Elevated concentrations of soluble E-selectin and vascular cell adhesion molecule-1 in NIDDM. Effect of intensive insulin treatment

OBJECTIVE: To evaluate the effects of a 14-day intensive insulin therapy and short-term improvement of glycemic control on serum levels of soluble forms of adhesion molecules, i.e., intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in NIDDM patients with poor glycemic control. RESEARCH DESIGN AND METHODS: A total of 16 NIDDM patients were compared with 23 healthy subjects (control group) and investigated before and after intensive insulin treatment. RESULTS: On day 0, sE-selectin and sVCAM-1 levels were significantly higher in NIDDM patients than in nondiabetic control subjects (median 87, range 63-115; median 544, range 408-797 vs. 58, 43-80; 443, 395-573 ng/ml, respectively) (P < 0.008 in both cases). On day 15, the fall in sE-selectin levels was significant (P < 0.0001) and at a lesser extent in sVCAM-1 levels (64, 48-85; 506, 417-678 ng/ml, respectively); these levels reached values that no longer differed from those of control subjects (P = 0.23 and 0.15, respectively). Moreover, the fall in sE-selectin was positively associated with the change in LDL cholesterol and the improvement of glycemia. CONCLUSIONS: In poorly controlled NIDDM patients, sE-selectin levels are increased and significantly fall to normal after short-term improvement of glycemic control. This suggests that assaying sE-selectin makes it possible to detect endothelium activation and to follow its reversal with euglycemia.     

Estimation of tumor necrosis factor-alpha in the diagnosis, the prognosis and the treatment follow-up of oral squamous cell carcinoma

This study evaluated usefulness of serum tumor necrosis factor-alpha (TNF-alpha) levels in the diagnosis and prognosis of oral squamous cell carcinoma (O-SCC). We performed a clinico-pathological estimation of 38 patients with O-SCC and determined the more valuable factors in making a prognosis. The mean serum concentration of TNF-alpha for the patients with O-SCC (14.13 +/- 13.17 pg/ml) was significantly higher (p < 0.05) than that of the healthy controls (3.49 +/- 2.97 pg/ml). The mean serum concentrations of TNF-alpha were significantly higher (p < 0.05) in the good-prognosis group (16.73 +/- 18.64 pg/ml) than in the poor-prognosis group (9.62 +/- 5.92 pg/ml). The survival curve revealed a better prognosis for patients with serum TNF-alpha-positive than for patients with serum TNF-alpha negative. There was a significant correlation (p < 0.05) with serum TNF-alpha levels and two tumor markers (SCCA, IAP). These results of the present study suggest that a evaluation of serum TNF-alpha levels in O-SCC is a valuable tool as a tumor marker for the diagnosis, prognosis and treatment monitoring of O-SCC.     

Synchrony in telomere length of the human fetus

We measured serum tumour necrosis factor-alpha (TNF-alpha) as well as interleukin-1betta (IL-1beta) and GH concentrations in 15 children with isolated growth hormone deficiency (GHD), age range 5.1-13.9 years, before and 4 and 24h after the first GH injection (0.1 IU/kg s.c.). No differences were found in basal concentrations of serum TNF-alpha and IL-1beta between GHD children (10.01 +/- 1.55 pg/ml and 2.14 +/- .16 ng/ml respectively) and sex- and age-matched controls (11.57 +/- 2.16 pg/ml and 3.78 +/- 1.46 ng/ml respectively). In GHD children, serum TNF-alpha and IL-1beta values had significantly increased (P < 0.002) 4h (26.75 +/- 5.57 pg/ml and 2.99 +/- 0.21 ng/ml respectively) and decreased again 24 h after GH administration. Likewise, serum GH levels had significantly increased 4 h (from 1.29 +/- 0.69 to 48.71 +/- 13.35 ng/ml, P < 0.001) and decreased to basal values 24h after GH administration. A significant correlation was found between basal serum concentrations of GH and those of both TNF-alpha (P < 0.01) and IL-1beta (P < 0.05). However, no correlation was found between serum GH concentration and either TNF-alpha or IL-1beta levels 4 and 24h after GH administration. Our data suggest that GH plays a role in modulating TNF-alpha and IL-1beta release in humans.     

