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Gonadal function abnormalities in sickle cell anemia. Studies in adult male patients.

Abbasi AA, Prasad AS, Ortega J, Congco E, Oberleas D.

Ann Intern Med 1976 Nov;85(5):601-5

Thirty-two adult patients with sickle cell anemia were evaluated endocrinologically. Secondary sex characteristics were abnormal in 29, and eunuchoidal skeletal proportions were present in all except one. The age at which different stages of pubic hair growth were attained in these patients was delayed in comparison to normals (P less than 0.005). Hormonal assays were carried out in 14 patients. Basal serum testosterone, dihydrotestosterone, and androstenedione values were lower (P less than 0.02) in patients than controls. Serum LH and FSH levels before and after stimulation with gonadotropin-releasing hormone were consistent with primary testicular failure. Erythrocyte and hair zinc concentrations were significantly decreased, and there was positive correlation between erythrocyte zinc and serum testosterone (r = 0.61, P less than 0.01) in sickle cell anemia. Our study shows that androgen deficiency in this disease is a result of primary rather than secondary hypogondadism. Further studies are required to establish the role of zinc in the pathogenesis of testicular failure in sickle cell anemia.

Folic acid deficiency can cause severe anemia and pancytopenia.

Brinch L, Tjonnfjord G, Ly B. Hematologisk seksjon, Medisinsk avdeling A, Rikshospitalet, Oslo.

Tidsskr Nor Laegeforen 1990 May 30;110(14):1830-1

Pancytopenia is occasionally a consequence of folate deficiency. The most important differential diagnostic considerations are haematologic malignancies, aplastic anaemia and vitamin B12 deficiency. We discuss the problem as exemplified by three patients. Bone marrow examination and determination of blood concentrations of vitamin B12 and folate will give the correct diagnosis.

Biological basis of anemia.

Bron D, Meuleman N, Mascaux C. Institut Jules Bordet, Brussels, Belgium.

Semin Oncol 2001 Apr;28(2 Suppl 8):1-6

Anemia is a frequent complication in cancer, occurring in more than 50% of patients with malignancies. Several factors can cause anemia in these patients, such as blood loss, hemolysis, bone marrow infiltration, hypersplenism, and nutrient deficiencies. However, in a considerable number of patients, no cause other than malignant disease itself can be implicated. This cancer-related anemia is similar to the anemia observed in other chronic diseases, such as rheumatoid arthritis and some chronic infections. The syndrome of anemia of chronic disease is characterized by a hyporegenerative, normocytic, ormochromic anemia associated with reduced serum iron and transferrin saturation but elevated (or normal) ferritin levels. Cancer-related anemia results from activation of the immune and inflammatory systems, leading to increased release of tumor necrosis factor, interferon-gamma, and interleukin-1. The cytokine-mediated relative failure of erythropoiesis has been further investigated, and three different mechanisms of action are proposed: (1) impaired iron utilization; (2) suppression of erythroid progenitor cells differentiation; and (3) inadequate erythropoietin production. In addition, the life span of red blood cells is shortened in cancer-related anemia and production cannot compensate sufficiently for the shorter survival time. Administration of recombinant human erythropoietin (r-HuEPO, epoetin alfa) can not only correct inadequate endogenous erythropoietin production, but also can overcome the suppression of erythroid progenitor cells and impairment of iron mobilization. Copyright 2001 by W.B. Saunders Company.

n-3 Polyunsaturated fatty acids and cytokine production in health and disease.

Calder PC. Division of Human Nutrition, School of Biological Sciences, University of Southampton, UK.

