role in the regulation of the inflammatory response. The aim of the present study was to investigate the intrinsic capacity of peripheral blood mononuclear cells (PBMC) to produce these cytokines.PBMC from 41 patients with Crohn's disease (CD), with ulcerative colitis (UC), and 23 healthy controls (HC) were cultured for 48 h in the presence of the T-cell activators anti-CD3 and anti-CD28. Biologically active total TNF (TNF alpha and beta), TNF alpha, and TNF beta production were measured using a bioassay for biologically active TNF and specific TNF alpha and TNF beta enzyme-linked immunosorbent assays.Large interindividual differences in TNF production were observed. Production of biologically active TNF after T-cell stimulation was significantly decreased in UC patients as compared with HC and CD patients (median, 337 U/ml, 800 U/ml, and 1050 U/ml, respectively). Stimulated TNF alpha production in UC patients (median, 432 U/ml) and in CD patients (median, 537 U/ml) did not differ statistically significantly from HC (median, 730 U/ml) as compared with HC and UC patients(median, 800 U/ml and 837 U/ml, respectively).These findings support the concept that UC and CD are homogeneous, clearly distinguishable disease entities but rather a heterogeneous group of diseases. Studies directed to assess the immunogenetic background of these different disease manifestations in IBD are underway.

Adenosine is an endogenous nucleoside that can modulate the function of cells involved in the inflammatory response, such as polymorphonuclear leukocytes (PMN) and monocytes. Production and release of cytokines by activated mononuclear phagocytes is an important event in the pathogenesis of ischemia-reperfusion injury, a pathologic phenomenon that is associated with excessive ATP catabolism and subsequent local release of adenosine. The "retaliatory" metabolite adenosine has been shown to interfere with PMN function, thereby attenuating the deleterious consequences of ischemia and reperfusion. In this study, we demonstrate that adenosine inhibits the production of TNF-alpha, IL-6, and IL-8 by LPS-activated human monocytes with a differential potency. The A2 receptor-specific adenosine analogues 2-chloroadenosine and 5'-N-ethylcarboxamidoadenosine (NECA) were most effective in attenuating LPS-induced cytokine production, whereas the A1-selective adenosine analogue N6-cyclopentyladenosine (CPA) was less effective, indicating that inhibition of cytokine production by adenosine is primarily an A2 receptor-mediated event. The observed inhibitory effects were not restricted to endotoxin-induced cytokine production, because adenosine also inhibited TNF-alpha production by monocytes stimulated with the proinflammatory cytokine IL-1 beta. Again, 2-chloroadenosine and NECA reduced IL-beta-induced TNF-alpha production more potently than CPA. In contrast, adenosine enhanced production of IL-6 and IL-8 by monocytes stimulated with IL-1 beta. Furthermore, only 2-chloroadenosine, but not NECA, strongly inhibited cytokine-induced IL-6 and IL-8 production. These results suggest an additional A2 receptor-mediated mechanism of retaliatory action of adenosine under pathologic conditions where cytokine production by activated mononuclear phagocytes is involved, such as ischemia-reperfusion injury and septic shock.

Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment.To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes.Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression.Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA-nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P0.001).Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective.

Over the last decade, numerous basic biological as well as experimental and clinical studies have firmly established the significance of tumor necrosis factor (TNF) as a principal proximal mediator of sepsis (1-4). One of the major insights that has emerged during recent years has been that under physiological circumstances, TNF activity is tightly controlled and locally restricted. In this respect, the soluble TNF receptors (sTNF-Rs) have been recognized to exert an important regulatory control on the biological actions of TNF, not only in the normal host defense against infection, but also in systemic inflammatory disorders that are related to infectious as well as noninfectious etiologies. Moreover, elevated systemic levels of sTNF-R have been demonstrated to have accurate diagnostic as well as prognostic significance in clinical sepsis and other critical illnesses (5-13). Therefore, accurate determination of sTNF-R in plasma or serum has become an important tool to gain information about a variety of pathological conditions that are characterized by TNF-mediated immune activation, both in the experimental and in the clinical setting.

