Anna-Maija Teppo

Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome☆

PURPOSEnIn order to evaluate the relationship between cachectin/tumor necrosis factor (TNF) and cachexia in the acquired immunodeficiency syndrome (AIDS), we studied the serum levels of endogenous cachectin/TNF in subjects with human immunodeficiency virus (HIV) infection.nnnPATIENTS AND METHODSnFifty-three serum samples were obtained from 39 HIV-seropositive patients. The condition of each patient was clinically classified as either asymptomatic, lymphadenopathy syndrome (LAS), AIDS-related complex (ARC), or AIDS. Control sera were obtained from 29 healthy male blood donors. A double antibody radioimmunoassay was used to measure the serum levels of cachectin/TNF.nnnRESULTSnCachectin/TNF levels were within the reference range of the control values in all (eight of eight) asymptomatic HIV-infected subjects and in 11 of 13 of the patients with LAS. In contrast, all patients with AIDS (nine of nine) and five of nine of the patients with ARC had raised levels of cachectin/TNF. Fluctuation of the levels of cachectin/TNF occurred during follow-up, but initially raised levels remained elevated.nnnCONCLUSIONnSince cachectin/TNF suppresses lipoprotein lipase in adipocytes in vitro, and causes weight loss under experimental conditions, the findings of raised levels of cachectin/TNF in patients with AIDS may have relevance to the pathogenesis of cachexia.

Elevated Circulating Levels of Inflammatory Cytokines in Patients With Abdominal Aortic Aneurysm

The basic feature in the pathogenesis of abdominal aortic aneurysm (AAA) is the degradation of extracellular matrix components. This process is induced partly by cytokines secreted from inflammatory and mesenchymal cells. Circulating levels of inflammatory cytokines were studied in AAA patients and compared with subjects suffering from atherosclerotic disease only. Furthermore, the predictive value of cytokine concentrations was evaluated for aneurysm expansion rate. Circulating levels of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were measured in 50 AAA patients (40 men, 10 women), 42 patients with coronary heart disease (CHD) (23 men, 19 women), and 38 controls whose angiogram was normal (17 men, 21 women). No differences in cytokine concentrations were found between the CHD patients and the controls. AAA disease was found to be associated with significantly higher IL-1 beta and IL-6 concentrations in both male patients (median concentrations of 19.40 pmol/L and 6.45 pmol/L, respectively) and female patients (19.26 pmol/L and 7.99 pmol/L) than in either the CHD patients or the controls (P < .005). TNF-alpha levels were slightly higher in the AAA patients (1.64 pmol/L in the males and 1.59 pmol/L in the females) than in the other groups (P < .05). IFN-gamma levels were elevated significantly in the female AAA patients (3.75 pmol/L) compared with levels found in the other female (P < .05) or male (P < .01) patient groups. The measured cytokine concentrations were not related to the size of the aneurysm or the maximal thickness of the thrombus within the aneurysm. IFN-gamma concentration showed a significant positive correlation to the aneurysm expansion (R = .37, P < .02) and negative correlation to the concentration of aminoterminal propeptide of type III procollagen during 6-month follow up (R = -.42, P < .005). The results show that circulating levels of inflammatory cytokines are elevated in patients with AAA disease, suggesting that the production of these cytokines is increased in these patients compared with CHD patients and controls. Elevated INF-gamma concentrations seem to predict an increased rate of expansion in AAA.

Renal growth and function 11-28 years after treatment of Wilms' tumour

In order to obtain more information on the long-term effects of treatment of Wilms tumour we investigated 30 subjects treated at the Childrens Hospital between 1960 and 1976. All had been nephrectomized and in 4 the length of the remaining kidney was subnormal. In the other subjects kidney length was related to follow up time and age at follow up. Blood pressure was elevated in 5 subjects. Urinary albumin excretion deviated only slightly from normal. Tubular functions were well preserved in all subjects. In this small series we were unable to establish any relation between the abnormalities observed and the treatment given. Our results suggest that, despite wide interindividual variation those who survive Wilms tumours seldom have long-term renal complications.