Low serum levels of tumor necrosis factor-alpha in insulin-dependent diabetic children

We measured serum levels of tumor necrosis factor-alpha (TNF-alpha) in 48 children with insulin-dependent diabetes mellitus (IDDM), divided into two groups according to disease duration (group I < 6 months and group II > 3 years): group I 15 patients, aged 2.2-13.7 years, and group II 33 patients, aged 4.5-25.5 years. Thirty-six age- and sex-matched healthy subjects served as controls. TNF-alpha levels were measured by immunoradiometric assay. We found that TNF-alpha levels were lower in all IDDM patients (29.65 +/- 3.83 pg/ml) than in controls (74.74 +/- 10.17 pg/ml) (p < 0.0001), as well as in group I (24.07 +/- 3.65 pg/ml) and group II (32.16 +/- 5.29 pg/ml) as compared to controls (p < 0.001). TNF-alpha levels were significantly lower in patients with antibodies than in those without antibodies and in controls. Similar results were found in longstanding IDDM patients. No correlation was found between serum TNF-alpha and chronologic age, duration of disease, metabolic control, insulin requirement and HLA typing. During a 1-year follow-up study in 12 group I patients no significant variations in TNF-alpha levels were observed. It has been reported that the administration of exogenous TNF suppresses the development of diabetes in nonobese diabetic mice, low producers of endogenous TNF. The results suggest that aberrant TNF-alpha synthesis may contribute to immune dysregulation thus favoring the development of autoimmune diseases.     

Relaxin levels in amniotic fluid, extraembryonic coelomic fluid and maternal serum in early human pregnancy

Separately identified samples of amniotic fluid and extraembryonic coelomic fluid together with maternal serum were collected from 22 women between 8 and 11 weeks of pregnancy and analysed for relaxin by immunoassay. Relaxin levels in maternal serum (median 1085 pg/ml; range 390-1259 pg/ml) were substantially higher than those in extraembryonic coelomic fluid (median 57.5 pg/ml; range 17-145 pg/ml; P < 0.0001; Mann-Whitney U-test). In turn, the levels of relaxin in coelomic fluid were higher than those in amniotic fluid (median 10 pg/ml; range 10-37 pg/ml; P < 0.0001; Mann-Whitney U-test). A linear correlation was found between relaxin levels in maternal serum and coelomic fluid (r = 0.68; P = 0.001) but there was no relation between levels in the other fluid compartments.     

Serum levels of tumor necrosis factor alpha and soluble tumor necrosis factor-receptor I in asthmatic patients and patients with chronic respiratory tract infection

In order to investigate the role of tumor necrosis factor alpha (TNF-alpha) in bronchial asthma or chronic respiratory infection, we measured serum levels of TNF-alpha and serum soluble tumor necrosis factor-receptor I (sTNF-RI) in asthmatic patients (n = 11) and patients (n = 10) with chronic respiratory infection by Pseudomonas aeruginosa. We also measured serum levels of eosinophil cationic protein (ECP) in the asthmatic patients. The serum levels of TNF-alpha in the asthmatic patients, patients with chronic respiratory tract infection and control group were 2.864 +/- 0.719 g/ml, 2.564-1.384 pg/ml and 0.681 +/- 0.453 pg/ml respectively. The levels of the former two groups were higher than those of the control group (p < 0.05). The serum levels of sTNF-RI in the asthmatic patients, the patients with chronic respiratory tract infection, and the control group was 758 +/- 268 pg/ml, 999 +/- 242 pg/ml and 909 +/- 268 pg/ml respectively. The levels of the former two groups did not differ significantly from those of the control group. There were significant correlations between TNF-alpha and sTNF-RI in the control group and in the patients with chronic respiratory tract infection, but there was no significant correlation in the asthmatic patients. In the asthmatic patients. TNF-alpha/s TNF-RI correlated with %best of PEF (r = 0.691, n = 9, p 0.0373). The serum levels of ECP correlated significantly with TNF-alpha, but not with sTNF-RI in the asthmatic patients. It is suggested that TNF-alpha plays a significant role in the pathogenesis of bronchial asthma and chronic respiratory tract infection as a factor causing inflammation and that the increase of TNF-alpha/sTNF-RI reflects the activation of eosinophil functions in an asthmatic attack.     

