Biomedical subjects

A M Teppo

Publications and source records attributed to A M Teppo.

At least 19 recordsLinked to original sources

PubMed2003

Studies of cytokine levels in bronchoalveolar fluid lavage from patients with interstitial lung diseases.

Cytokine levels in bronchoalveolar lavage fluid from patients with eosinophilic pneumonia (n = 7), allergic alveolitis (n = 11), (cryptogenic) fibrosing alveolitis (n = 8), sarcoidosis (n = 10) were determined, as well as levels in control samples from healthy non-smoking volunteers (n = 11). Fibronectin levels were increased in all the patient categories, the highest absolute levels of fibronectin (100-fold increase) being found in eosinophilic pneumonia and allergic alveolitis. TGF-beta (transforming growth factor-beta) was significantly elevated in allergic alveolitis only. There was a significant difference between allergic alveolitis on the one hand and both sarcoidosis and fibrosing alveolitis on the other. Tumour necrosis factor-alpha (TNF-alpha) was significantly increased in eosinophilic pneumonia and allergic alveolitis; allergic alveolitis and fibrosing alveolitis differed significantly in this respect. Platelet-derived growth factor-BB (PDGF-BB) levels were significantly elevated in allergic alveolitis and fibrosing alveolitis. It was found that the level of PDGF-BB was significantly decreased in the case of sarcoidosis, with no overlapping with allergic alveolitis or fibrosing alveolitis. Interferon-gamma (IFN-gamma) was decreased in all patient categories. A significant difference in extent of the decrease was found between allergic alveolitis and sarcoidosis. The interstitial lung diseases thus differed in the pattern of cytokines expressed, indicating that these cytokines could well be a part of the pathogenic process, and also that the measurement of cytokine levels could be diagnostically useful.

Adult↗

PubMed2003

Elevated serum C-reactive protein associates with deterioration of renal function in transplant recipients.

AIM: Since t he elevated concentration of serum C-reactive protein (CRP) is a sensitive indicator of underlying inflammation, we investigated the association between serum CRP during the initial 6 post-transplantation months and histopathological changes in the 6-month protocol biopsies in 79 patients. We stained the biopsies for CRP and C3 to elucidate a possible role of CRP in renal injuries. RESULTS: Forty patients showed no or minimal (Grade 0-1) tubular atrophy or interstitial fibrosis and 39 patients mild to moderate (Grade > or = 2) chronic histopathological changes. The latter group had had higher concentration of CRP during the first 6 post-transplant months. Because the histopathological changes predict poor long-term prognosis, we followed--from 6th month onwards--40 patients who had no or minimal histopathologic changes, and analyzed the association between CRP elevation and development of chronic allograft dysfunction. During this follow-up period (mean 51, range 14-72 months), 23 of 40 patients retained normal CRP level (Group A, mean CRP 1.12 mg/l), and 17 patients had elevated CRP concentrations (Group B, mean CRP 4.16 mg/l); 24-hour creatinine clearance improved or remained the same in all Group A patients, whereas it decreased in 7 of 17 (41%) of Group B patients (p < 0.001). In Group B patients, the annual change of creatinine clearance correlated inversely with the mean CRP concentration (r = -0.682, p < 0.01). CONCLUSION: Our results show that histological changes in 6-month biopsies were more prominent in patients with more transplantation-associated complications, infections and frequently higher CRP levels during the initial 6 post-transplant months than in those with lower CRP levels. During post-biopsy follow-up, we found low-grade systemic inflammation--measured as elevated CRP--to associate with impairment of graft function in patients with no or minimal histological findings in 6-month biopsies, and permanently low CRP to rule out chronic allograft dysfunction.

Adult↗

PubMed2001

Soluble intercellular adhesion molecule-1 (sICAM-1) after kidney transplantation: the origin and role of urinary sICAM-1?