Ann Nutr Metab 1997;41(4):203-34

Arachidonic-acid-derived eicosanoids modulate the production of pro-inflammatory and immunoregulatory cytokines. Overproduction of these cytokines is associated with both septic shock and chronic inflammatory diseases. The n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid, which are found in fish oils, suppress the production of arachidonic-acid-derived eicosanoids and EPA is a substrate for the synthesis of an alternative family of eicosanoids. Thus, dietary fats which are rich in n-3 PUFAs have the potential to alter cytokine production. Animal studies have provided a great deal of evidence that feeding plant or fish oils rich in n-3 PUFAs does alter the ex vivo production of tumour necrosis factor (TNF), interleukin 1 (IL-1), IL-6 and IL-2, but many contradictory observations have been made; it is most likely that the discrepancies in the literature result from differences in the cell types and experimental protocols used. Human studies provide more consistent data: several studies have shown that supplementation of the diet of healthy volunteers results in reduced ex vivo production of IL-1, IL-6, TNF and IL-2 by peripheral blood mononuclear cells. Similar findings have been made in patients with rheumatoid arthritis and multiple sclerosis. Animal studies indicate that dietary fish oil reduces the response to endotoxin and to pro-inflammatory cytokines, resulting in increased survival; such diets have been beneficial in some models of bacterial challenge, chronic inflammation and auto-immunity. These beneficial effects of dietary n-3 PUFAs may be of use as a therapy for acute and chronic inflammation and for disorders which involve an inappropriately activated immune response.

Polyunsaturated fatty acids and rheumatoid arthritis.

Calder PC, Zurier RB. Institute of Human Nutrition, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK.

Curr Opin Clin Nutr Metab Care 2001 Mar;4(2):115-21

Rheumatoid arthritis is characterized by infiltration of T lymphocytes, macrophages and plasma cells into the synovium, and the initiation of a chronic inflammatory state that involves overproduction of proinflammatory cytokines and a dysregulated T-helper-1-type response. Eicosanoids synthesized from arachidonic acid and cytokines cause progressive destruction of cartilage and bone. The n-6 polyunsaturated fatty acid gamma-linolenic acid is the precursor of di-homo-gamma-linolenic acid. The latter and the n-3 polyunsaturated fatty acid eicosapentaenoic acid, which is found in fish oil, are able to decrease the production of arachidonic acid-derived eicosanoids and to decrease the production of proinflammatory cytokines and reactive oxygen species, and the reactivity of lymphocytes. A number of double-blind, placebo-controlled trials of gamma-linolenic acid and fish oil in rheumatoid arthritis have shown significant improvements in a variety of clinical outcomes. These fatty acids should be included as part of the normal therapeutic approach to rheumatoid arthritis. However, it is unclear what the optimal dosage of the fatty acids is, or whether there would be extra benefit from using them in combination.

Anemia in critical illness.

Eckardt KU. Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Charite, Campus Virchow Klinikum, Berlin, Federal Republic of Germany.

Wien Klin Wochenschr 2001 Feb 15;113(3-4):84-9

Anemia is a frequent finding in patients treated in ICUs and results in a high number of red blood cell transfusions. Many patients are already admitted to ICUs with subnormal hemoglobin values. Surgery, frequent phlebotomies and overt bleeding episodes are obvious reasons for continuous blood loss during the ICU stay. However, these causes are usually not sufficient to explain the total blood consumption of critically ill patients, which may amount to several liters. Reduced red cell life span and occult gastrointestinal bleeding are possibly important contributory factors. Irrespective of the cause the erythropoietic response to anemia is severely blunted, as a consequence of an inappropriate increase in erythropoietin production, diminished iron availability and direct inhibitory effects of inflammatory cytokines. The importance of anemia for the course and outcome of critically ill patients and its optimal therapy remain to be defined. Considering red blood cell transfusions recent evidence indicates that a target range of 7-9 g/dl hemoglobin is at least as safe and may even be superior compared to a more liberal transfusion strategy. However, the optimal transfusion trigger in relation to patient comorbidity requires further investigation. Rigorous strategies of blood conservation may help to avoid transfusions. Red blood cell substitutes and recombinant erythropoietin are promising treatment options that are currently under investigation.

Clinical study of 63 patients with aplastic anemia by using in vitro culture of BFU-E, CFU-E, CFU-GM and of the relation between pathogenesis and treatment. [Article in Chinese]

Gao RL, Yu YX, Ma FS. Zhejiang Traditional Medical College Hospital.