Levels of circulating intercellular adhesion molecule 1 and E-selectin in serum and synovial fluid of juvenile chronic arthritis patients

OBJECTIVE: To measure the levels of two adhesion molecules (AM), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble E-selectin (sE-selectin), in serum and synovial fluid (SF) of patients with juvenile chronic arthritis (JCA). METHODS: Both soluble AM levels were tested, in serum and synovial fluid (SF) samples, with an enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Serum levels of sICAM-1 and sE-selectin in JCA patients were not significantly different from those of a control group. Synovial fluid levels of sICAM-1, but not of sE-selectin, assayed significantly higher (p < 0.05) in JCA patients than in controls. Moreover SF levels of both molecules correlated negatively with disease duration, being higher in the earliest phases. No significant correlations were found between JCA sICAM-1 and sE-selectin levels and leukocyte count or ESR. CONCLUSIONS: These observations may signify a more important role of ICAM-1 than E-selectin in the migration of inflammatory cells into JCA SF. The negative correlation of both AMSF levels in JCA patients with disease duration could reflect a higher expression of ICAM-1 and E-selectin during the earliest phases of the disease.     

Chronic sinusitis refractory to standard management in patients with humoral immunodeficiencies

Chronic refractory sinusitis is a common feature in patients with primary immunodeficiencies. The efficacy of standard therapeutic strategies is questionable. In an open trial we evaluated the efficacy of azithromycin, N-acetylcysteine and topical intranasal beclomethasone (100 microg twice daily for 6 weeks) in 16 patients with primary immunodeficiencies (median age 13.5 years, range 5-32 years). All patients suffered from chronic sinusitis despite regular immunoglobulin replacement therapy every 3 weeks. Magnetic resonance imaging (MRI) scans were performed before and after 6 weeks of treatment to evaluate morphological changes in the paranasal sinuses. Nasal swabs and washings were taken for microbial analysis and measurement of inflammatory mediators (IL-8, tumour necrosis factor-alpha (TNF-alpha), eosinophilic cationic protein (ECP)) before and post therapy. Inflammatory mediators in nasal secretions were significantly elevated in patients: IL-8 median 2436 pg/ml (range 441-5435 pg/ml), TNF-alpha 37.3 pg/ml (3.75-524 pg/ml) and ECP 33 ng/ml (1.5-250 ng/ml) versus age-matched healthy controls: IL-8 median 212 pg/ml (99-825 pg/ml), TNF-alpha 3.77 pg/ml (2.8-10.2 pg/ml) and ECP 1.5 ng/ml (1.5-14.8 ng/ml) (P < 0.0001). Inflammation of the maxillary sinuses was confirmed by MRI scans in all patients, additionally infection of the ethmoidal and frontal sinuses was recorded in five patients. Bacterial growth appeared in 11 out of 16 cultures. In spite of therapy, no improvement in sinal inflammation visualized by MRI was achieved. Moreover, no significant decrease in pathogens and levels of inflammatory mediators could be detected (IL-8 1141 pg/ml, 426-4556 pg/ml; TNF-alpha 13.9 pg/ml, 4.1-291.6 pg/ml; ECP 32.3 ng/ml, 3.7-58.4 ng/ml). Our results demonstrate that conventional management of sinusitis is of little benefit in patients with chronic refractory sinusitis with an underlying immunodeficiency. More studies are needed to test antibiotic regimens, probably combined with surgical drainage and anti-inflammatory agents.     

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Serum concentrations of tumour necrosis factor alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr-) bacteraemias after 2 h (TNF-alpha, IL-1ra and IFN-gamma), 4 h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-alpha value was higher in the Gr- group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr+, 14 pg/ml; range 7-60 pg/ml; P < 0.05) and blood culture negative episodes (BCN, 8 pg/ml; range 0-87 pg/ml; P < 0.05). Furthermore, the peak values of TNF-alpha, IL-1ra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the Gr- group in comparison to the Gr+ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.     

