Malaria in the southern sanitary district of Dakar (Senegal). 2. Entomologic data]

This study aimed to investigate the cause of persistently increased serum gastrin concentration seen in some Graves' disease patients even when euthyroid during antithyroid drug treatment. The subjects studied consisted of three groups: 33 patients with a common-type of Graves' disease, 14 with triiodothyronine (T3)-predominant Graves' disease (characterized from previous studies as having potent immunologic abnormalities including greater concentrations of thyroid-stimulating antibodies together with larger goiter size), and a group of 20 normal subjects. Fasting serum gastrin concentrations in common Graves' disease patients were significantly higher than those of normal subjects (58.4 +/- 38.9 pmol/L vs. 37.8 +/- 18.9 pmol/L [mean +/- SD], p < 0.05). The serum gastrin concentrations were even greater in T3-predominant Graves' disease patients than common Graves' disease patients (162.9 +/- 224.0 pmol/L vs. 58.4 +/- 38.9 pmol/L, p < .05). Serum pepsinogen I (PGI) concentrations were significantly lower in the T3-predominant patient group than the common Graves' group (24.0 +/- 12.9 ng/mL vs. 39.7 +/- 19.6 ng/mL, p < .05). Serum ratios of PG I to PG II were significantly lower in the T3-predominant Graves' disease patients than normal subjects (3.59 +/- 2.66 vs. 5.97 +/- 1.56, p < .01). The ratios also had a significant (p < .05) inverse correlation with serum gastrin concentrations in T3-predominant Graves' disease patients. The results suggest that autoimmune gastritis is associated with Graves' disease, particularly in patients with potent thyroid-autoimmunity.     

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.     

Cytokines in leprosy, II. Effect of treatment on serum cytokines in leprosy

BACKGROUND: Leprosy is a chronic infectious disease characterized by a broad spectrum of clinical forms depending on the patient's immune response, in particular cell-mediated immune response. METHODS: Cytokines can play a role in the cell-mediated immune response. Serum levels of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), interleukin-2 receptor (IL-2R), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were measured by enzyme-linked immunosorbent assay (ELISA) in 55 untreated leprosy patients and 35 reactional leprosy patients, in addition to 20 age- and sex-matched healthy controls. RESULTS: Leprosy patients showed significantly higher serum levels of the studied cytokines (except IL-2) compared with healthy controls. When the two poles were compared, tuberculoid leprosy (TT) patients showed significantly higher levels of IFN-gamma and TNF-alpha with significant negative correlations with the bacterial index (BI), whereas lepromatous leprosy (LL) patients showed significantly higher serum levels of IL-2R, IL-10, and IL-1beta with significant positive correlations with the BI. Both type I and type II reactional patients showed significantly higher serum IFN-gamma, IL-2R, and IL-1beta, in addition to IL-10 in type II reactional patients, compared with nonreactional leprosy patients. When compared with each other, type I reactional patients showed increased levels of IFN-gamma, whereas type II reactional patients showed increased levels of IL-10. CONCLUSIONS: In leprosy patients, both IFN-gamma and TNF-alpha are immunoprotective, whereas IL-2R, IL-10, and IL-1beta are immunosuppressive. Our results indicate that type I reaction, with increased levels of IFN-gamma, is a cell-mediated immune response, whereas type II reaction, with increased levels of IL-10, is essentially an immune complex disease.     

Interactions with the pharmaceutical industry: experiences and attitudes of psychiatry residents, interns and clerks