Zhonghua Nei Ke Za Zhi 1991 May;30(5):268-72, 316

63 patients with aplastic anemia were studied by using in vitro assay for committed erythroid and granulomonocytic progenitors from the bone marrow. The T cell-mediated effects of suppression of normal hematopoiesis were observed by PBMNC of the patients when cocultured with normal bone marrow. The stimulated effects of androgen on BFU-E and CFU-E with methyl testosterone were also studied. The results showed that the PBMNC of 44.4% of the 63 patients suppressed normal hematopoiesis. 41.3% of the patients responded to methyl testosterone (MT) and 14.3% of the patients had very obvious decrease or absence of BFU-E, CFU-E and CFU-GM without evidence of immunological effects or response to androgen. According to these findings, it may be useful for clinicians to choose better therapeutic regimens for aplastic anemia. Such as BMT for the patients with hematopoietic stem cells deficiency; immuno-suppression treatment or splenectomy may be of benefit for those who suffered from immune mediated aplastic anemia (IMAA) and androstenones chosen for those sensitive to MT in vitro. There were 15 patients with IMAA treated with immuno-suppressive agents and 19 patients sensitive to MT treated with androgens. All of them had satisfactory results.

Effects of interferon alpha on autocrine growth factor loops in B lymphoproliferative disorders.

Heslop HE, Bianchi AC, Cordingley FT, Turner M, Chandima W, De Mel CP, Hoffbrand AV, Brenner MK. Department of Haematology, Royal Free Hospital, London, UK.

J Exp Med 1990 Dec 1;172(6):1729-34

The B lymphoproliferative disorders B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) produce a number of autocrine growth factors, including tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-1, all of which may induce positive feedback growth loops. If such malignancies depend on these autocrine growth loops for survival, their interruption may be therapeutically valuable. Interferon alpha (IFN-alpha) abrogates TNF- or IL-6-induced proliferation of HCL and B-CLL cells in vitro and has therapeutic activity in these diseases. We have investigated the possibility that IFN-alpha may act by interrupting autocrine growth factor loops. If purified B-CLL or HCL cells are cultured in the presence of TNF, there is induction of mRNA for TNF, IL-1 alpha, IL-1 beta, and IL-6. However, culture in the presence of IFN-alpha in addition to TNF reduced the level of mRNA for all these cytokines, compared with cells cultured in TNF alone. While cytokine mRNA levels were diminished, levels of mRNA for the ribonuclease activator 2-5A synthetase were increased. Analysis of the kinetics of cytokine mRNA production showed that levels fall shortly after the rise of 2-5A synthetase mRNA. IFN-alpha may produce these effects by shortening the half-life of cytokine mRNA, since TNF mRNA half-life in B-CLL and HCL cells is substantially reduced when the cells are cultured with IFN-alpha. These data suggest that IFN-alpha may mediate its therapeutic effects in these malignancies by blocking autocrine growth factor loops.

Dietary polyunsaturated fatty acids and inflammatory mediator production.

James MJ, Gibson RA, Cleland LG. Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia, and the Department of Pediatrics and Child Health, Flinders Medical Center, Bedford Park, Australia.

Am J Clin Nutr 2000 Jan;71(1 Suppl):343S-8S

Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = 90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.

Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men.

Kelley DS, Taylor PC, Nelson GJ, Schmidt PC, Ferretti A, Erickson KL, Yu R, Chandra RK, Mackey BE. USDA, ARS, Western Human Nutrition Research Center, Presidio of San Francisco, California 94129, USA.