Stimulation of inflammatory markers after blunt trauma

BACKGROUND: Inflammatory mediators are released after trauma and may be related to the pathogenesis of sepsis. A prospective combined study of the pattern of release of an inflammatory mediator, interleukin (IL) 6, leucocyte activation (polymorphonuclear leucocyte (PMN) CD11b receptor expression and plasma elastase-alpha1 proteinase inhibitor complex (E-alpha1PI)) and soluble endothelial adhesion molecule expression (soluble E-selectin (sE-selectin) and soluble intracellular adhesion molecule 1 (sICAM-1)) was performed in patients suffering blunt trauma without adult respiratory distress syndrome (ARDS) or multiple organ failure syndrome (MOFS). METHODS: Thirty-one patients with a mean Injury Severity Score (ISS) of 14 (range 9-57) were studied. Venous blood samples were collected within 6 h of injury and then at 1, 3, 5 and 7 days. Leucocyte CD11b expression was quantified by flow cytometry. Serum IL-6, plasma E-alpha1PI, sE-selectin and sICAM-1 were measured by enzyme-linked immunosorbent assay. RESULTS: Serum IL-6, CD11b expression and E-alpha1PI levels were significantly raised above control values (P < 0.0001) on admission, slowly returning towards control values over the study period (median IL-6, 140 pg/ml versus undetectable; CD11b, 14.8 versus 6.4 mean channel fluorescence units; E-alpha1 PI, 208 versus 52 microg/l). The sICAM-1 level rose to a median of 539 ng/ml at 5 days (control 243 ng/ml). The median sE-selectin level also progressively increased to a maximum level of 80 ng/ml at 5 days (control 49 ng/ml). Eleven patients developed postoperative sepsis. Significant differences in CD11b expression were seen at days 3, 5 and 7 and in E-alpha1 PI at 6 h, 24 h and 3 days in patients who subsequently developed sepsis (P < 0.05). Severe injury (ISS 16 or greater) was associated with significantly greater responses in these measurements. CONCLUSION: These data show that markers of inflammation are specifically stimulated by trauma even when ARDS and MOFS do not occur. The CD11b receptor on PMNs may be useful in screening patients destined to develop post-traumatic sepsis.     

Dietary fat and body composition

Vascular endothelial growth factor (VEGF) is a cytokine that induces angiogenesis. Angiogenesis is a prominent histologic component of the luteinization process. Luteinization is also characterized by granulosa cell progesterone secretion in response to the luteinizing hormone (LH) surge. Local VEGF production in human pre-ovulatory follicles, induced by LH, was postulated to be a luteinization mediator in women. To investigate this hypothesis, serum and fluid from the dominant follicle of 31 healthy regularly cycling multiparous women undergoing laparoscopic sterilization were obtained. VEGF was measured by enzyme-linked immunosorbent assay, and LH and progesterone were measured by radioimmunoassay. Follicle aspiration was performed at a median of 13 days from the last menstrual period (range 11-17 days). The median pre-ovulatory follicle diameter was 16 mm (range 11-23 mm). Follicle fluid VEGF concentrations (mean 6900 pg/ml, range 1200-17 100 pg/ml) were correlated positively with follicle fluid progesterone concentrations (mean 10 176 nmol/l, range 636-66780 nmol/l, r=0.62, P=0.002). This correlation was even tighter (r=0.87, P < 0.0001) when only samples from the 22 women in the earliest stages of follicle luteinization were considered. In these women serum LH concentrations were also correlated with follicle fluid VEGF concentrations (r=0.51, P=0.02). Our findings demonstrate the close dynamic relationship between VEGF production and early luteinization in human follicles during normal non-stimulated cycles.     

Plasma endotoxin and cytokine levels in neutropenic and non-neutropenic bacteremic patients

Plasma endotoxin, tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 1 receptor antagonist (IL-1ra), and interleukin 6 (IL-6) concentrations in 69 bacteremic patients were compared with those in 54 nonbacteremic patients suffering from suspected bacterial infections. Only three (11%) of the 27 patients with gram-negative bacteremia showed detectable levels of endotoxin. TNF-alpha was detected in 6% of the bacteremic patients and in none of the nonbacteremic patients. Median IL-6 levels were significantly higher in bacteremic than in nonbacteremic patients (55 vs. 0 pg/ml, p = 0.0008). IL-6 concentrations were similar in neutropenic and non-neutropenic bacteremic patients (median 55 vs. 74 pg/ml). In contrast, neutropenic bacteremic patients had significantly lower concentrations of IL-1ra than non-neutropenic bacteremic patients (250 vs. 1,950 pg/ml, p < 0.0001). Patients with fatal bacteremia had significantly higher concentrations of IL-6 and IL-1ra than the survivors (median, 450 vs. 40, p = 0.012 and 7,600 vs. 420 pg/ml, p = 0.0075, respectively). Determinations of endotoxin or TNF-alpha in patients with suspected bacteremia failed to offer clinically relevant data on the prognosis of these patients. IL-6 levels correlated with both the presence of bacteremia and the risk of death. Granulocytopenic patients with bacteremia had lower levels of circulating IL-1ra than patients with normal granulocyte counts, and these levels correlated with poor outcome.     