The autoimmune lymphoproliferative syndrome (ALPS) is a chronic, nonmalignant lymphoproliferative disorder caused by mutations in the genes that are involved in programmed cell death (apoptosis). The impaired apoptosis causes accumulation of lymphocytes, which underlies the clinical manifestations of lymphadenopathy, autoimmune phenomena and a markedly increased risk of malignant lymphomas. During the last few decades, great progress has been achieved in elucidating the aetiology of this syndrome. Several mutations have been found in the genes encoding proteins that are involved in the apoptotic cascade, which starts with the binding of the Fas ligand to the transmembranous Fas protein and which is followed by intracellular processes. ALPS is an autosomal dominant hereditary disease with variable penetrance. Unravelling the genetic abnormalities that cause ALPS has provided key insights into the clinical consequences of defective apoptosis.

The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Enormous progress has been made recently in understanding the pathogenesis of these diseases. Through the study of patients and mouse models, it has emerged that Crohn's disease is driven by the production of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma), whereas ulcerative colitis is probably driven by the production of IL-13. A second area of progress is in the identification of specific genetic abnormalities that are responsible for disease. The most important finding is the identification of mutations in the gene that encodes NOD2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. Here, we discuss these recent findings and the implications for therapy.

Most patients with inflammatory bowel disease can be managed with conventional immunosuppressive therapy. The choice of agents to prevent relapses of inflammatory bowel disease must be based on efficacy, toxicity and cost. Studies in animal models of inflammatory bowel disease indicate that chronic intestinal inflammation results from enhanced immune responses to bacteria that are present normally in the lumen. Loss of tolerance, an abnormal function or defective healing of the mucosal barrier may all give raise to chronic intestinal inflammation. This hypothesis is the basis of new therapies aimed at either decreasing the levels of luminal bacterial antigens and/or selectively blocking detrimental mucosal immune responses. Anti-TNF is an example of this novel approach that is very effective in Crohn's disease. The use of biological therapy is costly, however, and the long-term complications are not yet known. The recent increase of tuberculosis in patients treated with anti-TNF indicates that careful monitoring is necessary. It is clear that the new forms of treatment may play an important role in tailoring the appropriate drug to a specific group of patients. However, for the time being, fine-tuning in the use of conventional immunosuppression is necessary. New knowledge in the pharmacogenetics of these compounds allows improvements to be made in their use. It is to be hoped that a critical approach in the use of current and future drugs, taking into account the advances in the aetiopathogenesis of inflammatory bowel disease, will contribute to the quality of life of patients with inflammatory bowel disease.

Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. We evaluated whether a TaqI polymorphism in the 3'UTR of the IL-12 p40 gene affects secretion of IL-12 in vitro, and whether this polymorphism is associated with susceptibility to Crohn's disease (CD). IL-12 p40 and p70 secretion by monocytes in relation to genotype was determined in 63 healthy donors. Genotype and allele frequencies of the TaqI polymorphism in 150 CD patients were compared with 145 ethnically matched healthy controls (HC). No significant association was found between genotype and IL-12 p40 secretion after stimulation of monocytes with SAC+IFNgamma. In contrast, increasing IL-12 p70 secretion was found across the categories of non-carriers, heterozygotes and homozygotes for the variant allele (median values+/-SEM: 147+/-27, 282+/-51 and 482+/-34 pg/ml, respectively; P

SIRS, Garcia-Buey and Moreno-Otero nicely summarise the literature on mycophenolate mofetil (MM) in autoimmune hepatitis (AIH) and overlap syndromes. The Dutch Autoimmune Hepatitis Group (DAHG) shows that second-line MM induces remission in 67% of patients with AIH and intolerance to azathioprine (AZA). In AIH and AZA nonresponse, remission was achieved with MMF in only 13%, and all deaths, liver transplantations and decompensations of cirrhosis occurred in this group. Therefore, in AIH and AZA-nonresponse other options, including liver transplantation, seem more appropriate. This is consistent with the findings of Hennes et al. For all patients with overlap syndromes, MM appears a valuable treatment option. In the DAHG cohort, MM induced remission in 63% and 57%, and response in 15% and 14% after AZA intolerance and nonresponse respectively. Recently, adding MM and budesonide appeared beneficial in primary biliary cirrhosis (PBC) with insufficient response to ursodeoxycholic acid. Further investigations of MM in PBC and overlap seem warranted. As first-line therapy for AIH, one randomised controlled study indicates that budesonide with AZA induces more remission with less side-effects than prednisolone with AZA. However, despite the one prospective cohort with MM as first-line therapy in AIH, and the limitations of earlier studies, most evidence for first-line therapy in AIH still is with AZA and prednisolone. We therefore still consider prednisolone with AZA the first-line treatment in AIH and overlap syndromes until further randomised studies prove otherwise. In case of steroid side-effects, in the absence of cirrhosis, budesonide could be considered, although a prospective maintenance study against prednisolone is still lacking. As second-line therapy in case of AZA-intolerance in AIH, or for all overlap syndrome patients, MM with prednisolone appears useful, but not for AIH with AZA nonresponse. In contrast to AZA, MM is contraindicated in pregnancy.