Lipids 1999 Apr;34(4):317-24

The purpose of this study was to examine the effects of feeding docosahexaenoic acid (DHA) as triacylglycerol on the fatty acid composition, eicosanoid production, and select activities of human peripheral blood mononuclear cells (PBMNC). A 120-d study with 11 healthy men was conducted at the Metabolic Research Unit of Western Human Nutrition Reach Center. Four subjects (control group) were fed the stabilization diet throughout the study; the remaining seven subjects were fed the basal diet for the first 30 d, followed by 6 g DHA/d for the next 90 d. DHA replaced an equivalent amount of linoleic acid; the two diets were comparable in their total fat and all other nutrients. Both diets were supplemented with 20 mg D alpha-tocopherol acetate per day. PBMNC fatty acid composition and eicosanoid production were examined on day 30 and 113; immune cell functions were tested on day 22, 30, 78, 85, 106, and 113. DHA feeding increased its concentration from 2.3 to 7.4 wt% in the PBMNC total lipids, and decreased arachidonic acid concentration from 19.8 to 10.7 wt%. It also lowered prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, in response to lipopolysaccharide, by 60-75%. Natural killer cell activity and in vitro secretion of interleukin-1beta and tumor necrosis factor alpha were significantly reduced by DHA feeding. These parameters remained unchanged in the subjects fed the control diet. B-cell functions as reported here and T-cell functions that we reported previously were not altered by DHA feeding. Our results show that inhibitory effects of DHA on immune cell functions varied with the cell type, and that the inhibitory effects are not mediated through increased production of PGE2 and LTB4.

Docosahexaenoic and eicosapentaenoic acids inhibit human lymphoproliferative responses in vitro but not the expression of T cell surface activation markers.

Khalfoun B, Thibault G, Lacord M, Gruel Y, Bardos P, Lebranchu Y. Groupe "Interactions Hote-Greffon", Laboratoire d'Immunologie, Faculte de Medecine, Tours, France.

Scand J Immunol 1996 Mar;43(3):248-56

The effects of polyunsaturated fatty acids (PUFAs: docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids) on induced lymphocyte proliferation and expression of CD25alpha chain of interleukin-2 receptor, CD71 and HLA-DR were investigated. PUFAs had no effect on phytohaemagglutinin (PHA)-induced lymphocyte agglutination, but they strongly inhibited the lymphoproliferative response to PHA. This inhibitory effect is PUFA dose-dependent and seems to be more potent with DHA than EPA, Pre-incubation experiments showed that lymphocytes cultured with PUFAs for 6 h then washed and exposed to PHA, still inhibited lymphocyte proliferation. The authors also showed that this inhibitory activity was time dependent but became nonsignificant when PUFAs were added after 48 h lymphocyte culture. The addition of excess exogenous human recombinant rIL-2 partly restored PHA-lymphocyte proliferation inhibited by EPA but not by DHA. On the other hand, the authors showed that PUFAS did not inhibit IL-2 stimulated lymphocyte proliferation. The addition of PUFAs to cell culture medium had no inhibitory action on the PHA-induced lymphocyte expression of CD25, CD71 and HLA-DR. Furthermore, this effect appeared independent of eicosanoid synthesis or peroxide formation. Indeed, the inclusion of aspirin and vitamin E in the culture medium did not prevent the inhibitory effects of PUFAs on lymphocyte proliferation. Regardless of the mechanism of action, the inhibitory effect of PUFAs on activated lymphocytes may explain why some clinical trials of fish oil supplemented diets containing high amounts of DHA and EPA have been successful in improving the health status of patients suffering from inflammatory and autoimmune disorders.

Antirheumatic effect of IDS 23, a stinging nettle leaf extract, on in vitro expression of T helper cytokines.

Klingelhoefer S, Obertreis B, Quast S, Behnke B. Strathmann Research GmbH, Hamburg, Germany.

J Rheumatol 1999 Dec;26(12):2517-22

OBJECTIVE: Stinging nettle leaf extracts are registered in Germany for adjuvant therapy of rheumatic diseases. In a whole blood culture system the nettle extract IDS 23 (Rheuma-Hek) inhibited lipopolysaccharide stimulated monocyte cytokine expression, indicating an immunomodulating effect. We investigated the immunomodulating effects of IDS 23 on phytohemagglutinin (PHA) stimulated peripheral blood mononuclear cells (PBMC) in vitro.