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) binds to leukocyte adhesion receptors LFA-1 and MAC-1, and mediates leukocyte adhesion to target structures. During acute rejection there is increased expression of ICAM-1 in vascular and tubulointestial cells, and consequently accumulation of inflammatory leukocytes. Soluble ICAM-1 (sICAM-1) is released from ICAM-1 expressing cells and excreted into the surrounding fluid. Increased serum sICAM-1 levels are found in patients with acute rejections of various allografts, and high urinary levels in steroid resistant acute kidney allograft rejection. METHODS: Urinary excretion of sICAM-1 was measured by EIA in 136 kidney allograft recipients during the first 1-6 post transplant weeks: 30 patients developed acute rejection, and 106 patients had stable graft function. The molecular weight, binding to hyaluronan, and the origin of urinary sICAM-1 were studied. RESULTS: We show that urinary sICAM-1 circulates as a monomer with a molecular weight between 50 and 100 kD. It binds to immobilized, but not to circulating hyaluronan. About one week after transplantation the mean sICAM-1/creatinine ratio (306 ng/mmol) in transplanted patients was higher than in the healthy controls (167 ng/mmol, P<0.01), and remained basically unchanged during the follow-up in patients with stable graft function, whereas it increased in patients developing rejection, being about 2.5-fold above the initial level a few days before rejection (P<0.01). Urinary sICAM-1 did not correlate with the urinary albumin, whereas in patients developing rejection it correlated with urinary IL-2R (r=0.5146, P<0.001), a marker of lymphocyte activation. In the urinary sediment of rejecting patients ICAM-1 was demonstrated in the tubular epithelial cells, and in the macrophages. CONCLUSIONS: Increased urinary excretion of sICAM-1 was demonstrated in kidney transplanted patients a few days before acute rejection. It seems to originate from activated macrophages and/or from the tubular epithelial cells. The fact that urinary sICAM-1 is not bound to hyaluronan or to leukocytes suggests that it is not able to compete with membrane-bound ICAM-1 for these bindings, but may do so for the binding of activated macrophages.

Albuminuria↗

PubMed2001

Human tear fluid PDGF-BB, TNF-alpha and TGF-beta1 vs corneal haze and regeneration of corneal epithelium and subbasal nerve plexus after PRK.

The aim was to determine the association of tear fluid cytokine levels and post-PRK corneal haze evaluated by in vivo confocal microscopy. In addition, the possible association between subbasal neural regeneration and haze formation, or epithelial regeneration were investigated. Twenty eyes of 20 patients (16 women and four men, age 30.7 +/- 7.5 years, range 21-48 years) underwent a myopic PRK. The spherical equivalent (SE) of the intended correction was -4.7 +/- 1.5 D (range -2.75 to -9.00 D). ELISA-methods were used to assess tear fluid concentrations of TGF-beta1, PDGF-BB and TNF-alpha pre-operatively, and post-operatively on day 2 and at 3 months. Tear fluid flow in the collection capillary was recorded, and rates of cytokine release (= tear fluid flow-corrected concentrations) were calculated. In vivo confocal microscopy was performed at 3 months to evaluate the corneal morphology and to determine numerical haze estimate. There was wide interindividual variation between pre-operative and post-operative concentrations and rates of release of TGF-beta1, PDGF-BB and TNF-alpha. Subepithelial haze was observed in all corneas and the mean haze estimate was 506 +/- 401 U (100-1410 U). However, no association was found between tear fluid cytokine levels and post-PRK haze. Regenerating subbasal nerve plexus was found in 18 out of 20 corneas; in two corneas it was absent or could not be visualized due to subepithelial haze. The density of the subbasal nerve fiber bundles had a positive correlation with the epithelial thickness (Pearson correlation, r = 0.56, P = 0.011), but not with the haze estimate or the thickness of the haze area. At 3 months post-PRK, haze could be observed in all patients. The results suggest that tear fluid cytokine analysis, as measured, may not be suitable for screening the potential candidates for haze formation. We did not find any correlation between haze and regeneration of subbasal nerve plexus, but we demonstrated that the regeneration of subbasal nerve plexus might have significant influence on regulation of epithelial healing.

Adult↗

PubMed2001

Increased secretion of TGF-beta1 by peripheral blood mononuclear cells from patients with Type 1 diabetes mellitus with diabetic nephropathy.

