Interferon-gamma administration does not affect human thyroid hormone metabolism in the post-surgical euthyroid sick syndrome.

Cytokines are thought to be involved in the pathogenesis the euthyroid sick syndrome. Experimental data from in vitro and animal in vivo studies suggest that interferon-gamma (IFN-gamma) could be another cytokine that might influence thyroid hormone metabolism, although in a previous study in healthy subjects we could not demonstrate an effect of IFN-gamma on thyroid hormone indices. Possibly, however, a non-stressed system is not a representative environment to study the effects of a mediator, which might exert its role during pathological circumstances in which it may interact synergistically with other inflammatory mediators. Therefore, we studied the effects of a single dose of recombinant human IFN-gamma (Immukine, 100 microg/m2, sc) on thyroid hormone concentrations in a placebo-controlled trial in 13 major surgery patients. Basal IFN-gamma levels did not increase. IFN-gamma induced a significant increase in monocyte HLA-DR expression (post-operative 50%; 24 h after IFN-gamma 90%), but did not affect thyroid hormone and thyroid stimulating hormone concentrations. We therefore conclude that IFN-gamma does not appear to be involved in the major changes in thyroid hormone metabolism in patients with non-thyroidal illness.

Interferon-gamma administration after abdominal surgery rescues antigen-specific helper T cell immune reactivity.

Antigen-induced activation of T cells is determined by many factors. Among these factors are (i) the number of T-cell receptors (TCRs) triggered by TCR ligands on antigen-presenting cells (APCs), and (ii) the intrinsic cellular threshold for activation. T-cell receptor triggering is optimized by adhesion molecules that form the interaction site between T cells and APCs, i.e. the immunological synapse. In addition, signals through co-stimulatory molecules lower the intrinsic T-cell activation threshold. Immunosuppressive agents and traumatic events such as major operative procedures change physiological T-cell responses. Depressed immune functions after surgery are presumed to render patients more susceptible to pathogens. Interferon-gamma (IFNgamma) is a type II homodimeric cytokine with multiple immunostimulatory properties. Several studies have been performed to assess the effects of IFNgamma treatment in patients in need of increased immune reactivity. However, until now, the effect of IFNgamma on human antigen specific CD4(pos) T-cell reactivity after surgically-induced immunosuppression has not been reported. Therefore, a comparative trial of recombinant human (rh) IFNgamma versus placebo in patients after abdominal surgery was initiated. Antigen-specific helper T cell immune reactivity was assessed by antigen-induced cytokine production, intracellular cytokine staining and flow cytometry. A single dose of rhIFNgamma rescued down-modulation of antigen-specific CD4(pos) T-cell reactivity, concomitant with an up-regulation of TCR-ligands on antigen-presenting cells. Selected patients may benefit from the immunostimulatory properties of rhIFNgamma administration in vivo.

Interferon-gamma in healthy subjects: selective modulation of inflammatory mediators.

BACKGROUND: It is suggested that interferon-gamma (IFN-gamma), like other cytokines, is a mediator in the host inflammatory response, which could be of importance in the pathophysiology of sepsis. The role of IFN-gamma in human host inflammatory responses, however, has not been studied. DESIGN: In a placebo-controlled trial we studied the acute effects of IFN-gamma administration on host inflammatory mediators in healthy men: i.e. the cytokine/chemokine cascade system, acute-phase proteins, activation markers of the innate cellular immunity and coagulation/fibrinolysis parameters. RESULTS: IFN-gamma increased plasma levels of interleukin-6 (IL-6), IL-8 and IFN-gamma-inducible protein-10 (IP-10) (P < 0.05), but did not affect plasma levels of other cytokines (IL-4, IL-10, tumour necrosis factor-alpha, IL-12p40/p70). Plasma concentrations of C-reactive protein and secretory phospholipase A2 both increased (P < 0.05). Plasma levels of the leucocyte activation marker elastase-alpha1-antitrypsin complexes increased after IFN-gamma administration (P < 0.05), IFN-gamma increased the percentage of high-affinity Fcgamma-receptor (FcgammaRI) -positive neutrophils (P < 0.05), but did not affect the mean fluorescence intensity of FcgammaRI on neutrophils. Procoagulant and profibrinolytic effects of IFN-gamma were evidenced by increased plasma levels of prothrombin fragment F1 + F2, tissue-plasminogen activator and plasmin-alpha2-antiplasmin complexes (P < 0.05). CONCLUSION: We conclude that IFN-gamma selectively affects host inflammatory mediators in humans.

