Intrinsic hyperreactivity of mucosal T cells to interleukin-2 in pediatric Crohn''s disease

1. The basic etiology of Alzheimer's disease remains unknown, although four genes have so far been involved: beta-amyloid precursor protein, presenilin-1, presenilin-2 and apolipoprotein E genes. 2. The largest familial Alzheimer's disease (FAD) kindred so far reported belong to a point mutation in codon 280 that results in a glutamic acid-to-alanine substitution in presenilin-1 characterized in Antioquia, Colombia. 3. A hypothetical unified molecular mechanism model of cell death in FAD mediated by presenilin-1, beta-amyloid, and oxidative stress is proposed as an attempt to explain the mechanisms of neuronal loss in this neurodegenerative disorder.     

Different intestinal permeability patterns in relatives and spouses of patients with Crohn''s disease: an inherited defect in mucosal defence?

The CHCl3 extract of the root of Angelica japonica showed high inhibitory activity against human gastric adenocarcinoma (MK-1) cell growth. From this extract, a new furanocoumarin named japoangelone and four furanocoumarin ethers of falcarindiol, named japoangelols A-D, were isolated together with caffeic acid methyl ester, four polyacetylenic compounds (panaxynol, falcarindiol, 8-O-acetylfalcarindiol, and (9Z)-1,9-heptadecadiene-4,6-diyne-3,8,11-triol), eight coumarins (osthol, isoimperatorin, scopoletin, byakangelicin, xanthotoxin, bergapten, oxypeucedanin methanolate, and oxypeucedanin hydrate), and two chromones (3'-O-acetylhamaudol, and hamaudol). The structures of the new isolates were determined based on spectral evidence. The ED50 of isolates against MK-1, HeLa, and B16F10 cell lines are reported.     

Production of tumor necrosis factor alpha and interleukin-6 by alveolar macrophages from patients with rheumatoid arthritis and interstitial pulmonary disease

The aim of this study was to measure the production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by alveolar macrophages in patients with rheumatoid arthritis and interstitial lung disease (ILD). Rheumatoid arthritis patients diagnosed by ACR criteria (n = 8) with associated ILD documented by pulmonary function tests and high resolution computerized tomography scanning, and 12 healthy volunteers (6 smokers and 6 nonsmokers). We determined the spontaneous and induced production of bacterial lipopolysaccharides (LSP), TNF-alpha and IL-6 by alveolar macrophages obtained by bronchoalveolar lavage. The macrophages were isolated by Ficoll-Hypaque gradient centrifugation and plastic adherence and cultured in serum-containing medium (low endotoxin) in the presence and absence of LPS (100 ng/ml). TNF-alpha and IL-6 levels contents were determined in supernatants by ELISA. In the patient group both spontaneous and induced production of TNF-alpha were significantly higher than in controls (p < 0.01). Macrophages stimulated with LPS in patients with rheumatoid arthritis and ILD also released greater amounts of IL-6 than did those of the healthy controls. IL-6 spontaneous and induced production was significantly lower in smokers than in nonsmokers. TNF-alpha and IL-6 production in patients with rheumatoid arthritis and ILD, studied in bronchoalveolar lavage specimens reveals that alveolar macrophages are hyperreactive in these patients, who are possibly sensitized as a consequence of the inflammatory lung process inherent to the disease. Further study is needed to define the pathogenic role of these mediators.     

Peritoneal fluid concentrations of interleukin-8 in women with endometriosis: relationship to stage of disease

There is increasing evidence that immunological mechanisms play a role in the pathogenesis and pathophysiology of endometriosis. It was therefore of interest to study interleukin-8 (IL-8), a chemokine, in the peritoneal fluid and peripheral blood of women undergoing laparoscopic procedures. The presence and concentrations of IL-8 in relation to endometriosis, infertility and abdominal pain were evaluated. Samples of peritoneal fluid (n = 49) and peripheral blood (n = 50) were obtained from 50 consecutive patients undergoing laparoscopic surgery for various gynaecological indications (abdominal pain, infertility, sterilization). IL-8 was present in the peritoneal fluid of most women (87%). The concentration of IL-8 in the peritoneal fluid was higher in women with endometriosis compared to women without (P = 0.02). This difference was more pronounced in early (stage 1) endometriosis (P = 0.001). IL-8 concentrations in the peritoneal fluid were also higher in women with early endometriosis compared to women with later stages of the disease (P = 0.003). Peripheral blood concentrations did not correlate with peritoneal fluid concentrations of IL-8 and/or the presence of endometriosis. We conclude that IL-8 is an important factor that may contribute to the pathogenesis of endometriosis possibly by promoting neovascularization. This information can be a guide in the development of new therapeutic approaches for the treatment of endometriosis.     