Changes in levels of cell adhesion molecules, acute phase proteins, lipids and hemostasis in relation to levels of endogenous estrogens during pregnancy and after ovariectomy

The protective effect of oestrogens is probably caused also by the active inhibition of the inflammatory reaction of the acute phase and release of inflammatory cytokines type IL-1 beta or TNF-alpha by this hormone. We formulated this hypothesis because we recorded a drop of the protein of the acute stage, orosomucoid, in relation to the rising oestrogen level during pregnancy (r = -0.511, p < 0.0001). It ensues also from the finding of a lower level of cytoadhesive molecules of sE-selectins in a group of 66 pregnant women (sE-sel.: 32.95 +/- 12.5 ng/ml) with a higher level of 17-beta estradiol (17-beta E2: 9.34 +/- 7.8 nmol/l), as compared with the sE-selectin level in a group of 14 women after ovariectomy (sE-sel.: 43.97 +/- 8.174 ng/ml, p < 0.016) who lacked oestrogen (17-beta E2 0.14 +/- 0.13 nmol/l) and in a group of pregnant women (n 19) in the first trimester with level of 17-beta E2: 1.89 +/- 0.711 nmol/l where the sE-selectin concentrations at the onset pregnancy was higher (sE-sel.: 35.59 +/- 9.5 ng/ml) than in a group of pregnant women (n 38) during the second and third trimester (sE-sel.: 30.58 +/- 13.3 ng/ml, p < 0.05) with 17-beta E2 concentration 11.96 +/- 7.18 ng/ml. The finding of lower sE-selectin levels which is a sign that the endothelium is not exposed to the action of inflammatory cytokines IL-1 or TNF may thus be associated with the active "control" of thrombophilia in pregnancy. When during pregnancy in conjunction with oestrogen levels changes in the lipid concentration were investigated a compensating mechanism could be observed. Hypercholesterolaemia and hypertriglyceridaemia in pregnant women was associated with a rise of oestrogen levels as well as of "cardioprotective" HDL-cholesterol (the HDL level was during the first trimester 1.31 +/- 0.26 nmol/l, in the second and third trimester 1.69 +/- 0.48 nmol/l, p < 0.0167).     

The soluble 60-kDa tumour necrosis factor receptor: no difference found between patients with relapsing-remitting multiple sclerosis and controls: increasing levels are associated with the recovery from Guillain-Barré syndrome

We determined serum and cerebrospinal fluid (CSF) levels of the soluble 60-kDa tumour necrosis factor (TNF) receptor (sTNF-R p60) in 50 patients with relapsing-remitting multiple sclerosis (MS) and in 18 patients with Guillain-Barré syndrome (GBS). Neither in serum nor in CSF samples was there a statistically significant difference between mean receptor concentrations of patients with MS (serum: 1064, SD 262 pg/ml; CSF: 555, SD 130 pg/ml), with other noninflammatory neurological diseases (serum: 1008, SD 248 pg/ml; CSF: 530, SD 112 pg/ml) and with healthy control subjects (serum: 918, SD 180 pg/ml). In order to determine disease activity, magnetic resonance imaging (MRI) of the brain was performed in all MS patients. The mean sTNF-R p60 levels of patients who showed gadolinium DTPA enhancement on MRI were not different from those without enhancement (1034, SD 274 pg/ml vs 1099, SD 248 pg/ml in serum samples and 546, SD 109 pg/ml vs 565, SD 152 pg/ml in CSF samples). In GBS, the sTNF-R p60 levels of serum and CSF samples were significantly higher than in MS and all control groups except for the group with viral meningitis (VM) (GBS: 1544, SD 834 pg/ml in serum, 882, SD 147 pg/ml in CSF; VM: 1518, SD 375 pg/ml in serum, 1131, SD 611 pg/ml in CSF; P < 0.001 for serum samples and P < 0.005 for CSF samples). Serial serum sTNF-R p60 measurements in 13 patients with GBS showed an increase in receptor levels parallel with the recovery from the disease (1276, SD 374 pg/ml at the time of disease onset, 1554, SD 482 pg/ml 14-24 days later and 1787, SD 525 pg/ml after 28-32 days). From our results and the conflicting data of previous studies, we could not agree with the suggestion that the assessment of sTNF-R p60 in MS patients is a useful marker for disease activity. In GBS, subsequently increasing sTNF-R p60 levels are associated with recovery from the disease. It remains to be shown whether they might represent a relevant pathogenetic factor during this stage of GBS.     