Alteration in leukocyte activation has been implicated as an etiological factor in the development of chronic venous stasis ulcers (CVSU). The purpose of this study was to determine differences in expression of cell surface activation markers on circulating leukocytes and systemic, soluble, serum cytokine levels between healthy controls and patients with CVSU. Twenty-three patients were separated into two groups. Group I consisted of 12 healthy, adult, age-matched male patients with no venous disease. Group II consisted of 11 adult male patients with CVSU who underwent air plethysmography (APG) and duplex scanning to determine the severity of venous insufficiency. All patients had measurements of systemic, serum-based, soluble IL-1 beta, IL-2, IL-6, TNF-alpha, and beta 2 microglobulin levels. Using fluorescence flow cytometry, we measured the percentage of lymphocytes (CD3), monocytes (CD14), and granulocytes (CD15) expressing various cell surface activation markers. By APG and duplex scan, all group II patients exhibited venous insufficiency, with a mean venous filling index of 6.9 +/- 3.9 sec. Relative to group I, group II patients demonstrated a decreased expression of the CD3+/DR+ (13.3 +/- 1.5, P < or = 0.01) and CD3+/CD38+ (31.1 +/- 2.1, P < or = 0.04) markers on T-lymphocytes and an increased expression of CD14+/CD38+ (99.6 +/- 0.2, P < or = 0.008) markers on monocytes. Circulating neutrophils showed no evidence of activation. In addition, a significant elevation in the T-helper to T-suppressor ratio (2.9 +/- 0.6, P < or = 0.0001) between groups I and II was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular executors of cell death--differential intrarenal expression of Fas ligand, Fas, granzyme B, and perforin during acute and/or chronic rejection of human renal allografts

BACKGROUND: Changes in peripheral thyroid hormone concentration and metabolism can occur in euthyroid patients suffering from severe non-thyroidal illnesses. Recently, sick euthyroid syndrome has been reported in patients suffering from advanced heart failure. AIM: This study was to evaluate prospectively the presence and pathophysiological implications of sick euthyroid syndrome in moderate-to-severe chronic heart failure patients. METHODS: The study population were 199 chronic heart failure patients admitted over a 2-year period to our heart failure unit for assessment of cardiac transplantation. They were closely followed up with clinical and instrumental examinations (including clinical, hormonal, nutritional and cardiac function evaluations). Sick euthyroid syndrome was defined as a serum total triiodothyronine value of less than the lowest normal limit (< 1.23 nmol.l-1) in the presence of a normal serum thyroid stimulating hormone concentration. RESULTS: Sick euthyroid syndrome was found in 36/199 patients (18%). According to the New York Heart Association (NYHA) classification of severity of heart failure, sick euthyroid syndrome patients appear in higher NYHA classes (31% of classes III and IV, vs 7% of class I and II). Such patients also weigh less and are more frequently malnourished. Alterations in cardiac index, ventricular filling pressures, functional impairment, and the liver function parameters, were more significant in sick euthyroid syndrome than in non-sick euthyroid syndrome patients. Serum norepinephrine and atrial natriuretic factor were significantly higher, and insulin significantly lower in the sick euthyroid syndrome group. During follow-up, deaths were significantly more frequent in sick euthyroid syndrome patients (13/27, 48%) than in non-sick euthyroid syndrome (30/141, 21%; P < 0.005). In six sick euthyroid syndrome patients who underwent heart transplantation, mean total triiodothyronine values increased from 0.9 +/- 0.1 before to 1.96 +/- 0.3 nmol.l(-1)post-transplantation (P < 0.05). CONCLUSIONS: In a large and representative population of patients with moderate-to-severe heart failure, sick euthyroid syndrome shows a prevalence of 18%. Its occurrence was related to the degree of functional cardiac impairment, but was not an independent negative prognostic factor. Preliminary results indicate that heart transplantation is associated with reversibility of sick euthyroid syndrome.     

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.     

Abnormal expression of a 170-kilodalton P-glycoprotein encoded by MDR1 gene, a metabolically active efflux pump, in CD4+ and CD8+ T cells from patients with human immunodeficiency virus type 1 infection

Peripheral blood CD4+ and CD8+ T cells from 16 patients with HIV-1 infection, 8 each with CD4+ T cell counts of > 200/mm3 (group I) and with CD4+ T cell counts of < 200/mm3 (group II), and 8 age- and sex-matched controls, were examined for the expression of P-glycoprotein (P-gp), a 170-kDa phosphoglycoprotein encoded by the MDR1 gene, using dual-color flow cytometric analysis. The function of P-glycoprotein was assessed by the accumulation of rhodamine-123 (Rh123) dye in the presence or absence of cyclosporin A (which inhibits Rh123 efflux). A significantly increased proportion of CD4+ T cells from patients with HIV-1 infection expressed P-glycoprotein as compared to controls, resulting in a significantly increased ratio of the proportions of CD4+P-gp+/CD8+P-gp+ cells. The ratio of CD4+P-gp+/CD8+P-gp+ in group II patients was significantly higher (p = 0.02) than in group I patients, suggesting a progressive increase in P-gp expression with the advancement of HIV-1 infection. The proportions of CD4+P-gp+ and CD8+P-gp+ T cells did not differ significantly between those who received AZT and those who were not treated with AZT. Contrary to expectation, both CD4+ and CD8+ T cells from patients accumulated significantly more Rh123 as compared to controls. Furthermore, cyclosporin A failed to increase intracellular accumulation of Rh123 in CD4+ and CD8+ T cells from patients. These data suggest a functionally defective P-gp expression in HIV-1 infection that appears to increase with the progression of HIV-1 infection. A study of a large number of patients with HIV-1 infection is needed to determine the effects of opportunistic infection and antiretroviral therapy on the expression of P-gp and to determine whether the expression of P-gp could serve as another surrogate marker for the progression of HIV-1 infection.     