AIMS: To study transforming growth factor (TGF)-beta1 secretion by peripheral blood mononuclear cells (PBMC) from Type 1 diabetic patients with and without nephropathy. METHODS: Thirty normoalbuminuric Type 1 diabetic patients (urinary albumin excretion rate (AER) < 20 microg/min), 12 microalbuminuric (AER 20-200 microg/min), 10 nephropathic (AER > 200 microg/min), and 13 non-diabetic individuals were recruited. TGF-beta1 secretion by PBMC was measured by enzyme immunoassay (EIA) after 48 h culture with and without phytohaemagglutinin (PHA) (5 microg/ml). RESULTS: After 48 h culture, the highest TGF-beta1 levels secreted by unstimulated PBMC were found in patients with nephropathy (median 6.2 (range 0.9-20.0) ng/ml) when compared to patients with normal albumin excretion (4.1 (0.2-11.3) ng/ml), microalbuminuria (1.8 (0.2-6.4) ng/ml) and healthy controls (1.0 (0.2-7.0) ng/ml); P = 0.02 for the three diabetic groups and P = 0.006 for all groups. At 48 h, the PHA-stimulated TGF-beta1 levels were 12.4 (2.9-30.0) ng/ml in nephropathic, 7.3 (0.5-21.2) ng/ml in normoalbuminuric, and 5.5 (0.5-27.6) ng/ml in microalbuminuric patients (P = 0.05). A correlation was observed between TGF-beta1 and diastolic blood pressure in the subgroup of patients with incipient and overt nephropathy (r = 0.45, P = 0.04). CONCLUSIONS: Type 1 diabetic patients with overt nephropathy show increased TGF-beta1 secretion by PBMC. Diastolic blood pressure levels correlated with TGF-beta1 secretion in diabetic patients with nephropathy. Increased TGF-beta1 secretion by PBMC may be associated with renal and vascular disease in Type 1 diabetes mellitus.

Adult↗

PubMed2001

Concentration of the complement activation product, acylation-stimulating protein, is related to C-reactive protein in patients with type 2 diabetes.

Type 2 diabetes is characterized by increased acute phase serum proteins. We wanted to study how these proteins are related to complement activation in type 2 diabetes and how improvement of glycemic control affects them or complement activation. A total of 29 type 2 diabetic patients (age, 55.2 +/- 1.8 years, glycosylated hemoglobin [HbA(1c)] 8.9% +/- 0.2%, body mass index [BMI] 30.9 +/- 0.8 kg/m(2), duration 5.9 +/- 1.3 years) participated in the study. They were previously treated either with diet alone or in combination with 1 oral antihyperglycemic medication. After a period of at least 4 weeks run-in on diet only, the patients were randomized to pioglitazone, glibenclamide, or placebo. Blood samples were taken before the treatments and at the end of the 6-month therapy. Basal C-reactive protein (CRP) level was related to acylation-stimulating protein (ASP) concentration (r =.55, P <.01), and many acute phase serum protein concentrations were associated with each other. The treatment reduced HbA(1c) level in the pioglitazone (from 9.1 +/- 0.3% to 8.0 +/- 0.5%, P <.05) and glibenclamide (from 8.9 % +/- 0.3% to 7.7% +/- 0.2%, P <.05) groups. Glibenclamide treatment was associated with a reduction in alpha-1-antitrypsin (P <.05), ceruloplasmin (P <.01), and complement C3 protein (C3) (P <.05). Although ASP did not change significantly in any of the treatment subgroups, in the whole patient population, the change in HbA(1c) during the treatments correlated positively with the change in ASP, (r =.43, P <.05). The changes in many acute phase serum proteins and ASP were related to each other. In conclusion, (1) inflammatory factors and complement activation are associated in patients with type 2 diabetes, and (2) changes in hyperglycemia are related to changes in the concentration of the complement activation product, ASP.

Acute-Phase Proteins↗

PubMed2001

The effect of ketorolac and sevoflurane anesthesia on renal glomerular and tubular function.