An infant with 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase deficiency presenting with typical neonatal hepatitis syndrome: the first Japanese case

We investigated the in vivo effects of thalidomide on the production of tumor necrosis factor-alpha (TNF-alpha). An in vivo systemic release of TNF-alpha occurred after the injection of lipopolysaccharide (LPS) in male ddY mice, and the TNF-alpha serum levels reached 652.2 +/- 75.7 pg/ml 90 min after the injection of LPS (0.3 mg/kg, i. p.). When thalidomide (1, 3, or 6 mg/kg) was administered intraperitoneally 3 h before the injection of LPS (0.3 mg/kg, i. p.), thalidomide markedly enhanced LPS-induced TNF-alpha release in a dose-dependent manner. The TNF-alpha serum levels at 90 min were 640 +/- 58.6, 1985 +/- 132.6, and 2795 +/- 203.5 pg/ml, respectively, compared to 628.6 +/- 64.4 pg/ml in mice treated with LPS-alone. Pretreatment with a single injection of thalidomide (1, 3, or 6 mg/kg, i. p.) dose-dependently increased the subsequent mortality caused by a challenge with LPS (15 mg/kg, i. p.), a dose that caused death in 10% of the control mice. We conclude that thalidomide enhances in vivo TNF-alpha secretion and the lethality of LPS in mice.     

Anorexigen (TNF-alpha, cholecystokinin) and orexigen (neuropeptide Y) plasma levels in peritoneal dialysis (PD) patients: their relationship with nutritional parameters

BACKGROUND: Malnutrition has definitely been related to mortality among dialysis patients. Persistent loss of appetite is one of the major symptoms found in these patients. It is also well recognized that several substances produce anorexia or disorders of the hunger-satiety cycle in several diseases. The aim of this study was to identify the role of anorexigen substances (TNF-alpha and cholecystokinin or CCK) and an orexigen substance (neuropeptide Y or NPY) in anorexia and malnutrition among 55 clinically stable peritoneal dialysis (PD) patients. RESULTS: High TNF-alpha plasma levels were found in 41 of 42 patients (97.6%) with a mean of 70.5+/-32.3 pg/ml. Patients with anorexia (n=11) or anorexia with nausea or vomiting (n=5) had higher TNF-alpha values than patients without these symptoms (75.9+/-34 vs 52.1 +/-24.5 pg/ml, P<0.05). Eight patients with a prior diagnosis of acid pylori disease showed higher TNF-alpha values (87.2+/-24.3) than 30 unaffected patients (63.6+/-30.5, P<0.05). TNF-alpha showed a significant negative linear correlation with retinol binding protein (RBP) (r=-0.37, n=34, P<0.05), and venous pH (r=-0.4, n=42, P<0.01); also, TNF-alpha values higher than 65 pg/ml were inversely associated with transferrin, cholesterol, blood urea nitrogen (BUN) and CCK. Patients with prealbumin levels lower than 30 mg/dl, a BMI lower than 30 kg/m2, nPCR lower than 1.1 g/kg/day and urea KT/V lower than 2.2 showed higher serum TNF-alpha levels. Patients who had been on CAPD treatment for longer periods showed higher TNF-alpha values. High plasma CCK levels were found in 38 of 45 patients (84%), mean 45.9+/-32.3 pg/ml. Patients with anorexia had no difference in CCK values compared with those without. A direct association was found between CCK levels and some nutritional markers (albumin, fibronectin, triglycerides, folic acid and nPCR in non diabetic patients). Although CCK has a recognized anorectic effect, this direct association might be because of an abnormal stimulation of CCK glucose feedback (trypsin) due to continuous peritoneal glucose absorption. This suggests that CCK could be an immediate food intake marker in PD patients. The NPY plasma levels were normal in 33 patients, high in 6 and low in 11. Patients with anorexia showed lower NPY levels than those without. NPY values greater than 50 pg/ml were directly associated with higher transferrin, prealbumin, RBP, nPCR and urea KT/V values. Importantly, a negative linear correlation between NPY and TNF-alpha was found (r=-0.42, n= 41, P<0.01). There was no significant relationship between residual renal clearance and the serum levels of the three peptides. CONCLUSION: In conclusion, our data suggest that high TNF-alpha and low NPY serum levels are associated with anorexia. High TNF-alpha, low CCK and low NPY serum levels are also related to a poor nutritional status. Further research on these circulating substances is required.     