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.     

Do increased lipoprotein(a) levels in euthyroid autoimmune thyroid diseases predict an increased risk of arteriosclerosis?

Elevated serum levels of lipoprotein(a) [Lp(a)] represent an independent risk factor in the development of arteriosclerosis and coronary heart disease. In overt but also in subclinical hypothyroidism a reversible increase of Lp(a) occurs. We compared Lp(a) serum levels, cholesterol, triglyceride, HDL- and LDL-cholesterol in 19 hypothyroid patients prior to and following the state of euthyroidism (group 1). On the other hand in group 2 we investigated 20 euthyroid patients having elevated thyroid antibodies as against 50 euthyroid normolipemic control subjects without detectable thyroid antibodies. Group 1: The elevated Lp(a) serum levels of the hypothyroid patients decreased significantly in the euthyroid state (37.9 +/- 8.24 vs. 28.1 +/- 6.13 mg/dl, mean +/- SEM). Group 2: The mean Lp(a) serum levels of the patients with increased thyroid antibodies were significantly higher than those of the control group (24.8 +- 5.78 vs. 9.6 +/- 1.56 mg/dl, mean +/- SEM). In other parameters of lipid metabolism and thyroidal function no significant differences between both groups could be seen. The question arises whether such isolated Lp(a) elevation will lead to an increased arteriosclerotic risk. To minimize this possible risk regular controls of thyroid function should be carried out in euthyroid patients with elevated thyroid antibodies. In this way hypothyroidism may be detected and treated at an early stage.     

Plasma lipoprotein(a) levels in patients with hyperthyroidism

Thyroid function and regulation were studied in 14 consecutive male outpatients with asymptomatic human immunodeficiency virus (HIV) infection (CDC II/III, n = 8) or AIDS (CDC IV, n = 6) who were free of concomitant infections and hepatic dysfunction, and in eight healthy, age- and weight-matched male controls. Blood was sampled every 10 minutes over 24 hours for measurement of thyrotropin (TSH). Thereafter, thyroid hormones and TSH responsiveness to thyrotropin-releasing hormone (TRH) were measured. Triiodothyronine (T3) and thyroxine (T4) did not differ between HIV-infected patients and controls, but HIV patients had lower thyroid hormone-binding index ([THBI] HIV patients, 1.01 +/- 0.02; controls, 1.11 +/- 0.03; P < .02), free thyroxine (FT4) index (94 +/- 3 v 110 +/- 4, P < .01), FT4 (11.8 +/- 0.4 v 14.3 +/- 0.4 pmol/L, P < .01), and reverse triiodothyronine (rT3) values (0.18 +/- 0.01 v 0.26 +/- 0.02 nmol/L, P < .001) and higher thyroxine-binding globulin ([TBG] 20 +/- 1 v 16 +/- 1 mg/L, P < .02) values. Mean 24-hour TSH levels were increased in HIV patients (2.39 +/- 0.33 v 1.44 +/- 0.16 mU/L, P < .05), associated with increased mean TSH pulse amplitude and TSH responsiveness to TRH. No differences were observed between asymptomatic HIV-seropositive and AIDS patients. In conclusion, there is a hypothyroid-like regulation of the pituitary-thyroid axis in stable HIV infection, which differs distinctly from the euthyroid sick syndrome in non-HIV-nonthyroidal illnesses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Daily variation in circulating cytokines and acute-phase proteins correlates with clinical and laboratory indices in community-acquired pneumonia