Over the last decade, numerous basic biological as well as experimental and clinical studies have firmly established the significance of tumor necrosis factor (tnf) as a principal proximal mediator of sepsis (1–4). One of the major insights that has emerged during recent years has been that under physiological circumstances, tnf activity is tightly controlled and locally restricted. In this respect, the soluble tnf receptors (stnf-rs) have been recognized to exert an important regulatory control on the biological actions of tnf, not only in the normal host defense against infection, but also in systemic inflammatory disorders that are related to infectious as well as noninfectious etiologies. Moreover, elevated systemic levels of stnf-r have been demonstrated to have accurate diagnostic as well as prognostic significance in clinical sepsis and other critical illnesses (5–13). Therefore, accurate determination of stnf-r in plasma or serum has become an important tool to gain information about a variety of pathological conditions that are characterized by tnf-mediated immune activation, both in the experimental and in the clinical setting.keywordstumor necrosis factorwash bufferpolypropylene tubesoluble tumor necrosis factor receptorsystemic inflammatory disorderthese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Epidemiological and family studies have shown that the inflammatory bowel diseases (IBD), encompassing ulcerative colitis and Crohn's disease, are in large part genetically determined. This genetic susceptibility is complex and does not follow Mendelian inheritance patterns. The search for susceptibility genes is further complicated by genetic and clinical heterogeneity. Recent developments in molecular biology have enabled the identification of chromosomal regions and genes underlying IBD. Genetic association studies have established a role of HLA genes and cytokine gene polymorphisms in the pathogenesis of IBD. Whole genome linkage analysis studies using microsatellite markers and affected sib-pair analysis have identified two chromosomal locations (IBD1 on chromosome 16 and IBD2 on chromosome 12) associated with IBD. Recent investigations have shown that some chromosomal regions play a role in several autoimmune disorders. This suggests the presence of two types of genes in these diseases: genes that encode proteins that play a key role in the immune response and predisposing for autoimmune diseases in general, and disease-specific genes that are responsible for the phenotype and the severity of the disease.

Crohn’s disease (CD) appears in forms so diverse that it has been hypothesized CD might be a syndrome, with different pathogenic mechanisms leading to the various clinical phenotypes. This may plausibly explain the conflicting and inconclusive results with regard to HLA associations in unselected groups of patients. The power of these association studies may increase when disease heterogeneity is taken into account. As fistulising CD has been proposed as a separate subgroup of patients with CD, we studied the carrier frequencies (CF) of the DRB1 alleles in 35 unrelated Caucasian Dutch CD patients with proven peri-anal fistulas. A striking decrease in the frequency of the DRB1 * 03 allele was found in those patients with peri-anal fistulas when compared with a panel of 2400 healthy controls (HC) (3% vs 25%; P = 0.005; Odds Ratio [OR] = 0.09). The DRB1 * 03 allele is in strong linkage disequilibrium with a polymorphism at position –308 in the promoter region of the gene encoding TNFα (TNFA-308 * 2). We investigated whether this allele frequency was decreased as well. Surprisingly, the CF of TNFA-308 * 2 was 29%, not different from the CF of 98 HC (34%; P = 0.7; OR = 0.8). This study is the first showing a significant negative association between DRB1 * 03 and a particular subgroup of CD patients. Thus, patient selection may largely determine the outcome of genetic association studies in CD, as we previously observed no association with this allele in an unselected population of CD patients. As DRB1 * 03 frequency, but not the closely linked TNFA-308 * 2, was decreased, this suggests recombination between the DRB1 and TNFA loci in this group of patients, and may help to define the biological basis of fistula formation.