Dietary fat content alters insulin-mediated glucose metabolism in healthy men.

BACKGROUND: A high dietary fat intake is involved in the pathogenesis of insulin resistance. OBJECTIVE: The aim was to compare the effect of different amounts of dietary fat on hepatic and peripheral insulin sensitivity. DESIGN: Six healthy men were studied on 3 occasions after consuming for 11 d diets with identical energy and protein contents but different percentages of energy as fat and carbohydrate as follows: 0% and 85% [low-fat, high-carbohydrate (LFHC) diet], 41% and 44% [intermediate-fat, intermediate-carbohydrate (IFIC) diet], and 83% and 2% [high-fat, low-carbohydrate (HFLC) diet]. Insulin sensitivity was quantified by using a hyperinsulinemic euglycemic clamp (plasma insulin concentration: approximately 190 pmol/L). RESULTS: During hyperinsulinemia, endogenous glucose production was higher after the HFLC diet (2.5 +/- 0.3 micromol x kg(-1) x min(-1); P < 0.05) than after the IFIC and LFHC diets (1.7 +/- 0.3 and 1.2 +/- 0.4 micromol x kg(-1) x min(-1), respectively). The ratio of dietary fat to carbohydrate had no unequivocal effects on insulin-stimulated glucose uptake. In contrast, insulin-stimulated, nonoxidative glucose disposal tended to increase in relation to an increase in the ratio of fat to carbohydrate, from 14.8 +/- 5.1 to 20.6 +/- 1.9 to 26.2 +/- 2.9 micromol x kg(-1) x min(-1) (P < 0.074 between the 3 diets). Insulin-stimulated glucose oxidation was significantly lower after the HFLC diet than after the IFIC and LFHC diets: 1.7 +/- 0.8 compared with 13.4 +/- 2.1 and 19.0 +/- 2.1 micromol x kg(-1) x min(-1), respectively (P < 0.05). During the clamp study, plasma fatty acid concentrations were higher after the HFLC diet than after the IFIC and LFHC diets: 0.22 +/- 0.02 compared with 0.07 +/- 0.01 and 0.05 +/- 0.01 mmol/L, respectively (P < 0.05). CONCLUSION: A high-fat, low-carbohydrate intake reduces the ability of insulin to suppress endogenous glucose production and alters the relation between oxidative and nonoxidative glucose disposal in a way that favors storage of glucose.

No beneficial effect of interferon-gamma treatment in 2 human immunodeficiency virus-infected patients with Mycobacterium avium complex infection.

Two human immunodeficiency virus-infected patients with refractory disseminated Mycobacterium avium complex infection were treated with recombinant interferon-gamma (IFN-gamma) given subcutaneously for 3 and 4 months, respectively. Although both patients demonstrated some clinical improvement initially, IFN-gamma therapy did not produce sustained benefit.

Administration of interferon-gamma in healthy subjects does not modulate thyroid hormone metabolism.

Cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL-2), IL-6, and interferon-alpha (IFN-alpha), alter human thyroid hormone metabolism and may be involved in the pathogenesis the euthyroid sick syndrome. Experimental data suggest that interferon-gamma (IFN-gamma) could be another cytokine that might influence thyroid hormone metabolism. To evaluate whether IFN-gamma can be involved in the pathogenesis of the alterations in thyroid hormone metabolism in humans with nonendocrine illness, we measured thyroid hormone concentrations in six healthy volunteers during 24 hours in a placebo controlled trial: once after subcutaneous administration of IFN-gamma (Immukine, [Boehringer Ingelheim GmbH, Ingelheim/Rheim, Germany] 100 microg/m2 subcutaneous) and once after the administration of saline (control). In addition, we measured cytokine concentrations in plasma (TNF-alpha and IL-6). IFN-gamma did not induce effects on any of the measured thyroid hormone and thyroid-stimulating hormone (TSH) plasma concentrations. Moreover, IFN-gamma did not affect TNF-alpha plasma levels. Only a modest but significant elevation of plasma IL-6 levels was detected after administration of IFN-gamma (p < 0.05 vs. control). It is concluded that IFN-gamma administration to healthy humans does not result in short term alterations of thyroid hormone metabolism. These data do therefore not support a role of IFN-gamma in the pathogenesis of the euthyroid sick syndrome in humans as might be deduced from in vitro and in vivo animal studies.