Our objective was to investigate the initial levels of circulating proinflammatory cytokines, such as interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), and tumour necrosis factor alpha (TNF-alpha), of certain acute-phase proteins, such as C-reactive protein (CRP), fibrinogen (FBN) and albumin, and of the glycoprotein fibronectin at presentation and their daily variation during the clinical course of community-acquired pneumonia (CAP) in relation to clinical and laboratory indices of infection. Thirty otherwise healthy hospitalized patients aged 48 +/- 3 years (mean +/- SEM) and with bacteriologically confirmed CAP were studied prospectively. IL-1 beta and IL-6 were found to be 15-fold higher on admission (122 +/- 9 pg mL-1 and 60 +/- 4 pg mL-1 respectively), whereas TNF-alpha was three-fold higher (102 +/- 5 pg mL-1) than those of controls, all of them showing a decline towards normal. Initial CRP levels were increased 90-fold (416 +/- 1 mg L-1), whereas fibronectin levels were reduced (242 +/- 9 mg dL-1). The presence of parapneumonic effusion was associated with a higher TNF-alpha serum level (127 +/- 7 vs. 86 +/- 4 pg mL-1, P = 0.0002), a more rapid daily decline in TNF-alpha (-7.2 +/- 0.7 vs. -3.8 +/- 0.5 pg mL-1 day-1, P = 0.0005), a slower rate of decline in CRP (-42.8 +/- 3.0 vs. -54.6 +/- 3.0 mg L-1 day-1, P = 0.02) and a slower rate of increase in FBN (5.9 +/- 1.0 vs. 11.7 +/- 1.0 mg dL-1 day-1), P = 0.001]. Furthermore, daily progression of serum levels of cytokines and acute-phase proteins correlated strongly with pyrexia, erythrocyte sedimentation rate (ESR), neutrophil count, alveolar-arterial oxygen difference and radiographic resolution, clinically manifested by improvement in the patients' condition.     

Plasma tumor necrosis factor-alpha, its soluble receptors and interleukin-1beta levels in critically burned patients

Levels of plasma TNF-alpha, interleukin-1beta(IL-1beta ), soluble TNF-receptor I (sTNF-R I) and soluble TNF-receptor II (sTNF-R II) were determined in 16 critically burned patients. Seven of the 16 patients showed hypovolemic shock (shock group), 9 with sepsis (sepsis group), 8 with multiple organ dysfunction syndrome (MODS group) and 6 of them died (non-survival group). Plasma TNF-alpha, sTNF-R I and R II were significantly higher in the shock group, the MODS group and the non-survival group than each of the control groups. TNF-alpha and sTNF-Rs increased gradually in the MODS group and the non-survival group from 1 to 5 days postburn. TNF-alpha, sTNF-R I and R II correlated positively with Goris' multiple organ failure score. Molecular sTNF-Rs/TNF-alpha ratios were lower in the sepsis group than in the non-sepsis group. These results suggest that circulating TNF and soluble TNF receptors system play an important role in the development of burn shock and MODS; high molecular ratios of endogenous sTNF-Rs might not reduce the morbidity of MODS and the mortality in critically burned patients.     

HIV-1 gp120 modulates hypothalamic cytokine mRNAs in vivo: implications to cytokine feedback systems

HIV-1-derived envelope glycoprotein 120 (gp120) may play an important role in HIV-1 neuropathology. Gp120 may act through mediators including proinflammatory cytokines. Here, we investigated the regulation of the IL-1 beta system [IL-1 beta, IL-1 receptor type I (IL-1RI), IL-1 receptor antagonist (IL-1Ra), IL-1 receptor accessory proteins (IL-1R AcP I and II)], TNF-alpha, TGF-alpha, and TGF-beta 1 mRNAs in the hypothalamus of Wistar rats in response to the chronic intracerebroventricular (ICV) microinfusion (via osmotic minipumps) of HIV-1 gp120 (100, 500, and 1000 ng/24 h for 72 h). Gp120 increased IL-1 beta, IL-1Ra, TNF-alpha, and TGF-beta 1 mRNAs. Gp120-induced cytokine mRNA profiles were highly intercorrelated in the same samples. Levels of IL-1RI, IL-1R AcP I and II, and TGF-alpha did not change significantly, and levels of GAPDH mRNA were constant. The data suggest potential cytokine-cytokine interactions with positive (IL-1 beta<-->TNF-alpha) and negative (IL-1Ra-->IL-1 beta; TGF-beta 1-->IL-1 beta/TNF-alpha) feedback in gp120 action. A dysregulation of the balance between stimulatory and inhibitory cytokine mechanisms may participate in the initiation, propagation, and/or aggravation of HIV-1 neuropathology.     