Use of hepatic lidocaine metabolism to monitor patients with chronic liver disease

OBJECTIVES: Public policy has treated drinking and boating as though it were analogous to drinking and driving. Accordingly, recent Federal and state laws to prevent drinking and boating have focused solely on alcohol use by the boat operator. This study was designed to determine boaters' knowledge about the epidemiology of boating fatalities and how boaters perceive the risks of drinking and boating. METHODS: In the summer of 1995, the authors conducted a survey by mail of a random sample of 600 owners of boats registered in Massachusetts. RESULTS: Survey results indicated that boaters believe passengers can safely drink more than operators. Respondents also thought that people on boats at rest can safely drink more than people on boats underway. CONCLUSIONS: The results of this study could be helpful in designing future boating safety campaigns by identifying gaps in knowledge about about the risks of drinking and boating for both operators and passengers.     

Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis

Serum levels of interleukin-1 (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured preoperatively in 24 patients with colorectal cancer. IL-1 beta was not elevated, IL-6 and IL-8 were markedly elevated, and GM-CSF was slightly elevated. TNF-alpha was not detected in most patients. Serum IL-6 levels correlated closely with serum IL-8 levels and with serum carbohydrate antigen (CA) 19-9 levels. Serum IL-6 levels were significantly higher in patients whose tumors exceeding 5.0 cm in diameter or spreading circumferentially. Serum IL-8 levels showed significant differences according to histological type, being lower in well differentiated adenocarcinoma compared to other types. Serum levels of IL-6 and IL-8 were significantly higher in patients with liver metastasis than in those without liver metastasis and serum levels of both these cytokines were also significantly higher in patients with lung metastasis than in those without lung metastasis. These results suggest that IL-6 and IL-8 may play an important role in the hematogenous metastasis of colorectal cancer.     

Heterogeneity of plasma glucagon. Circulating components in normal subjects and patients with chronic renal failure

Plasma immunoreactive glucagon (IRG) concentrations were measured in 36 patients with chronic renal failure (CRF) and 32 normal subjects. In addition, the components of circulating IRG were analyzed by gel filtration in the fasting state and after physiological stimuli. Fasting IRG was elevated (P less than 0.001) in CRF patients (534 +/- 32 pg/ml) compared with the levels found in healthy subjects (113 +/- 9 pg/ml). Oral glucose suppressed plasma IRG in CRF patients from a basal level of 568 +/- 52 to a nadir of 354 +/- 57 pg/ml (120 min). This degree of suppression (38%) was comparable to that found in normal subjects (basal = 154 +/- 20 to 100 +/- 23 pg/ml) at 120 min (35%). Intravenous infusion of arginine (250 mg/kg) resulted in a 71% rise in IRG in CRF patients and a 166% increase in normal subjects. Gel filtration of fasting plasma from CRF patients showed three major peaks. The earliest (A) was found in the void volume (mol wt greater than 40,000) and constituted 16.5 +/- 4.7% of the elution profile. The middle peak (B) eluted just beyond the proinsulin marker (approximately 9,000 mol wt) and constituted the largest proportion of the elution profile (56.5 +/- 3.4%). The third peak (C) coincided with the standard glucagon and [125I]glucagon markers (3,485 mol wt) and comprised 27.0 +/- 4% of the IRG profile. In contrast, only peaks A and C were found in fasting plasma of normal subjects (53.6 +/- 10.4% in A and 46.4 +/- 10.4 in C). After oral glucose, glucagon immunoreactivity in the 3,500 mol wt peak (C) was markedly suppressed, while the B peak in patients with CRF declined to a lesser extent. The A peak in both groups was unchanged. After an arginine infusion only the C peak increased in both groups of subjects. Gel filtration of plasma in 3 M acetic acid gave similar profiles to those obtained in glycine albumin buffer. Exposure of serum to trypsin indicated that the B and C peaks were digestible, while the A peak was resistant to the action of the enzyme. In one sample, peak C increased after a 2-h exposure of serum to trypsin. We conclude that circulating IRG in normal subjects and patients with CRF is heterogenous. The hyperglucagonemia of renal failure is largely due to an increase in IRG material of approximately 9,000 mol wt, consistent with proglucagon, although the 3,500 mol wt component is also considerably elevated (threefold). The significance of circulating IRG levels should be interpreted with caution until the relative biological activity of the three components is established.     