METHODS: Using commercial immunoassays the distinct cytokine patterns of Th1 and Th2 cells were determined. Interleukin 2 (IL-2) and interferon-gamma (IFN-gamma) mRNA expression was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) with PHA stimulated PBMC.

RESULTS: IDS 23 inhibited PHA stimulated production of Th1-specific IL-2 and IFN-gamma in PBMC culture (n =10) in a dose dependent manner up to 50+/-32% and 77+/-14%, respectively. In contrast, IDS 23 stimulated the secretion of Th2-specific IL-4. The dose dependent inhibiting effect on IL-2 and IFN-gamma expression was also detected with RT-PCR, while the amount of actin-specific mRNA transcript was not modified by IDS 23.

CONCLUSION: Our results suggest the effective ingredient of IDS 23 acts by mediating a switch in T helper cell derived cytokine patterns. IDS 23 may inhibit the inflammatory cascade in autoimmune diseases like rheumatoid arthritis.

Long-term treatment of renal anaemia with mesterolone. [Article in German]

Kraft D.

Dtsch Med Wochenschr 1980 Jun 6;105(23):830-2

Mesterolone, 150 mg daily by mouth, was given to 26 patients (10 men, 16 women) with renal anaemia on chronic haemodialysis (3 times for 5 hours). At the beginning of treatment the patients had been dialysed for at least 6 months under stable conditions: iron deficiency had been excluded or treated. Progressive improvement in the anaemia was observed during the treatment period. After 39 months the haemoglobin concentration had risen from 74 +/- 4 g/l to 95 +/- 5 g/l, haematocrit from 0.22 +/- 0.01 to 0.28 +/- 0.02, and the red-cell count from 2.44 +/- 0.12 X 10(12)/l to 3.09 +/- 0.2 X 10(12)/l. Side effects were rare; some patients developed increased appetite with a rise in body weight, while some women developed acne or hirsutism. There was no effect of mesterolone on liver function. The results indicate that mesterolone can favourably influence renal anaemia and that the side effects of this testosterone derivative are not such as to prohibit its use in women.

Clomiphene-responsive hypogonadism in sickle cell anemia.

Landefeld CS, Schambelan M, Kaplan SL, Embury SH.

Ann Intern Med 1983 Oct;99(4):480-3

Two 19-year-old men with sickle cell anemia and hypogonadism had hypothalamic dysfunction that responded to oral clomiphene therapy. The patients had no nutritional deficiencies or anatomic lesions known to result in the hypogonadism associated with sickle cell anemia. Their sickle cell disease was characterized by infrequent crises, severe hemolytic anemia, urinary iron loss, and iron deficiency. Partial hypothalamic hypogonadism was shown by low levels of testosterone, low to low-normal levels of luteinizing hormone and follicle-stimulating hormone, and a nearly normal rise in gonadotropin levels in response to exogenous gonadotropin releasing hormone. Treatment with oral clomiphene raised luteinizing hormone, follicle-stimulating hormone, and testosterone levels to normal, and induced puberty in both patients. Treatment was discontinued in one patient because of the onset of priapism, but was continued for 10 months without side effects in the other. Severe hypogonadism in patients with sickle cell anemia should be thoroughly evaluated and clomiphene therapy considered in patients with hypothalamic dysfunction.

Antiglucocorticoid function of androstenetriol.

Loria RM. Virginia Commonwealth University, Medical College of Virginia, Richmond 23298-0678, USA.