Adhesion of leukocytes to the vascular endothelium hallmarks a key event in neutrophil-mediated organ injury after ischemia-reperfusion. The autacoid adenosine has been shown to inhibit activated neutrophil function and to interfere with leukocyte-endothelial adherence. Its therapeutic use in ischemia-reperfusion, however, has been limited by severe cardiovascular side effects. We therefore investigated the effects of the adenosine kinase inhibitor GP515 in vivo on hepatic leukocyte-endothelial interactions in a rat model of hemorrhagic hypotension and resuscitation, using intravital microscopy. Rats were pretreated with either GP515 (0.25 mg/kg) or saline in a randomized and blinded manner and subjected to pressure-controlled hemorrhagic hypotension at a mean arterial pressure of 40 mmHg for 60 min followed by 5 h of resuscitation. Five hours after resuscitation in saline-treated animals, firm leukocyte-sinusoidal adhesion was strongly enhanced in the periportal and midzonal sublobular regions, and sinusoidal diameters were also markedly reduced. Compared with saline treatment, GP515 significantly attenuated shock and resuscitation-induced leukocyte adhesion in both sublobular regions. Moreover, although GP515 did not significantly affect macrohemodynamical and hematological parameters, it enlarged narrowed sinusoidal diameters and tended to improve sinusoidal blood flow. We propose that the adenosine-regulating agent GP515 has a therapeutic potential to attenuate ischemia-reperfusion-induced inflammation by capitalizing on the beneficial anti-inflammatory effects of endogenous adenosine.

Adenosine, acting via A2 receptors, is a potent inhibitor of neutrophil oxidative burst, but its effects and mechanisms of action on neutrophil degranulation have been less well characterized. We, therefore, investigated the effects of adenosine and its receptor-specific analogues on neutrophil degranulation in stimulated human whole blood. Adenosine dose-dependently inhibited the LPS- and TNF-alpha-induced release of the azurophilic granule proteins bactericidal/permeability-increasing protein, elastase, and defensins to approximately the same extent, with a maximum inhibition of 70 to 80% and an IC50 ranging from 14 to 24 microM. The inhibitory effects of adenosine were partially blocked by the A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine, the A1/A2 antagonist 8(p-sulfophenyl)theophyline, and the A1/A3 antagonist xanthine amine congener, but not by the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine. The highly selective A3 agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide and the nonselective agonist 2-chloroadenosine reduced degranulation more potently than the A1 agonist N6-cyclopentyladenosine. The inhibitory effects of N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide and 2-chloroadenosine were strongly reversed by xanthine amine congener, but were not affected by 8(p-sulfophenyl)theophyline. In addition, the adenosine kinase inhibitor GP515 attenuated degranulation via an adenosine-mediated mechanism. These data indicate that adenosine acts via A2 as well as A3 receptors to inhibit neutrophil degranulation and add to the anti-inflammatory potential of adenosine and adenosine-regulating agents in neutrophil-mediated tissue injury.

SUMMARY Family and epidemiological studies support a genetic susceptibility to UC and CD. Conflicting reports regarding associations between UC and HLA-DR2 and between CD and various HLA alleles have been published. The aim of this study was to determine whether molecularly defined HLA-DR genes are associated with these diseases in a Dutch group of patients. Fifty-nine unrelated Dutch UC patients and 89 CD patients were typed using DNA-based methods. A total of 2400 healthy local blood donors served as controls. The phenotype frequency of the HLA-DRB1*15 allele was increased in UC patients compared with controls (42% versus 26% in controls; P = 0.006; odds ratio (OR) = 2.1), and was predominantly found in female patients (53% versus 24%; P = 0.001; OR = 3.5). The DRB1*15 allele was increased in UC patients having a positive family history (P = 0.01; OR = 5.8). Among the 16 patients who showed an increase in extent of disease during follow up, 10 were DRB1*15+ (P = 0.002; OR = 4.8). The frequency of the DRB1*13 allele was decreased in patients with UC (15% versus 28% in controls; P = 0.04; OR = 0.5). In CD, no association was observed between disease or particular clinical subgroups and any allele tested. The present study provides additional evidence for the genetic association between UC and HLA-DRB1*15, and supports recent findings that the susceptibility gene(s) for CD is not located in the HLA class II region.