Inhaled nitric oxide in patients with pulmonary hypertension due to valvular heart disease and chronic lung disease

The objective of this study was to investigate the effects of inhaled nitric oxide (NO) on chronic pulmonary hypertension (PH). Thirty patients with valvular heart diseases (n=8, group A), chronic lung diseases (n=16, group B), primary PH or PH due to collagen disease (n=6, group C) were studied. NO was delivered for 20 min at concentration of 5, 10, and 20 ppm in spontaneous respiration. After inhalation, percentages of systolic pulmonary artery pressure (%SPAP) levels in group A were significantly decreased compared with those for pre-inhalation by 12%, 14%, and 14% at 5, 10 and 20 ppm, respectively (p<0.05). In group B, %SPAP also significantly decreased by 7, 10, and 14% at 5, 10, and 20 ppm, respectively (p<0.05). However, inhaled NO did not significantly affect %SPAP in group C (p=0.4). There was no significant difference in gas exchange in any of the groups. However, 4 out of 8 patients in group A and 10 out of 16 patients in group B showed decreased partial pressure of arterial oxygen in response to inhaled NO. This study demonstrated that inhaled NO is a selective pulmonary vasodilator in decreasing pulmonary artery pressure (PAP); however, the reaction was different in line with the background disease cause of PH. NO inhalation was most effective on patients with moderate PAP. Furthermore, higher concentrations of NO would be risky in some patients with chronic PH.     

Ventilatory response to positive and negative work in patients with chronic obstructive pulmonary disease

The consequences of extreme violence such as war torture affect children in different ways and may immediately manifest at the physical and/or psychologic level, or may remain hidden and unrecognized for years. The victims are usually very reluctant to speak about their traumatic experiences, and try to deny the existence of psychological disturbances. They often seek help for somatic problems. Taking these physical complaints seriously helps to progressively reach the psychological effects of violence. Therefore, identification of such children should be directed to more complete evaluation of their symptomatology and functioning. This can be done by: a) individual evaluation to get enough information on the historical events, functioning and symptoms of these children; and b) standardized instruments which may allow the children to disclose more about their psychological experiences during the war. In this study rating scales and assessment instruments for children aged < 15, such as CPRS with General Scoring Sheet (Fish, 1985), were used to assess the broad spectrum of psychopathology in this age group. These questionnaires were used in a large group of school children (N = 1888), 989 girls and 899 boys aged 7-16 years. The sample was divided into 3 groups: 843 non-displaced, 377 displaced and 669 refugee children. Results of statistical analysis (arithmetical mean and standard deviation of discriminative variables transformed in Z-values with F-ratio) showed the three groups of children (non-displaced, displaced and refugees) to significantly differ in 13 out of 15 psychopathologic clusters. Discriminative cannonic analysis of the 3 groups of children (non displaced, displaced and refugees) also showed significant differences. The first discriminative function (80.24% of total variance) indicated depression, violence and antisocial behavior to be rare in non-displaced children, more pronounced in displaced, and most pronounced in refugee children. The second discriminative function (19.76% of total variance) showed hyperactivity, anxiety and psychosomatic disturbances to be rare in non-displaced children; more frequent in refugee, and most expressed in displaced children. According to the results, the authors concluded that war is very painful for a large group of children, among whom the displaced and refugee children are most affected by psychopathologic disturbances.     