Psychoneuroendocrinology 1997;22 Suppl 1:S103-8

The anti-inflammatory and immunosuppressive functions of corticosteroids have been well established and characterized. In contrast, a different group of native steroids, which include dehydroepiandrosterone (DHEA) and two of its metabolites, androstenediol (5-androstene-3 beta-17 beta-diol, AED) and androstenetriol (5-androstene-3 beta-7 beta-17 beta-triol, beta AET), function in vivo to up-regulate host immune response against infections and counteract stress-induced immunosuppression. Indeed, DHEA and particularly, AED and beta AET, have been shown to protect mice from viral, bacterial, and parasitic infections. In vivo, these three hormones are in opposition to the widely demonstrated immunosuppressive action of glucocorticoids, suggesting a possible new immune regulation mechanism. The individual activity in vitro of each of these steroids, i.e. DHEA, AED, and beta AET, on a mitogen-induced mixed splenocyte proliferation assay were determined. The results showed that DHEA suppressed the proliferation of cultures activated with concanavalin A (ConA) or lipopolysaccharide (LPS) in a dose-dependent manner. AED had little influence on the activation response. However, beta AET potentiated the response to both mitogens significantly above control. The regulation of the cytokine secretion, of both interleukin-2 (IL-2) and interleukin-3 (IL-3), from ConA-activated lymphocytes was affected in the same manner. These functions were depressed by DHEA, unaffected by AED, and potently increased by beta AET. Moreover, the classic immunosuppressive effects of hydrocortisone on ConA-induced lymphocyte proliferation, as well as on IL-2 and IL-3 production, were unaffected by being co-cultured with DHEA and only minimally counteracted by AED at high doses. In contrast, co-culturing with beta AET significantly counteracted the immunosuppressive effects of hydrocortisone on lymphocyte proliferation and cytokine production. These data show that in-vivo, DHEA, AED, and beta AET may have some similar functions, while in vitro, their effects are dramatically different from one another. Only beta AET could markedly potentiate the cellular response by increasing lymphocyte activation and counteracting the immnosuppressive activity of hydrocortisone on lymphocyte proliferation and cytokine production.

Correlation between traditional Chinese medicine classification of 53 patients with aplastic anemia and varieties of hemopoietic progenitor cells in vitro culture. [Article in Chinese]

Luo XS. Dept. of Hemotology, Affiliated Hospital of Zhejiang College of TCM, Hangzhou.

Zhongguo Zhong Xi Yi Jie He Za Zhi 1992 Mar;12(3):139-41, 131

Aplastic anemia can be classified distinctively three types as progenitor depletive; immunosuppressive and androgenic sensitive. Using bone marrow culture in vitro which had been accomplished in our laboratory, 53 patients with aplastic anemia were also classified according to TCM term in three groups as Yin deficiency, Yang deficiency and both Yin and Yang deficiency, and the correlation was observed between TCM classification and lab character of these patients. The results showed that the number of CFU-GM, CFU-E and BFU-E in Yang deficiency group was significantly higher than that in the other two groups (P less than 0.01 and P less than 0.05). It also showed that the sensitivity of progenitor cells to androgenic hormones of Yang deficiency group was preferential to all (P less than 0.005 and P less than 0.05). The percentage of immunosuppressive type of aplastic anemia in Yin deficiency group was much higher than those in the other two groups (P less than 0.005). These observations suggested that TCM classification for aplastic anemia in this paper has objective material foundation.

Biochemical effects of a diet containing foods enriched with n-3 fatty acids.

Mantzioris E, Cleland LG, Gibson RA, Neumann MA, Demasi M, James MJ. Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia.

Am J Clin Nutr 2000 Jul;72(1):42-8

BACKGROUND: Results of many studies indicate that consumption of n-3 fatty acids can benefit persons with cardiovascular disease and rheumatoid arthritis. However, encapsulated fish oil is unlikely to be suited to lifetime daily use and recommendations to increase fish intake have not been effective.

OBJECTIVE: The objective was to examine the effectiveness of a diet that incorporates foods rich in n-3 fatty acids in elevating tissue concentrations of eicosapentaenoic acid and in suppressing the production of inflammatory mediators.