UNLABELLED: We assessed the renal effects of the combination of ketorolac and sevoflurane anesthesia by using sensitive and specific markers of renal proximal and distal tubular and glomerular function. Thirty women (ASA physical status I and II) undergoing breast surgery received either ketorolac 30 mg IM or saline at premedication, at the end, and 6 h after anesthesia maintained with sevoflurane. Peak levels of serum fluoride at 2 h after the end of anesthesia were 30.1 micromol/L (21.0-50.0 micromol/L) in the Ketorolac group and 33.3 micromol/L (13.0-38.0 micromol/L) in the Control group (mean and range, not significant). Urine alpha1-microglobulin indexed to urine creatinine was increased from 2 h after the start of anesthesia until the first postoperative day in the Ketorolac group (peak level, 0.8 +/- 0.4 mg/mmol; upper limit of normal, 0.7 mg/mmol) but did not change in the Control group. Urine glutathione-S-transferase (GST)-alpha indexed to urine creatinine (GST-alpha/creatinine) and GST-pi/creatinine were increased 2 h after anesthesia and returned to baseline values thereafter in both groups. There were no changes in serum cystatin C and urine kallikrein or urine output per hour between groups. The perioperative administration of ketorolac to healthy, well hydrated patients anesthetized with sevoflurane did not produce renal glomerular or tubular dysfunction. IMPLICATIONS: Ketorolac 90 mg IM, given in divided doses over approximately 10 h to patients anesthetized with sevoflurane with a fresh gas flow rate of 4-6 L/min, did not result in clinically significant changes in renal glomerular or tubular function.

Adolescent↗

PubMed2000

Changes of urinary alpha1-microglobulin in the assessment of prognosis in renal transplant recipients.

BACKGROUND: After transplantation, even if the graft starts functioning immediately, there are morphological and functional changes in tubular structures. In addition, acute allograft rejection causes damage in the tubular epithelium, tubular basement membrane, and intertubular connective tissue. It also affects the functional capacity of proximal tubular cells resulting in impaired reabsorption and thus increased urinary excretion of low molecular weight proteins. METHODS: We present a double-antibody radioimmunoassay for determination of the concentration of alpha1-microglobulin (alpha1 M) in urine. It was used to measure urinary excretion of alpha1 M approximately once a week during the first 1-6 posttransplant weeks in 136 consecutive patients: 30 patients developing acute rejection (75 24-hr urine samples) and 106 patients with stable graft function (223 24-hr urine samples). The results are expressed as alpha1 M/creatinine ratios. RESULTS: Approximately 8 days after transplantation the mean (+/-SD) urinary alpha1 M/creatinine ratio of all patients was 17.0+/-14.8 mg/mmol, being about the same both in patients with uncomplicated posttransplantation course (16.3+/-14.0 mg/mmol) and in those who later developed rejection (19.3+/-15.1 mg/mmol), but about 60-fold higher than in healthy controls (0.27+/-0.15 mg/mmol). At that time, when all patients were included there was a correlation (r=0.3465, P<0.001) between alpha1 M/creatinine ratio and duration of cold ischemia. Thereafter, during the second week alpha1 M/creatinine ratio decreased in 89% of patients with stable graft function, but only in 14% of patients who later developed rejection (P<0.001). On the contrary, a significant increase (P<0.01) of alpha1 M/creatinine ratio was observed 4 to 1 day before rejection in all 15 patients, who had urines collected at that time. At the end of the follow-up period, alpha1 M/creatinine ratio in patients with rejection was 3-fold compared with the nonrejecting patients, and 100-fold compared with the healthy controls. CONCLUSION: These results show that cadaveric transplantation results in impaired low molecular weight protein reabsorption, the degree of dysfunction relating to the duration of cold ischemia, and suggest that during the posttransplant weeks decreasing alpha1 M/creatinine ratio in consecutively collected urine samples indicates improved tubular function and in most cases rules out development of acute rejection.

Adolescent↗

PubMed2000

Decreased urinary excretion of vascular endothelial growth factor in idiopathic membranous glomerulonephritis.