Expression of the mucosal homing receptor alpha4beta7 correlates with the ability of CD8+ memory T cells to clear rotavirus infection

The integrin alpha4beta7 plays an important role in lymphocyte homing to mucosal lymphoid tissues and has been shown to define a subpopulation of memory T cells capable of homing to intestinal sites. Here we have used a well-characterized intestinal virus, murine rotavirus, to investigate whether memory/effector function for an intestinal pathogen is associated with alpha4beta7 expression. Alpha4beta7(hi) memory phenotype (CD44hi), alpha4beta7- memory phenotype, and presumptively naive (CD44(lo)) CD8+ T lymphocytes from rotavirus-infected mice were sorted and transferred into Rag-2 (T- and B-cell-deficient) recipients that were chronically infected with murine rotavirus. Alpha4beta7(hi) memory phenotype CD8+ cells were highly efficient at clearing rotavirus infection, alpha4beta7- memory cells were inefficient or ineffective, depending on the cell numbers transferred, and CD44(lo) cells were completely unable to clear chronic rotavirus infection. These data demonstrate that functional memory for rotavirus resides primarily in memory phenotype cells that display the mucosal homing receptor alpha4beta7.     

Differential proliferative and interleukin-10 responses to fractionated filarial antigens: preferential recognition by patients with chronic lymphatic dysfunction

To characterize filarial antigens that may be associated with the development of chronic lymphatic dysfunction in persons with lymphatic filariasis, T cell responsiveness to Brugia pahangi adult worm extracts and SDS-PAGE antigen fractions were examined among Haitians from an area in which Wuchereria bancrofti is endemic. Greater T cell proliferation and interleukin-10 (IL-10) production were observed in amicrofilaremic patients with hydrocele or elephantiasis than in amicrofilaremic or microfilaremic asymptomatic persons. Antigen fractions that stimulated the highest proliferative responses (in the 25-49 kDa range) and IL-10 production were not identical. Further separation of an immunodominant 30- to 38-kDa fraction by ion exchange high-pressure liquid chromatography identified several subfractions, including a 32-kDa protein band, that elicited T cell responses from patients with elephantiasis or hydrocele. By immunoblot, these patients also had markedly greater humoral reactivity to parasite antigens of approximately 52, 43, 32, and 30 kDa.     

Long-term effects of a selective alpha 1-adrenergic inhibitor on right and left ventricular masses in patients with chronic pulmonary disease]

The effects of pinacidil and nimodipine on endothelin-1-induced contractions in isolated cerebral arteries with and without endothelium were compared. The sensitivity to endothelin-1 was increased (0.5 log units) in the rabbit basilar artery after removal of the endothelium. The nitric oxide synthase inhibitor N omega-nitro-L-arginine (0.1 mM) also increased the sensitivity to endothelin-1 (0.6 log units) in basilar arteries with endothelium, whereas N omega-nitro-D-arginine (0.1 mM) and indomethacin (3 microM) had no effect, indicating that withdrawal of endothelium-derived nitric oxide may account for the enhancement of the endothelin-1-induced contraction after endothelial denudation. Pinacidil (1 microM) shifted the concentration-response curve for endothelin-1 to the right without affecting the maximal response in arteries without endothelium, but had no effect on the endothelin-1-induced contraction in vessels with endothelium. Nimodipine (1 microM) reduced the maximal endothelin-1-induced contraction by approximately 50% in both the presence and absence of endothelium, whereas the sensitivity to endothelin-1 was reduced only in vessels without endothelium. Incubation in "calcium-free" medium reduced the maximal endothelin-1-induced contraction by 69% and 80% in vessels with and without endothelium, respectively. In human pial arteries with endothelium, pinacidil did not affect the endothelin-1-induced contraction, whereas nimodipine and exposure to "calcium-free" solution reduced the maximal response by 31% and 74% respectively. The results show that, in the rabbit, pinacidil and to a lesser extent nimodipine preferentially act on cerebral arteries with disrupted endothelium, indicating that vasoactive factors liberated from the endothelium may modify the effect of a vasodilator.     