DESIGN: Healthy male volunteers were provided with foods that were enriched in alpha-linolenic acid (cooking oil, margarine, salad dressing, and mayonnaise) and eicosapentaenoic and docosahexaenoic acids (sausages and savory dip) and with foods naturally rich in n-3 fatty acids, such as flaxseed meal and fish. Subjects incorporated these products into their food at home for 4 wk. Fatty acid intakes, cellular and plasma fatty acid concentrations, and monocyte-derived eicosanoid and cytokine production were measured.

RESULTS: Analyses of dietary records indicated that intake of eicosapentaenoic acid plus docosahexaenoic acid averaged 1.8 g/d and intake of alpha-linolenic acid averaged 9. 0 g/d. These intakes led to an average 3-fold increase in eicosapentaenoic acid in plasma, platelet, and mononuclear cell phospholipids. Thromboxane B(2), prostaglandin E(2), and interleukin 1beta synthesis decreased by 36%, 26%, and 20% (P < 0.05), respectively.

CONCLUSIONS: Foods that are strategically or naturally enriched in n-3 fatty acids can be used to achieve desired biochemical effects without the ingestion of supplements or a change in dietary habits. A wide range of n-3-enriched foods could be developed to support large-scale programs on the basis of the therapeutic and disease-preventive effects of n-3 fatty acids.

Clinical roles of vitamins in hematopoietic disorders. [Article in Japanese]

Matsuda M, Kanamaru A. Third Department of Internal Medicine, Kinki University School of Medicine.

Nippon Rinsho 1999 Oct;57(10):2349-55

Vitamins are essential organisms which promote various metabolisms and physiological systems. Several vitamins play important roles in hematopoietic system. Vitamin B12, C and folic acid are associated with DNA synthesis of erythroid nucleus, the deficiency of which causes the megaloblastic anemia. Some megaloblatic anemia and sideroblastic anemia might response to vitamin B1 and B6, respectively. Vitamin K participates in some coagulation factors in coagulation-fibrinogenolysis system. It has been reported that vitamins A, D and K potentially differentiate leukemic cells and then induce the apoptosis, suggesting that they would be new therapeutic agents in acute leukemia.

Effect of intravenous infusion of omega-3 and omega-6 lipid emulsions on equine monocyte fatty acid composition and inflammatory mediator production in vitro.

McCann ME, Moore JN, Carrick JB, Barton MH. Department of Physiology, College of Veterinary Medicine, University of Georgia, Athens 30602, USA.

Shock 2000 Aug;14(2):222-8

The effect of intravenous administration of lipid emulsions enriched with omega-3 (n3) and omega-6 (n6) fatty acids on equine monocyte phospholipid fatty acid composition and the synthesis of inflammatory mediators in vitro was evaluated. In a randomized crossover design, horses were infused intravenously with 20% lipid emulsions containing n3 or n6 fatty acids. Monocytes were isolated from the horses before and 0 h, 8 h, 24 h, and 7 days after lipid infusion. Monocyte fatty acid analysis demonstrated incorporation of the parenteral n3 and n6 fatty acids in monocyte phospholipids immediately after infusion, with changes in the fatty acid composition persisting for up to 7 days after infusion. In vitro production of the inflammatory mediators thromboxane B2/thromboxane B3 (TXB(2/3)) and tumor necrosis factor-alpha (TNFalpha) by peripheral blood monocytes was diminished by n3 lipid infusion and was unchanged or increased by n6 lipid infusion. The results of this study demonstrate that short-term infusions of n3 and n6 fatty acid-enriched lipid emulsions alter the fatty acid composition of equine monocyte phospholipids and modify the inflammatory response of these cells in vitro. These results also support further investigation into the use of parenteral n3 fatty acids as part of the supportive therapy of patients with multiple organ dysfunction (MODS) or systemic inflammatory response syndrome (SIRS).

Haematological disorders in liver disease.

Mehta AB, McIntyre N. Royal Free Hospital and School of Medicine, London, England, UK.