Immunoglobulin- and hepatitis B surface antigen-specific circulating immune complexes in chronic hepatitis B virus infection

24 consecutive AIDS patients with wasting, and who had never received anabolic therapies, were evaluated to determine their profile of sex hormones and whether transformation of testosterone (T) to the nuclear androgen, dihydrotestosterone (DHT), was impaired. Eleven (46%) patients had normal testosterone and DHT (group I), 10 (42%) had normal testosterone but low DHT (group II), and 3 (12%) had low testosterone and low DHT (group III). Age, prior opportunistic complications, symptoms, serum albumin, hemoglobin levels, and CD4 lymphocyte counts were similar in the groups. DHT was significantly lower (22.2 +/- 6.8 microg/dl) in group II compared with group I (50.8 +/- 15.3 microg/dl). The ratio of T/DHT, a measure of the conversion of testosterone to DHT, in group I was 15.1 +/- 3.5, which was within the range for eugonadal young men. In group II, the ratio was 22.3 +/- 1.5, indicating a defect in generation of DHT. Patients in group II had lost 9.2 +/- 3.5 kg compared with 5.6 +/- 2.6 kg in group I (p = .015). Thus, a syndrome of low DHT with normal testosterone was associated with significantly greater weight loss than in patients with normal testosterone and DHT. Further studies are needed to clarify whether low DHT is a result of AIDS wasting or is causally related to weight loss and whether androgen therapy in the form of DHT could reverse some of the metabolic changes associated with AIDS wasting.     

Serum beta-2 microglobulin is a marker of high bone remodelling in elderly women

Beta-2 microglobulin (beta2m), the water soluble extrinsic light chain of class I MHC, has been recently isolated from the adult bone culture medium. Serum beta2m plays a role as a bone-derived growth factor regulating both osteoblast and osteoclast cell activity. Serum beta2m has been proposed as a bone remodeling biological marker in high bone turnover conditions. The purpose of our study was to determine the relationship between beta2m and vitamin D status in post-menopausal women. We have studied 44 healthy women from 20 to 80 years with normal hepatic and renal function, without diabetes mellitus and/or inflammatory, tumoral or infectious diseases. We measured the serum levels of calcium, phosphorus, parathyroid hormone (PTH), vitamin D binding protein (DBP), 25-OHD3 (calcidiol), 1,25(OH)2D3 (calcitriol) and beta2m. Serum beta2m levels increased with age (r = 0.54, P < 0.001). Post-menopausal women had higher serum levels than pre-menopausal women of beta2m (1.76 +/- 0.22 mg/l vs. 1.35 +/- 0.2 mg/l, P < 0.01); PTH (61.5 +/- 7.5 ng/ml vs. 39 +/- 6 ng/ml, P < 0.001) and lower serum levels of 25-OHD3 (7.5 +/- 2.3 ng/ml vs. 18.2 +/- 2.5 ng/ml, P < 0.001). Moreover, serum levels of beta2m were negatively correlated with 25-OHD3 (r = -0.34, P < 0.05) and with ionized calcium (r = -0.45, P < 0.01) and positively with PTH (r = 0.48, P < 0.01). These results support the role of beta2m as a regulator of bone metabolism and its potential use as a marker of high bone turnover in post-menopausal women, specially in elderly women with vitamin D deficiency and secondary hyperparathyroidism.     