Biologic responses to IFN-alpha administration in humans.

Although interferon-alpha (IFN-alpha) was discovered over 40 years ago, it was many years before it was registered as a therapeutic agent. Because of its unique qualities, it has been registered for both antiviral and antitumor indications. In addition to its therapeutic effects in viral diseases and cancer, IFN-alpha interferes with several important physiologic systems. It interacts with the immune system and affects several neuroendocrine and metabolic circuits. The specific mechanisms by which IFN-alpha exerts its therapeutic effects are complex, and it is very difficult to tie the biologic actions of IFN-alpha to specific clinical effects.

Interferon-gamma preferentially reduces memory/effector CD8 T lymphocytes in healthy subjects.

To evaluate the influence of interferon-gamma (IFN-gamma) on leukocyte dynamics, with a focus on naive and memory T cells, we studied 6 healthy subjects twice in a placebo-controlled trial: once after the administration of recombinant human IFN-gamma (rhIFN-gamma; 100 microg/m2 subcutaneously) and at least 4 weeks later, after the administration of saline solution. Additionally, we studied the expression of adhesion molecules on T lymphocytes after in vitro incubation of whole blood with rhIFN-gamma. IFN-gamma induced a significant depletion in the number of T lymphocytes (P < .05 vs control), which was more severe in the CD8+ cell subset than in the CD4+ T cell subset. The numbers of naive CD4+ T cells and memory CD4+ T cells were equally affected by IFN-gamma, whereas within the CD8+ T cell subset, memory/effector cells disappeared preferentially as compared with naive cells (P < .05 vs control). In addition, IFN-gamma induced a decrease in B cells, NK cells, and monocytes. After an initial increase, granulocyte counts decreased significantly as compared with controls. These effects appeared not to be caused by the minimal rise in plasma cortisol levels (P < .05 vs control). In vitro, IFN-gamma did not up-regulate the expression of CD11a, NKI L16, CD11b, LFA-3, or VLA-4. We conclude that the administration of a single dose of IFN-gamma to healthy subjects profoundly affects the numbers of several leukocyte subsets in the peripheral blood compartment.

Interferon-gamma has immunomodulatory effects with minor endocrine and metabolic effects in humans.

To evaluate whether interferon-gamma (IFN-gamma) is involved in the interaction between the immune and endocrine systems in vivo, we studied six healthy subjects twice in a placebo-controlled trial: once after administration of recombinant human IFN-gamma and, on another occasion, after administration of saline. The rate of appearance of glucose was determined by infusion of [6,6-2H2]glucose and resting energy expenditure by indirect calorimetry. Human leukocyte antigen-DR gene expression on monocytes and serum neopterin increased after administration of IFN-gamma (P < 0.05 vs. control). IFN-gamma increased serum interleukin-6 levels significantly. Levels of tumor necrosis factor-alpha remained below detection limits. IFN-gamma increased plasma concentrations of ACTH and cortisol (P < 0.05 vs. control), IFN-gamma did not alter concentrations of growth hormone, (nor)epinephrine, insulin, C peptide, glucagon, or insulin-like growth factor I. IFN-gamma did not alter plasma concentrations of glucose and free fatty acids nor the rate of appearance of glucose. IFN-gamma increased resting energy expenditure significantly. We conclude that IFN-gamma is a minor stimulator of the endocrine and metabolic pathways. Therefore, IFN-gamma by itself is probably not a major mediator in the interaction between the immune and the endocrine and metabolic systems.

Differential effects of dihydroergotamine on the circulatory actions of arterial and venous dilators in the rat.