Serum IL-8 levels and localization of IL-8 in liver from patients with chronic viral hepatitis

BACKGROUND/AIMS: Interleukin 8 is known as a chemotactic factor for neutrophils and T cells. Such inflammatory cells are observed in the liver tissue in chronic viral hepatitis. However, it is not known whether interleukin 8 relates to hepatic injury in patients with chronic viral hepatitis. Therefore, we determined serum interleukin 8 levels and identified the cells related to interleukin 8 production in liver tissue. METHODOLOGY: Studies were performed on 29 patients with chronic viral hepatitis and 20 normal controls. Serum interleukin 8 levels were assayed using a sandwich ELISA. Immunohistochemical examination was performed to identify the cells related to interleukin 8 production by using a rabbit polyvalent antibody to human interleukin 8. RESULTS: Serum interleukin 8 levels were found to be increased significantly (p<0.05) in patients with chronic viral hepatitis compared with normal controls. They were also increased significantly in patients with chronic active hepatitis compared with chronic persistent hepatitis (p<0.05), and during exacerbation stages compared with remission stages (p<0.05). Out of the 10 patients examined immunohistochemically, interleukin 8 positive cells in the liver tissue were visualized in 7 patients and observed mainly along sinusoids. There was significant correlation between serum interleukin 8 levels and intensity of staining for interleukin 8 in the liver tissue (p<0.05, r=0.869). CONCLUSIONS: Interleukin 8 plays a role in hepatic injury in patients with chronic viral hepatitis, and is mainly produced by nonparenchymal cells in the liver.     

Serum levels of sCD23, interleukin-10 and interferon-gamma in patients with coeliac disease

The role of cellular and humoral immunity coeliac disease was investigated by the measurement of serum levels of interleukin-10 (IL-10), interferon-gamma (IFN-gamma) and soluble CD23 (sCD23). Coeliac disease was diagnosed by duodenal biopsy and response to a gluten-free diet (GFD). The results were compared with age and sex-matched patients with non-specific upper gastrointestinal symptoms and normal duodenal histology. While the levels of serum IL-10 were significantly elevated (P < 0.01) in patients with coeliac disease taken as a whole, the levels of serum IFN-gamma were normal and sCD23 significantly decreased (P < 0.002). The median serum sCD23 was significantly lower in the coeliac disease patients not on a GFD compared with those asymptomatic on a GFD (P < 0.03) and the control group (P < 0.0004). The coeliac disease patients on a GFD also had significantly lower serum sCD23 and higher IL-10 compared with the control group (P < 0.01 and P < 0.015). There was no significant difference in the serum IL-10 between the coeliac disease patients on a GFD and those not on a GFD and between the latter and the control group. The low levels of serum sCD23 in coeliac disease suggest diminished humoral immunity and, conversely, exaggerated cellular immunity. The aetiology of the raised levels of IL-10 in coeliac disease is unclear and similar to that observed in patients with inflammatory bowel disease. However, this may represent a regulatory response to the elevated levels of proinflammatory cytokines described in coeliac disease. A combination of diminished sCD23 and raised IL-10 is clearly unusual as both are associated with Th2-type functions. The possible causes of this finding are discussed.     

Fecal excretion and the clearance of alpha 1-antitrypsin in patients with Crohn's disease

In previous work we defined the normal values of faecal alpha-1 antitrypsin (A1ATF) and their plasmatic clearance (CLAT) in 25 healthy patients. The aim of the present study is to compare these previous results with new results obtained when we applied this test to 30 patients with Crohn's disease (CD). We also show the good performance of the mentioned tests as indicators of the intestinal inflammatory activity. We compare the values of A1ATF and CLAT of healthy patients with those of CD patients. We also compare the Crohn's Disease Activity Index (CDAI) and Simple Index between active and inactive CD patients. Our results show significant differences between A1ATF excretion and CLAT as measured in healthy and CD patients. The relationship between those parameters could be explained by the equation CLAT = 0.325 x A1ATF. Active and inactive CD patients only differ significantly with respect to their leucocytes and C reactive protein values. In our group the A1ATF excretion is larger in CD patients with colonic disease.     

Clonal analysis of peripheral blood lymphocytes from three patients with advanced neuroblastoma receiving recombinant interleukin-2 and interferon alpha

Cultures of both isolated and conjugated explants from early gastrulae of Bufo arenarum were prepared for a study of the development of ventral mesoderm. Only combinations including components of the deep ventral marginal zone and the animal pole successfully differentiated into blood cells (erythrocytes). Histological studies indicated that, while prospective mesodermal cells constituted the only source of such cells, prospective ectodermal cells provided the necessary stimulus for this kind of differentiation. Differentiated cultures, in which the tracer of cell-lineage fluorescein dextran amine was used to label these components, confirmed the above conclusions. These findings are discussed in the context of current concepts about the formation of mesoderm.