BACKGROUND: Membranous glomerulonephritis (MGN) has, for unknown reasons, an unpredictable and highly variable clinical course. Vascular endothelial growth factor (VEGF) enhances endothelial cell proliferation, angiogenesis, microvascular permeability, and monocyte chemotaxis, and it activates proteinases. In normal kidneys, it is predominantly expressed by glomerular podocytes, where its physiological function and role in development of renal diseases are obscure. This study was designed to evaluate the urinary excretion of VEGF in MGN compared with several other glomerular disease and to asses its relationships to the clinical activity of MGN. METHODS: Urinary VEGF was studied during renal biopsy using a sandwich enzyme immunoassay from 30 patients with idiopathic MGN, 8 with minimal change glomerulonephritis, 10 with focal segmental glomerulosclerosis (FSGS), 8 with necrotizing glomerulonephritis associated with systemic vasculitis, and 12 with diabetic nephropathy. In addition, 33 healthy controls were examined. Fifteen patients with MGN were re-evaluated 12 months later, and the evolution of proteinuria was compared with changes in urinary VEGF excretion. RESULTS: In healthy control subjects, urinary VEGF excretion was 68 +/- 10 (95% CI, 49 to 88) ng/mmol creatinine (UCr). In MGN, the excretion was decreased to 16 +/- 3 (CI, 10 to 23) ng/mmol crea (P < 0.0001, ANOVA), whereas in minimal change glomerulonephritis and diabetic nephropathy, it was unchanged [55 +/- 14 (CI, 24 to 86) and 101 +/- 25 (CI, 45 to 156) ng/mmol UCr, respectively, P = NS]. In vasculitis and FSGS patients, the excretion was higher than normal [184 +/- 68 (CI, 24 to 344), P = 0.01, and 160 +/- 29 (CI 95 to 226), P = 0.002 ng/mmol UCr, respectively]. The excretion did not correlate with serum VEGF, renal function, or proteinuria. In the follow-up of 15 patients, improving MGN (decreasing proteinuria) was associated with increasing VEGF excretion, while persistent disease (no change or increase of proteinuria) was associated with constantly low urinary VEGF excretion. The change in urinary protein excretion over one year correlated inversely with the change in urinary VEGF (r = -0.57, P = 0.026). CONCLUSIONS: MGN is associated with decreased urinary VEGF compared with normal subjects, which is in contrast with other proteinuric diseases. Moreover, decreasing clinical activity (proteinuria) is accompanied by increasing VEGF excretion. Urinary VEGF may serve as an indicator of activity of MGN.

Adult↗

PubMed2000

Vascular changes in erythropoietic protoporphyria: histopathologic and immunohistochemical study.

BACKGROUND: Erythropoietic protoporphyria (EPP) is an inherited disease caused by deficient activity of ferrochelatase in the heme biosynthetic pathway. Accumulation of protoporphyrins and light exposure results in acute phototoxic skin reactions. The histopathologic findings of the light-exposed skin are thickening of the superficial dermal vessel walls and amorphous deposits around the vessels, but the origin and detailed composition of the perivascular material have been unclear. OBJECTIVE: The vascular morphology and composition of the perivascular material were studied in the skin samples of patients with EPP. METHODS: Skin biopsy specimens of 8 patients with EPP representing 7 Finnish EPP families with different genotypes were studied by means of light and electron microscopy and immunohistochemical methods. RESULTS: The characteristic finding was thickened, periodic acid-Schiff-positive vessel walls caused by concentric reduplication of basal lamina and excess of fine granular material at the basal membrane zone in the superficial dermis. The perivascular deposits in the vicinity of vessel walls had a homogeneous or fine granular appearance without filaments. Direct immunofluorescence showed constant IgG deposits together with IgA, IgM, and C3 in the vessel walls. In immunohistochemistry, collagen IV and laminin could be demonstrated at the vascular basal membrane together with serum amyloid P protein, kappa and lambda light chains, and a 90-kd glycoprotein. CONCLUSION: The vascular involvement indicates that the blood vessel walls in the papillary dermis are the primary tissues affected during an acute photoreaction. The repeated acute damage and repair processes in the basement membrane zone result in thickening of the vessel walls. Perivascular deposits are a secondary and irreversible phenomenon resulting from the leakage and accumulation of different serum components. These changes were not found in the nonexposed skin, indicating that an increased level of erythrocyte protoporphyrin per se is not responsible for the cutaneous manifestations, but the interaction of solar radiation is mandatory. Amorphous deposits distinguish EPP from variegate porphyria and porphyria cutanea tarda; a histopathologic examination may be a helpful tool in differentiating porphyric and nonporphyric photosensitivity.

Adolescent↗

PubMed2000

Complement C3 cleavage and cytokines interleukin-1beta and tumor necrosis factor-alpha in otitis media with effusion.