Soluble interleukin-1 receptor antagonist serum levels in smokers and nonsmokers with Graves' ophthalmopathy undergoing orbital radiotherapy

Interleukin-1 (IL-1) plays an important role in the pathogenesis of Graves' ophthalmopathy (GO). Impaired antagonism of the proinflammatory cytokine IL-1 by the naturally occurring IL-1 receptor antagonist (IL-1RA) has been implicated in the initiation and perpetuation of various autoimmune diseases and may play a role in the evolution of GO. Cigarette smoking appears to adversely affect the course of GO. We have evaluated the course of IL-1 alpha, IL-1 beta, and soluble IL-1RA (sIL-1RA) serum levels in smokers and nonsmokers with GO undergoing orbital radiotherapy (OR). We prospectively studied the eye status of 27 randomly selected patients (mean age 47.3 +/- 11.0 yr; 20 females; 18 smokers) with active, moderately severe GO before and 3 and 6 months following OR, respectively. None had received any previous treatment for GO, and all patients were kept euthyroid on carbimazole. Serum concentrations of IL-1 alpha, IL-1 beta, and sIL-1RA were measured using highly sensitive enzyme linked immunosorbent assay systems. Baseline sIL-1RA levels were negatively correlated with the number of cigarettes smoked before and following OR (P < 0.0001). Patients with no or minor therapeutic response to OR (n = 8), all of whom were smokers, revealed mean baseline sIL-1RA levels of 114 +/- 85 pg/mL, which increased to 172 +/- 103 pg/mL at 3 months and 149 +/- 96 pg/mL at 6 months after initiation of OR, respectively. By contrast, patients with a good clinical response (n = 19, 9 nonsmokers), revealed significantly higher baseline sIL-1RA levels at 294 +/- 148 pg/mL (P = 0.004), which increased to 845 +/- 668 pg/mL at 3 months (P = 0.01) and 634 +/- 337 pg/mL at 6 months (P < 0.001), respectively, following initiation of OR. Serum concentrations of IL-1 alpha IL-1 beta were below 3.9 pg/mL in all patients with GO who were studied, and were not correlated with gender, age, smoking status, clinical course, or outcome. Low baseline levels and impaired surge of sIL-1RA serum levels following OR were strongly correlated with smoking status and a less favorable therapeutic outcome in patients with active, moderately severe GO. Measurement of sIL-1RA may contribute to predict the therapeutic response to OR in patients with active, moderately severe GO. Strategies designed to raise local or systemic concentrations of sIL-1RA may be of benefit to patients with GO.     

The effects of thyroid hormone modulation on rat liver injury associated with ischemia-reperfusion and cold storage

We investigated the effects of thyroid hormone modulation on liver injury associated with ischemia-reperfusion (I-R) and cold storage in rats. First, euthyroid and thyroxine (T4)-pretreated rats were exposed in vivo to 20-min global liver ischemia, then 30-min reperfusion. Liver injury was assessed by measuring serum alanine aminotransferase (ALT) levels. Liver concentrations of adenine nucleotides, reduced glutathione (GSH), and oxidized glutathione were evaluated. Second, rats were given the antithyroid drug propylthiouracil (PTU). Livers stored at 0-1 degrees C in Euro-Collins' solution for 20 h were reperfused at 37 degrees C for 15 min. Lactate dehydrogenase (LDH) in the effluent perfusate and bile flow were evaluated during reperfusion. Serum ALT levels increased after ischemia and I-R. ALT increased significantly more in T4-pretreated than in euthyroid rats after ischemia and I-R. Preischemic levels of adenosine triphosphate (ATP) were significantly lower in livers from T4-pretreated than in euthyroid rats (6.22 +/- 0.7 and 11 +/- 0.9 nmol/mg protein, respectively; P < 0.05). After ischemia, liver ATP was similarly reduced in T4-pretreated and euthyroid rats. After reperfusion, ATP partially recovered in euthyroid rats but remained low in T4-pretreated rats (6.7 +/- 1.0 and 1.91 +/- 0.7 nmol/mg protein, respectively; P < 0.05). Preischemic levels of liver GSH decreased to 44% in T4-pretreated rats. After ischemia, GSH decreased similarly in euthyroid and T4-pretreated rats. GSH recovered promptly after reperfusion in euthyroid rats but remained low in T4-pretreated rats (13.9 +/- 3.3 and 3.9 +/- 0.9 nmol/mg protein, respectively; P < 0.02). During reperfusion after cold storage, LDH in effluent perfusate was significantly lower and bile flow higher in livers from PTU-pretreated rats than from euthyroid rats. The histopathological changes observed after I-R and cold storage confirmed the biochemical findings. Our results suggest that T4 administration exacerbates pretransplant liver damage by increasing liver susceptibility to I-R, whereas PTU administration reduces the liver injury associated with cold storage. Implications: We studied the effects of thyroid hormone modulation on liver injury associated with ischemia-reperfusion and cold storage in rats. Thyroxine administration increased susceptibility to ischemia-reperfusion injury, whereas the antithyroid agent propylthiouracil reduced the deleterious effects associated with cold storage.     