SUMMARY Recent reports have shown that allele 2 of the IL-1 receptor antagonist (IL-1Ra) gene is over-represented in ulcerative colitis (UC). Healthy individuals carrying allele 2 of this gene have increased production of IL-1Ra protein. Since the final outcome of the biological effects of IL-1β may depend on the relative proportion of these two cytokines, we have studied if a TaqI polymorphism in the IL-1β gene, which is relevant to IL-1β protein production, may be involved in the genetic susceptibility to UC and Crohn's disease (CD), in association with the established IL-1Ra gene polymorphism. Polymorphisms in the closely linked genes for IL-1β and IL-1Ra were typed in 100 unrelated Dutch patients with UC, 79 with CD, and 71 healthy controls. The polymorphic regions in exon 5 of the IL-1β gene and in intron 2 of the IL-1Ra gene, were studied by polymerase chain reaction (PCR)-based methods. The IL-1β allele frequencies in UC and CD patients did not differ from those in healthy controls. In order to study if the IL-1β gene polymorphism might participate synergistically with the IL-1Ra gene polymorphism in susceptibility to UC and CD, individuals were distributed into carriers and non-carriers of allele 2 of the genes encoding IL-1β and IL-1Ra, in each of the patient groups and controls. Results indicated a significant association of this pair of genes, estimated by the odds ratio (OR) after performing Fisher's exact test, in the UC group (P= 0·023, OR = 2·81), as well as in the CD group (P= 0·01, OR = 3·79). Thus, non-carriers of IL-1β allele 2 were more often present in the subgroup of patients carrying the IL-1Ra allele 2. By contrast, no association of these alleles was detected in the group of healthy controls (P= 1·00, OR = 0·92). These results suggest that the IL-1β/IL-1Ra allelic cluster may participate in defining the biological basis of predisposition to chronic inflammatory bowel diseases.

An NcoI restriction fragment length polymorphism in the first intron of the lymphotoxin alpha gene was investigated in 35 patients with Crohn's disease, 40 patients with ulcerative colitis, and 30 unrelated healthy controls, all of Dutch origin. The results showed that no significant differences existed in the genotype frequencies of the NcoI polymorphism in the first intron of the LT alpha gene between ulcerative colitis patients or Crohn's disease patients and the healthy controls. The study indicates that the NcoI polymorphism in the LT alpha gene can not be used as a genetic marker for the predisposition to inflammatory bowel diseases. However, since this polymorphism may control the production of tumor necrosis factor, study of this and other related tumor necrosis factor gene polymorphisms may be used as markers to identify patient subgroups and to define patient heterogeneity. Further studies are being carried out on other polymorphisms and on the relevance of LT alpha and TNF alpha haplotypes.

Nitric oxide is an important mediator in inflammatory and autoimmune-mediated tissue destruction and may be of pathophysiologic importance in inflammatory bowel disease. We studied whether serum levels of nitrate, the stable end-product of nitric oxide, are increased in active Crohn's disease or ulcerative colitis, in comparison with quiescent disease and healthy controls. The setting was the gastroenterology unit of the Free University Hospital, Amsterdam.In 146 patients--75 with ulcerative colitis and 71 with Crohn's disease--and 33 controls serum nitrate was measured by the Griess reaction after enzymatic conversion of nitrate to nitrite with nitrate reductase.Median serum nitrate concentrations did not differ statistically significantly between ulcerative colitis (median, 34.2 mumol/l; range, 15.6-229.4 mumol/l), Crohn's disease (median 32.3 mumol; range 13.2-143.2 mumol/l), and healthy controls (median, 28.7 mumol/l; range, 13.0-108.4 mumol/l). However, when active ulcerative colitis patients (median, 44 mumol/l; range, 29.1-229.4 mumol/l were compared with inactive ulcerative colitis patients (median, 31.2 mumol/l; range, 15.6-59.7 mumol/l), a significant difference in nitrate concentration was found (p0.0001). A significant positive correlation was found between serum nitrate levels in ulcerative colitis and erythrocyte sedimentation rate (ESR) (r = 0.30, p - 0.01), leucocyte count (r = 0.27, p = 0.02), and thrombocyte count (r = 0.24, p = 0.04). Comparing active Crohn's disease patients (median, 37.5 mumol/l; range, 13.2-143.2 mumol/l) with inactive Crohn's disease patients (median, 31.3 mumol/l; range, 14.5-92.3 mumol/l) also showed a significant difference in serum nitrate concentration (p0.009). Serum nitrate levels correlated with the ESR (r = 0.26, p = 0.028) and serum albumin (r = 0.38, p = 0.004) as well.Nitric oxide production is increased in both active ulcerative colitis and Crohn's disease and may be implicated in the pathogenesis of inflammatory bowel disease.