OBJECTIVES: To analyze whether complement C3a anaphylatoxin, other C3 fragments, interleukin-1beta (IL-1beta), or tumor necrosis factor-alpha (TNF-alpha) contributes to inflammation in chronic otitis media with effusion (OME). METHODS: The amount of C3a was measured by enzyme-linked immunoassay. Further breakdown of C3 was analyzed by Western blotting. IL-1beta and TNF-alpha concentrations were measured by radioimmunoassay. Bacteria were analyzed by culture and polymerase chain reaction. RESULTS: Highly elevated levels of C3a and other C3 cleavage fragments were found in all middle ear effusion (MEE) samples. The mean values (+/- SEM, n = 26) for C3a, IL-1beta, and TNF-alpha were 5,973 +/- 1,124 ng/mL, 1,043 +/- 490 pg/mL, and 79 +/- 14.3 pg/mL, respectively. Comparison to an average C3 level of 555 (+/-108) microg/mL indicated that at least 40.5% +/- 6% of total C3 had become activated within the MEE. C3a concentrations were higher in the group in which the effusion had been present in the middle ear for a prolonged period (> or =4 mo) (P = .04). Children with multiple tube insertions had higher C3 (P = .006) and TNF-alpha (P = .04) concentrations in their MEE samples than those receiving their first tubes. C3 and C3a concentrations in MEE correlated to each other (correlation coefficient [r] = 0.513, P = .0056), as did concentrations of IL-1beta and TNF-alpha (r = 0.7016, P < .0001). No significant correlation was found between complement C3 or C3a levels and IL-1beta, TNF-alpha, or bacterial growth. CONCLUSIONS: Highly elevated levels of C3a in MEE indicate ongoing complement activation, which is stronger than in almost any other disease demonstrated previously. Elevated C3a levels contribute to chemotactic and inflammatory potential in the MEE and correlate with the chronicity of the disease.

Blotting, Western↗

PubMed2000

Urinary transforming growth factor-beta1 and alpha1-microglobulin in children and adolescents with type 1 diabetes.

OBJECTIVE: Transforming growth factor (TGF)-beta1 is an important mediator in the pathogenesis of diabetic nephropathy. Urinary TGF-beta1 reflects TGF-beta1 production in the kidney, and alpha1-microglobulin tubular dysfunction. These 2 markers were studied in the early phases of type 1 diabetes. RESEARCH DESIGN AND METHODS: There were 113 type 1 diabetic children and adolescents (mean +/- SD: age 14.1 +/- 2.9 years, and diabetes duration 7.4 +/- 2.9 years, HbA1c 9.3 +/- 1.5%) and 39 healthy subjects (age 13.8 +/- 2.8 years) who participated in the study. Of the diabetic patients, 105 were normoalbuminuric (2-3 consecutive overnight urinary albumin excretion rates [AERs] <20 microg/min) and 8 had microalbuminuria (at least 2 AERs 20-200 microg/min). Overnight urinary TGF-beta1 and alpha1-microglobulin levels were measured and the results expressed as the ratio to urinary creatinine concentration. RESULTS: Data are medians (range). Diabetic patients had higher urinary TGF-beta1 levels than those of control subjects: 0.9 ng/mg (0.05-122.3) vs. 0.3 ng/mg (0.05-2.2) creatinine, respectively (P = 0.003). Urinary TGF-beta1 levels correlated with urinary glucose (r = 0.2, P = 0.03) and alpha1-microglobulin (r = 0.2, P = 0.02) levels, but not with HbA1c, AER, age, or duration of diabetes. In 43 patients with urinary TGF-beta1 above the control levels, urinary TGF-beta1 levels correlated with urinary glucose (r = 0.6, P < 0.001) and alpha1-microglobulin (r = 0.6, P < 0.001) levels. Diabetic patients had higher urinary alpha1-microglobulin levels than those of control subjects: 4.8 microg/mg (0.6-48.8) vs. 2.7 microg/mg (0.8-11.6) creatinine, respectively (P < 0.001). Alpha1-microglobulin levels correlated with AER (r = 0.2, P = 0.02), HbA1c (r = 0.3, P = 0.001), urinary glucose (r = 0.5, P < 0.001), and urinary TGF-beta1 levels. CONCLUSIONS: An early rise in urinary TGF-beta1 levels was observed in young type 1 diabetic patients. Urinary TGF-beta1 is associated with 2 interrelated tubular markers, alpha1-microglobulin and urinary glucose.

Adolescent↗

PubMed1999

Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Amino Acid Sequence↗

PubMed1999

Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with Type II diabetes.