Improved and effective assays of the glutamic oxaloacetic transaminase by the coenzyme-apoenzyme system (CAS) principle

257 patients have been reviewed 1-5 years (mean 3 years 2 months) after receiving one of five dose regimes of 125I for thyrotoxicosis. The cumulative incidence of hypothyroidism was 34% and of persistent thyrotoxicosis 17%. The group receiving doses between 351 and 500 muCi/g had the highest proportion of euthyroid patients (65%) with the lowest requirement for repeat therapy (46%). In the euthyroid patients, increasing dose of 125I was associated with progressive decline in mean thyroxine (T4) level and free thyroxine index (FTI) within the respective normal ranges, and increase in mean thyroid stimulating hormone (TSH) level to above the normal range. Euthyroid patients with elevated TSH levels had significantly lower T4 and FTI values compared with those with normal TSH, and showed a 3-4-fold increased rate of development of hypothyroidism over 1 year. Euthyroid patients with elevated T3 levels remained euthyroid during the subsequent year and mean T3 levels declined significantly, suggesting that abnormally elevated T3 levels after 125I do not generally indicate impending relapse of thyrotoxicosis. It is concluded that the potential admantages of 125I therapy for thyrotoxicosis in reducing the incidence of hypothyroidism have not been realized in practice.     

Accelerated evolution of cytochrome b in simian primates: adaptive evolution in concert with other mitochondrial proteins?

We have devised a practical, sensitive and specific method for simultaneous measurement of free thyroxine (FT4) and free triiodothyronine (FT3) in undiluted serum by direct equilibrium dialysis radioimmunoassay (RIA). Two hundred microliters serum sample was dialyzed against buffer (pH 7.4) for 20 hours at 37 degrees C and approximately 800 microL of the dialysate was used for measuring FT4 and FT3 simultaneously. The assay was set up in polystyrene tubes coated with anti-T4 antibody and available commercially for FT4 measurement (Quest-Nichols Institute, San Juan Capistrano, CA). The mean +/- SE (range) FT4 concentration (ng/dL) was 1.2 +/- 0.04 (0.7.0 to 2.30) in 54 normal subjects. It was significantly increased (3.6 +/- 0.4 [1.8 to 9.6], n = 20) in hyperthyroidism and clearly decreased (0.40 +/- 0.04 [1.10 to 0.70], n = 26] in hypothyroidism. All nonthyroid illness (NTI) patients had normal FT4 except 3, 2 of whom were on amiodarone and 1 had received heparin. Serum FT4 concentration was minimally elevated in 18 newborn cord blood serum (1.40 +/- 0.08 [0.90 to 2.2], cf. normal p < .05). The mean serum FT3 concentration (pg/dL) was 285 +/- 10 (134 to 454) in 54 normal sera. It was clearly increased in hyperthyroidism (1033 +/- 98 [593 to 2134], n = 20, p < .001). However, serum FT3 varied widely in hypothyroidism (27 to 597, mean 235 +/- 24, NS) as did serum total T3 (19 to 175). Interestingly, however, the mean serum FT3 concentration was normal (273 +/- 28 [62 to 575, NS]) in 25 NTI patients. All of these patients had low serum total T3 (46 +/- 5.0 [10 to 84], ng/dL; normal 84 to 160, p < 0.001), while FT3 was clearly normal in 21 of 25 patients and low in the remaining 4 patients. Similarly, among 18 newborn cord blood sera serum FT3 concentration was normal in 15 and subnormal only in the remaining 3 while all had clearly subnormal total T3 (28 to 74 ng/dL). CONCLUSIONS: (1) A practical, sensitive, and specific assay for simultaneous measurement of FT4 and FT3 is described; (2) FT3 is consistently elevated in hyperthyroidism while FT4 is elevated in most (approximately 85%) cases; (3) FT4 is consistently decreased in hypothyroidism but FT3 varies widely; (4). Serum FT3 concentration is normal in approximately 83% of patients with the low T3 syndrome in NTI and newborn cord blood serum. These data suggest that normal FT3 may explain clinical euthyroidism in many patients with the low T3 syndrome.     

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.