Arteriovenous fistula of the jugular vein: detection and follow-up with color-coded duplex ultrasound]

Increased levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) have been reported in various diseases, including lung cancer. The role of the soluble form of the IL-6 receptor (sIL-6R) remains to be explored. We therefore measured IL-6, IL-8 and sIL-6R in effusion fluid and blood serum of 10 lung cancer patients with carcinomatous pleurisy (5 men, 5 women, age 64.3 +/- 4.4 years) by enzyme-linked immunosorbent assays. Serum levels of healthy individuals served as control. Concentrations of sIL-6R were much higher in serum compared to pleural effusion fluids of tumor patients (25,698 +/- 1,993 vs. 9,438 +/- 1,407 pg/ml: p < 0.0001). In contrast, IL-6 and IL-8 were found at high concentrations in carcinomatous pleural effusions in comparison to serum (IL-6: 964 +/- 176 vs. 10.2 +/- 1.3 pg/ml, p < 0.0001; IL-8: 319 +/- 85 vs. 9.6 +/- 9.6 pg/ml, p < 0.0001). The serum concentrations of IL-6 were not significantly increased in lung cancer patients (10.2 +/- 1.3 pg/ml) in comparison to controls (7.3 +/- 1.0 pg/ml). IL-8 was detected in the serum of only 1 patient and in low levels in the serum of controls (8.0 +/- 1.5 pg/ml; all values are mean +/- SEM). We conclude from this study that decreased levels of sIL-6R, but increased levels of IL-6 and IL-8, are found in pleural effusion fluid of patients with lung cancer and carcinomatous pleurisy. The low sIL-6R levels in the presence of high IL-6 levels in pleural effusions and the high sIL-6R levels in the presence of low IL-6 levels in serum may suggest a downregulation of sIL-6R expression of sIL-6R shedding in the presence of excessive amounts of IL-6.     

Induction of granulomas in interferon-gamma gene-disrupted mice by avirulent but not by virulent strains of Mycobacterium tuberculosis

Tumor necrosis factor-alpha (TNF-alpha) levels were measured in the serum (sTNF-alpha) or bone marrow (BM) biopsies of 43 patients with myelodysplastic syndromes (MDS) who subsequently received therapy with a combination of pentoxifylline and ciprofloxacin (PC) with or without dexamethasone (PCD). All 43 patients received only PC therapy for 12 weeks, after which 18 of 36 nonresponders received PCD. A total of 18 of 43 patients showed a hematologic or cytogenetic response or both. BM TNF-alpha levels were semiquantitatively assessed using immunohistochemistry on a scale of 0-8+ and in the serum using enzyme linked immunoassay. The median TNF-alpha for the entire group was 3.0 in BM and 6.9 pg/ml in the serum, and 14 patients had no detectable levels. Responders had higher BM levels (median 3.5 vs. 2.0) than nonresponders, although this was not statistically significant. During PC therapy, a decline in BM TNF-alpha level was seen in the entire group, which was significant at 2 weeks (p = 0.02), 8 weeks (p = 0.001), and 12 weeks (p = 0.0001). Both responders (p = 0.01) and nonresponders (p = 0.03) had a decline at 8 weeks, but at 12 weeks, only the responders continued to show a significant decline (p = 0.03). We conclude that MDS patients with high BM TNF-alpa levels have a better chance of responding to PCD therapy and that the therapy is quite successful in reducing the TNF-alpha levels in a sustained fashion. Future studies need to be directed at identifying agents that would be more potent suppressors of the proapoptotic cytokines in these patients.     

Long-term follow-up of a patient with hepatocellular carcinoma associated with triple hepatitis virus (HBV, HDV, HCV) infection

OBJECTIVE: To determine the serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin) in patients with systemic sclerosis (SSc). METHOD: Serum samples from 80 patients with SSc and 20 healthy control subjects were examined by a sensitive enzyme-linked immunosorbent assay. RESULTS: The serum levels of sVCAM-1 and sE-selectin were significantly higher in the patients with SSc than in the healthy controls. The serum levels of sVCAM-1 were correlated with the presence of pulmonary fibrosis, joint involvement and elevated erythrocyte sedimentation rate levels. The serum levels of sE-selectin were correlated with the presence of pulmonary fibrosis. CONCLUSION: These results suggest that endothelial activation is involved in the development of this disease.