Optical correituon is an efficient parallel implementation of image classifiers. One formulation of theholographic filter in the optical correlator is the Least Squares Discriminant Function (LSDF), whereinthe shape of the whole correlation function is specified when training the filter. An issue of particular interest is the capacity of the filter, or the number of training images that can be used while stillretaining discrimination capability. To investigate the capacity of an LSDF filter, and to be more general than just testing on a particular type of image, the fractal dimension of the images was used asan objective complexity measure of the images that the filter is trained with. Non-linear preprocessing,specifically edge detection, was used to increase the filter capacity and the discriminatory capabilities ofthe correlator. Simulation experiments of these issues are described and the results are discussed. 1 INTRODUCTION Optical correlation using a matched spatial filter[1] was one of the first parallel image recognition systems.In its initial formulation, the optical correlator can only discriminate between the presence (indicated bya peak in the output image) or absence (derived from the absence of a peak) of an object. Since theseearly days, several extensions of the original formulation have been employed [2, 3, 4, 5, 6, 7, 8], of whichthe most important aspects are. incorporating several training images per class, by formulation of the concept synthetic discriminantfunction (SDF)• a formulation for multi-class problems, by specifying a different peak value for each class whentraining the filter• methods to compensate for possible distortions of the input images, e.g. scale and rotation varia-tions.One of the most recent techniques to combine training images in the holographic filter of the correlatoris the Least Squares Discriminant Filter (LSDF) formulation of Barnard and Vermeulen[9] wherein theshape of the whole correlation function (output) is specified when training the filter. We chose thiscorrelation filter formulation for our experiments, due to its excellent performance.The LSDF filter was originally formulated as an alternative to the naive "peak vs. no peaK" technique,and a special case of the SDF wherein the shape of the output correlation plane is partially restricted.

We read with interest the article of Liu et al in Gut , in which the authors emphasise the need for monitoring of clonality and intraepithelial lymphocyte (IEL) immunophenotype in the surveillance of refractory coeliac disease (RCD).1 The authors state there is no consensus on the cut-off of aberrant cells distinguishing between non-complicated coeliac disease (CD), RCD type I (RCDI) and RCD type II (RCDII). However, in 2000 it was shown that based on the number of aberrant T cells, CD can be distinguished from RCD by immunohistochemistry.2 Furthermore, using flow cytometry, Verbeek defined a clinically well-validated cut-off of 20% IELs as being diagnostic for RCDII.3 In their paper, the authors describe that a high percentage of patients (80%) progress from RCDI to RCDII. This is somewhat …

Pyramidal neurons in the rat CA1 hippocampal area contain intracellular receptors for the steroid hormone corticosterone, and membrane associated alpha- and beta-adrenergic receptors. We compared the effect of noradrenaline (NA) on the synaptically evoked CA1 field potential in adrenalectomized (ADX) rats, where corticosteroid receptors are not occupied, with sham-operated controls. It appeared that the increase in the amplitude of the field potential induced by 10-mu-M NA was more pronounced in slices from ADX rats than in sham operated controls. In vitro application of 30 nM corticosterone (20 min) to slices from ADX rats shifted the NA-evoked increases in synaptic efficacy towards the level of the sham operated rats. The incidence of a secondary population spike after application of NA was increased in slices from ADX rats compared to slices from sham controls or ADX rats treated with corticosterone. Occupation of receptors for corticosterone in the hippocampal CA1 area may therefore potentially lead to suppression of excitability.

In this report of two patients with acute malaria, the electrocardiogram on admission showed changes of repolarisation. In both cases these electrocardiographic changes normalised after anti-parasitic treatment. The first patient recovered completely; however, the second patient developed signs of congestive heart failure compatible with cardiomyopathy. In acute malaria, an electrocardiogram should be considered to detect myocardial involvement.

This review summarizes the clinical results of Infliximab for the treatment of Crohn's disease, the limited data of its use in other digestive disorders and disorders related to the gastrointestinal tract. The etiology of these disorders remains enigmatic. As long as the precise etiology remains unknown, therapeutic options to treat these patients are predominantly symptomatic (i.e., immunosuppressive drugs or surgical intervention). To be able to develop more rational therapeutic regimens, it is pivotal to understand the immunopathological events that lead to, or are involved in, the pathogenesis of these diseases. Therefore, we also briefly summarize what at the present is known in this respect.