MECHANISM OF REDUCED AMYLOID-A-DEGRADING ACTIVITY IN SERUM OF PATIENTS WITH SECONDARY AMYLOIDOSIS

Human serum contains amyloid-A-degrading (AADP) activity. This activity is reduced in amyloidosis associated with rheumatoid arthritis. Since AADP co-migrates with albumin on agarose-gel electrophoresis, the relationship between these serum factors was studied in patients with amyloidosis and patients with amyloidosis and patients with altered albumin synthesis and/or distribution. AADP activity correlated positively with albumin levels in patients with rheumatoid arthritis complicated by amyloidosis. A weaker association was noted between serum activity and prealbumin levels. The AADP activity in patients with rheumatoid arthritis without signs of amyloidosis and patients with liver cirrhosis was also positively associated with serum albumin level. During the acute-phase reaction after surgery serum AADP activity fell in parallel with serum albumin level. Purified albumin preparations displayed AADP activity. The results show that serum albumin level reflects AADP activity. It is suggested that the development of hypoalbuminaemia in patients with amyloidosis may give rise to a vicious circle which leads to an accelerated reduction in AADP activity and accelerated amyloidogenesis.

Early Rise in Serum Concentration of Transferrin Receptor Induced by Recombinant Human Erythropoietin in Very-Low-Birth-Weight Infants

ABSTRACT: The serum transferrin receptor (TfR) level reflects iron status and the rate of erythropoiesis. This study was undertaken to assess the role of serum TfR in the iron status and erythropoiesis in very-low-birth-weight infants under conditions in which erythropoiesis is stimulated by large doses of recombinant human erythropoietin (rHuEPO) and oral iron. The first 34 infants were followed from the 3rd to 11th wk of life or until discharged. They received iron at a rate of 3 mg/kg/d. The subsequent 21 infants were given rHuEPO (300 U/kg three times a week s.c.) and iron at a rate of 6 mg/kg/d from the 3rd or 4th wk of life for a mean of 3.4 wk. With this treatment, the need for transfusion was reduced from 1.4 ± 0.4 to 0.1 ± 0.1 transfusions per infant (p = 0.02). The serum TfR concentrations in the rHuEPO-treated infants increased gradually to values several-fold higher than those in the untreated infants. This increase was not related to intrauterine or postnatal growth, protein intake, or serum albumin concentration. Neither was an association observed between Hb and TfR concentration. In the treated infants, the serum ferritin concentration was lower at the 4th, 5th, and 7th wk of life than in the untreated infants. The very-low-birth-weight infants who were given large doses of rHuEPO and iron had a marked rise in serum TfR concentration and a small decline in serum ferritin concentration. These events have been related to iron deficiency.

DEMONSTRATION OF TISSUE 90 kD GLYCOPROTEIN AS ANTIGEN IN CIRCULATING IgG IMMUNE COMPLEXES IN DERMATITIS HERPETIFORMIS AND COELIAC DISEASE

Mannose-rich 90 kD glycoprotein, a constituent of skin and small-bowel mucosa, was identified as antigen in circulating IgG-type immune complexes in dermatitis herpetiformis and coeliac disease by means of an enzyme-linked immunosorbent assay. High levels of 90 kD glycoprotein-IgG complexes were found in 7 out of 12 patients with dermatitis herpetiformis and in 10 out of 20 patients with coeliac disease but in only 2 out of 20 patients with systemic lupus erythematosus. The highest levels of 90 kD antigen-IgG complexes were found in patients with dermatitis herpetiformis. The amount of these complexes did not correlate with the degree of jejunal villous atrophy. The 90 kD glycoprotein-containing immune complexes with targets in skin and gut may be involved in the pathogenesis of dermatitis herpetiformis and coeliac disease.

Correlation Between the Severity of Infectious Diseases in Children and the Ratio of Serum Amyloid A Protein and C-reactive Protein

The aim of this study was to assess whether measurements of serum amyloid A protein (SAA) could provide additional information on the severity of acute infection beyond that obtained from C-reactive protein (CRP) assays. The SAA and CRP concentrations were analysed from the sera of 334 children hospitalized for suspected pneumonia, meningitis or sepsis. SAA significantly correlated with CRP (r = 0.682, p < 0.001) and did not alone provide any further clinically useful information. By contrast, the median ratio (and interquartile range) of SAA to CRP varied significantly between clinical conditions of different severity and was significantly lower in the patients who died [1.9 (0.0-8.9)] than in those who survived [6.8 (3.2-13.6)] (p = 0.001).