AIMS/HYPOTHESIS: Inflammation could play a part in insulin resistance. Thiazolidinediones, new antidiabetic drugs, possess anti-inflammatory effects in vitro. We investigated if acute-phase serum proteins are increased in patients with Type II (non-insulin-dependent) diabetes mellitus who had been treated with insulin and whether troglitazone has anti-inflammatory effects in vivo. METHODS: A total of 27 patients (age 63.0+/-1.7 years, HbA1c 8.8+/-0.3%, BMI 32.7+/-0.8 kg/m2, duration 15.2+/-1.4 years, insulin dose 73.3+/-7.0 U/day) participated in the study. The patients received daily either 400 mg troglitazone or placebo for 16 weeks. Blood samples were taken at baseline, at the end of therapy and after a follow-up time of 23+/-4 days. RESULTS: The concentrations of serum amyloid A (6.2+/-1.1 mg/l) and C-reactive protein (6.1+/-1.1 mg/l) were increased (p < 0.001) and complement protein C3 (1.69+/-0.05 g/l) was also above the reference range for healthy subjects. Placebo treatment had no effect on glucose or inflammation, whereas troglitazone reduced fasting glucose (from 10.4+/-0.6 mmol/l to 8.1+/-0.5 mmol/l, p < 0.01), HbA1c (from 8.7+/-0.3% to 7.5+/-0.3%, p < 0.01), insulin requirements (from 75+/-10 U/day to 63+/-10 U/day, p < 0.05), serum amyloid A (from 6.3+/-1.5 mg/l to 4.0+/-1.3 mg/l, p = 0.001), alpha-1-acid glycoprotein (from 906+/-51 mg/l to 729+/-52 mg/l, p = 0.001) and C3 (from 1.72+/-0.07 g/l to 1.66+/-0.06 g/l, p < 0.05) but not alpha-1-antitrypsin, ceruloplasmin, C-reactive protein or haptoglobin significantly. Concentrations of glucose and acute-phase reactants had returned to those before treatment at the follow-up visit. CONCLUSION/INTERPRETATION: In Type II diabetic patients serum amyloid A and complement protein C3 are raised. Troglitazone exerts a selective reversible action on some acute-phase proteins and C3 but not on others in conjunction with the improvement in glucose metabolism.

Acute-Phase Proteins↗

PubMed1999

Immune responses to osteoarticular allografts of the knee--cytokine studies.

Immunological behaviour in correlation with bone allograft survival was studied in peripheral blood and synovial fluid from seven patients who had undergone large bone resection and allograft transplantation of the knee. Plasma and synovial fluid samples for cytokine measurements [interleukin (IL-1beta, IL-6) and tumour necrosis factor alpha (TNF-alpha)] were drawn from peripheral blood for diagnostic arthrocentesis. Two patients were monitored using consecutive sampling up to 12 months postoperatively. Graft survival was considered excellent, but local or diffuse resorption and also fatigue fractures were seen. These findings show that soluble products of T-cell, macrophage and osteoblast origin, produced as a response to the bone-graft antigens, might be responsible for the bone resorption seen in our material. The elevated IL-1beta and TNF-alpha levels detected support this statement.

Adult↗

PubMed1999

Soluble Fas and Fas ligand in human tear fluid after photorefractive keratectomy.

BACKGROUND/AIMS: The Fas-Fas ligand system is thought to be involved in stromal cell apoptosis after corneal wounding. The aim was to measure changes in human tear fluid levels of soluble Fas (sFas) and Fas ligand (sFasL) following myopic photorefractive keratectomy (PRK). METHODS: Tear samples of 59 patients were collected preoperatively, and 1 or 2 days after PRK. Tear fluid sFas or sFasL concentrations were determined using sandwich ELISAs. Subsequently, tear flow corrected concentrations (releases) were calculated to compensate for the postoperative tear hypersecretion. RESULTS: The preoperative tear fluid flows (TFF) were 6.4 (1.7) microl/min (mean (SEM)) in sFas group (n = 18), and 7.5 (1.5) microl/min in sFasL group (n = 39). Postoperatively TFFs increased to 37.9 (10.9) microl/min (p = 0.003) and 58.3 (7.0) microl/min (p = 0.000), respectively. The mean preoperative sFas concentration (24.4 (11.6) U/ml) decreased to 9.7 (4.1) U/ml (p = 0.001) postoperatively, and the mean sFasL concentration (299.1 (28.8) ng/l) to 118.7 (15.9) ng/l (p = 0.000). However, the release of both substances increased significantly: sFas from 87.3 (29.4) mU/min to 229.4 (82.9) mU/min (p = 0.002) and sFasL from 1620.6 (226.4) fg/min to 4777.1 (596.1) fg/min (p = 0.000). CONCLUSIONS: Both sFas and sFasL are normal constituents of human tears. Despite a decrease in concentrations related to reflex tears, the release of sFas and sFasL increases significantly after excimer laser photorefractive keratectomy, which suggests that they are involved in corneal healing after PRK in humans.