We attempted to characterize in six vasodilators with respect to their arterial or venous activity by studying their interaction with the circulatory effects of dihydroergotamine (DHE) in phenobarbital-anesthetized rats. DHE is a selective venoconstrictive agent which increases mean arterial pressure (MAP) and cardiac output (CO) in the pithed rat without affecting peripheral resistance (R). In the anesthetized rat the hypotensive effect of venodilators (sodium nitrite, glyceryl trinitrate, and molsidomine) was diminished after pretreatment with DHE, ve venoconstrictive agent which increases mean arterial pressure (MAP) and cardiac output (CO) in the pithed rat without affecting peripheral resistance (R). In the anesthetized rat the hypotensive effect of venodilators (sodium nitrite, glyceryl trinitrate, and molsidomine) was diminished after pretreatment with DHE, ve venoconstrictive agent which increases mean arterial pressure (MAP) and cardiac output (CO) in the pithed rat without affecting peripheral resistance (R). In the anesthetized rat the hypotensive effect of venodilators (sodium nitrite, glyceryl trinitrate, and molsidomine) was diminished after pretreatment with DHE, whereas the decrease in MAP induced by arterial vasodilators (hydralazine, diazoxide, and endralazine) remained unaltered after pretreatment with DHE. After pretreatment with DHE, the decrease in CO by sodium nitrite was diminished, whereas its effect on R was not altered. The response of CO and R to hydralazine was not altered after pretreatment with DHE. Pretreatment with DHE offers the possibility of differentiating between arterial or venous activity of vasodilators in vivo.

Lower body negative pressure: a method to differentiate vasodilators in the intact rat.

1. In rats lower body negative pressure induced venous pooling in a reproducible manner. The response to LBNP in the pentobarbitone-anaesthetized rat appeared not to be influenced by the autonomic nervous system. 2. The hypotensive effect of arterial vasodilators was diminished at 5 mmHg LBNP, compared with effects at 3 mmHg, whereas the hypotensive effect of venous vasodilators was not changed at 5 mmHg LBNP, compared with that at 3 mmHg LBNP. 3. In the pithed rat dihydroergotamine caused venoconstriction. In the phenobarbitone-anaesthetized rat the hypotensive effect of venous vasodilators was decreased significantly by pretreatment with this drug, whereas it did not influence the hypotensive effect of arterial vasodilators. 4. Thus venodilatation by LBNP and venoconstriction by dihydroergotamine provide a method for differentiating arterial and venous sites of action of vasodilators in intact rats.

Comparison of various vasodilator drugs using lower body negative pressure.

The present investigations were designed to enable a differentiation in vivo between various types of vasodilator drugs by studying their influence on mean arterial blood pressure (MAP) in anaesthetized rats, simultaneously subjected to lower body negative pressure (LBNP). In anaesthetized rats the application of various degrees of LBNP caused a proportional decrease in MAP, cardiac output and central venous pressure, whereas heart rate remained unchanged. Reflex tachycardia was not observed as a result of general anaesthesia. The autonomic nervous system does not play a part in the physiological events induced by LBNP, since various pretreatments (vagotomy, adrenalectomy, pharmacological sympathectomy) did not change the response to LBNP. It is concluded that the reduction in MAP due to LBNP is a purely mechanical, haemodynamic phenomenon. Upon combined application of drugs and LBNP, vasodilator drugs which mainly dilate veins (sodium nitrite, isosorbide, nitroglycerine) were more active with respect to their hypotensive action at a LBNP of 5 mm than at 3 mm Hg. However, vasodilator drugs with a predominantly arterial site of action (hydralazine, papaverine, phentolamine, diazoxide) were more potent at a LBNP of 3 mm than at 5 mm Hg. This different behavior may be used to discriminate in vivo between various types of vasodilator drugs. The method is accurate, reproduci0le and relatively easy to perform.

Optical design of a laser system for nuclear fusion research.

High power laser improvements, high quality aspheric lenses, and sharp focusing on a solid deuterium target enable us to get numerous nuclear fusion reactions inside the deuterium plasma. Since Maiman successfully built the first light amplifier in 1960 [Nature 187, 493 (1960)] and Terhune performed air breakdown experiments in 1962 ["Optical Third Harmonic Generation," Comptes rendus de la 3ème Conférence Internationale d'Electronique Quantique, Paris, 11-15 février 1963, P. Grivet and N. Bloembergen, Eds. (Dunod, Paris, 1964), pp. 1559-15761, the laser has been thought of as a valuable energy source for fusion devices. Now a kind of race has started toward high temperature plasmas created by powerful lasers. However, the peak power of solid state laser is limited by glass damage, pump efficiences, and unwanted effects such as superradiance. So it is necessary to improve all the optical properties of the laser and the focusing of the lens on the target. In this paper, requirements for fusion implying a very high flux will be stated. Successive optical designs will be described together with measurement methods, and the contribution of optical improvements to the occurrence of nuclear fusion reaction in deuterium targets will be evaluated.