Serum tumor necrosis factor does not correlate with changes in muscle volume in children with malignancies.

This study examined the connection between serum tumor necrosis factor (TNF) concentration and the development of cachexia in 12 children with acute lymphoblastic leukemia (ALL). The changes in muscle thickness were used as criteria for malnutrition, estimated by an ultrasound method during the 16 weeks of chemotherapy subsequent to diagnosis. Serum TNF concentrations were elevated at diagnosis and gradually decreased toward the reference limits by week 16. There was no correlation between TNF and muscle thickness. The results were also compared to those obtained from 8 children with other malignancies in whom the mean relative weight remained below normal whereas in those with ALL it gradually increased to +15%. Thus, we found no evidence of the association between elevated serum TNF concentrations and cachexia in man.

Increased Serum Neutral Endopeptidase Activity in Acute Renal Allograft Rejection

Neutral endopeptidase (EC 3.4.24.11; NEP), originally isolated from renal tubular brush border, is a cell surface peptidase identical to the CD10 antigen (or CALLA; common acute lymphoblastic leukemia antigen) in lymphoid cells. We studied the serum NEP levels daily after transplantation (Tx) in 19 renal allograft recipients. The NEP activity was determined with a two-step enzymatic assay utilizing a fluorogenic substrate (Suc-Ala-Ala-Phe-AMC; see text) and related to clinical signs of graft rejection, to signs of immunoactivation in transplant fine-needle aspiration biopsy (FNAB) specimens, to renal function, and to serum levels of C-reactive protein. The serum NEP levels remained normal (peak level 10.3 +/- 1.8 micrograms/l on days 6-9 after Tx, initial level after Tx 7.3 +/- 1.4 micrograms/1 on day 2; mean values +/- SEM) in patients who neither showed clinical signs of rejection nor had findings of immunoactivation in FNAB samples. On the contrary, the serum NEP levels rose clearly in patients developing acute rejection verified clinically and in FNAB samples (peak value 90.4 +/- 18.7 micrograms/l on days 6-9 post-Tx; p < 0.001 compared with patients without sings of immunoactivation) and even in patients having immunoactivation in FNAB without clinical evidence of rejection (108.2 +/- 22.4 micrograms/l, p < 0.001). Serum NEP peak appeared 2-3 days before clinical diagnosis of rejection and a positive findings in FNAB samples. Serum NEP increments did not correlate with changes in serum creatinine, delayed onset of renal excretory function, blood leukocyte count, C-reactive protein level, or infections. Thus, the serum NEP activity was shown to increase after renal allotransplantation associated with early phases of immunoactivation and development of acute graft rejection. Because of the limited number of patients studied, the clinical implications of these preliminary observations for kidney transplant monitoring clearly need confirmation in larger studies.

Potentially detrimental effects of N-acetylcysteine on renal function in knee arthroplasty

Ischaemia/reperfusion induces systemic inflammation and oxidative stress and thereby remote organ injury in the kidney. In a double-blind, placebo-controlled clinical trial of 30 patients undergoing knee arthroplasty with tourniquet, this study evaluated the effect of N-acetylcysteine (NAC) infusion on renal function by measuring urine alpha-1-microglobulin, N-acetyl-beta-D-glucosaminidase (NAG), glutathione-S-transferase-alpha and -phi and serum creatinine and cystatin C concentrations up to 24 h post-operatively. Compared to the baseline, urine alpha-1-microglobulin/creatinine increased in both groups and was higher in the NAC group than in the placebo group at tourniquet deflation and at 3 h thereafter. Urine NAG/creatinine increased at deflation and at 3 h thereafter in the NAC group and the ratio was higher than in the placebo group. The two sensitive indicators of proximal tubular damage and function used in the present study suggest that use of NAC in clinical setting of ischaemia/reperfusion injury may increase the risk of remote kidney injury.