Adolescent↗

PubMed1999

High pleural fluid hyaluronan concentrations in rheumatoid arthritis.

Previous studies have shown that high pleural fluid (Pf) hyaluronan (HYA) concentrations may be due not only to malignant mesothelioma but also to inflammatory diseases. The objective of this study was to evaluate Pf-HYA in various nonmalignant inflammatory pleural disorders. A radiometric assay was used to determine HYA in Pf and serum (S) of 126 patients, 12 of whom had rheumatoid arthritis (RA), 22 tuberculosis, 22 pneumonia, 41 lung cancer, 10 malignant mesothelioma and 19 congestive heart failure. Pf-HYA values were correlated with values for Pf-tumour necrosis factor (TNF)-alpha and Pf-interleukin (IL)-1beta, as determined by radioimmunoassay. The highest median Pf-HYA (125.6 mg x L(-1), range 0.04-386.5 mg x L(-1)) occurred in patients with malignant mesothelioma. Among patients with nonmalignant inflammatory diseases, significantly higher median Pf-HYA were observed in those with rheumatoid arthritis (64.2 mg x L(-1), range 25.8-106.9 mg x L(-1)) than in those with tuberculosis (25.5 mg x L(-1), range 14.9-57.1 mg x L(-1), p<0.0005) or pneumonia (20.9 mg x L(-1), range 9.5-129.4 mg x L(-1), p<0.005). There was no correlation between Pf-HYA and S-HYA. Pf-HYA correlated positively with Pf-TNF-alpha (r=0.62) and Pf-IL-1beta (r=0.52). High pleural fluid hyaluronan occurs not only in malignant mesothelioma, but also in certain nonmalignant inflammatory diseases, especially rheumatoid arthritis. One explanation for the increase in pleural fluid hyaluronan may be local production of proinflammatory cytokines, such as tumour necrosis factor-alpha and interleukin-1beta.

Adult↗

PubMed1999

Acute phase response in dairy cows with experimentally induced Escherichia coli mastitis.

Six Finnish Ayrshire cows were challenged intramammarily with 1500 CFU of Escherichia coli (E. coli) into single udder quarters, and the challenge was repeated into contralateral quarters 3 weeks later. All cows received flunixine meglumine once, and 3 of them were also treated with enrofloxacin. At the 2nd challenge, treatments were changed vice versa. The development of mastitis was followed by monitoring of systemic and local clinical signs, and with serial milk and serum samples. Intramammary challenge with E. coli produced clinical mastitis in all cows, the severity of the disease varying greatly between the animals. No significant changes between the 2 treatment regimens or sequent challenges were found for any of the clinical parameters. The response of each cow followed the same pattern after both challenges; three of the cows became mildly and the other 3 either moderately or severely affected. Two severely affected cows had to be euthanized because of severe mastitis. Serum haptoglobin and amyloid-A concentrations peaked 2-3 days after bacterial challenge. Serum haptoglobin did not correlate with the severity of the disease. Serum amyloid-A rose gradually in the severely affected cows, and significant differences were found between severely versus moderately or mildly affected cows at day 4. Serum tumor necrosis factor alpha concentrations increased only in the severely affected cows. Serum cortisol response was prolonged in the severely diseased animals, and was significantly lower after the second challenge. Serum nitrite/nitrate concentration increased in the severely affected cows. This indicated excess nitric oxide production during acute E. coli mastitis. Strongly decreased milk production, and high bacterial growth in the infected quarters were best predictors for the outcome from acute E. coli mastitis.

Acute-Phase Reaction↗