Forum (Genova) 1998 Jan-Mar;8(1):8-25

The liver plays a central role in haemopoiesis and synthesis of coagulation proteins; liver disease is associated with a broad range of haematological abnormalities. Anaemia arises through multiple mechanisms, haem metabolism is disturbed, and liver disease causes alterations in red cell lipid metabolism. Defects of platelet number and function arise due to the effects of liver disease, immune mechanisms and hypersplenism. Coagulation disturbances are due to impaired vitamin K metabolism, defective synthesis of coagulation factors and regulatory proteins, impaired clearance of activated coagulation factors and increased fibrinolysis. Treatment, including blood component therapy, is discussed. Recent data indicate an emerging role for disturbances in Epo, cytokines (TNF, IL-6) and thrombopoietin in causing haematological changes in liver disease.

Ex-vivo in-vitro inhibition of lipopolysaccharide stimulated tumor necrosis factor-alpha and interleukin-1 beta secretion in human whole blood by extractum urticae dioicae foliorum.

Obertreis B, Ruttkowski T, Teucher T, Behnke B, Schmitz H. Strathmann AG & Co., Hamburg, Germany.

Arzneimittelforschung 1996 Apr;46(4):389-94

An extract of Urtica dioica folium (IDS 23, Rheuma-Hek), monographed positively for adjuvant therapy of rheumatic diseases and with known effects in partial inhibition of prostaglandin and leukotriene synthesis in vitro, was investigated with respect to effects of the extract on the lipopolysaccharide (LPS) stimulated secretion of proinflammatory cytokines in human whole blood of healthy volunteers. In the assay system used, LPS stimulated human whole blood showed a straight increase of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion reaching maximum concentrations within 24 h following a plateau and slight decrease up to 65 h, respectively. The concentrations of these cytokines was strongly positively correlated with the number of monocytes/macrophages of each volunteer. TNF-alpha and IL-1 beta concentration after LPS stimulation was significantly reduced by simultaneously given IDS 23 in a strictly dose dependent manner. At time 24 h these cytokine concentrations were reduced by 50.8% and 99.7%, respectively, using the highest test IDS 23 assay concentration of 5 mg/ml (p < 0.001). After 65 h the corresponding inhibition was 38.9% and 99.9%, respectively (p < 0.001). On the other hand IDS 23 showed no inhibition but stimulated IL-6 secretion in absence of LPS alone. Simultaneously given LPS and IDS 23 resulted in no further increase. In contrast to described effects on arachidonic acid cascade in vitro, tested Urtica dioica phenol carbon acid derivates and flavonoides such as caffeic malic acid, caffeic acid, chlorogenic acid, quercetin and rutin did not influence LPS stimulated TNF-alpha, IL-1 beta and IL-6 secretion in tested concentrations up to 5 x 10(-5) mol/l. These further findings on the pharmacological mechanism of action of Urticae dioica folia may explain the positive effects of this extract in the treatment of rheumatic diseases.

Review of oxymetholone: a 17alpha-alkylated anabolic-androgenic steroid.

Pavlatos AM, Fultz O, Monberg MJ, Vootkur A, Pharmd. Northside Family Medicine, Chicago, Illinois 60659-4120, USA.

Clin Ther 2001 Jun;23(6):789-801; discussion 771

BACKGROUND: Oxymetholone (17beta-hydroxy-2-[hydroxymethylene]-17-methyl-5alpha-androstan-3-one) is a 17alpha-alkylated anabolic-androgenic steroid and a synthetic derivative of testosterone. It has been approved by the US Food and Drug Administration for the treatment of anemias caused by deficient red cell production.

OBJECTIVES: This review summarizes the pharmacokinetics, current and future clinical applications, and adverse effects of oxymetholone. Relevant studies were identified using a search of MEDLINE through March 2001, supplemented by conference abstracts and presentations.

RESULTS: Because of its anabolic properties, oxymetholone has been studied for the treatment of HIV-associated wasting, antithrombin III deficiency, pediatric growth impairment, and damaged myocardium, with varying degrees of success. Hepatotoxicity is a major adverse effect associated with the use of oxymetholone, with cholestatic jaundice the most important hepatic side effect. Less common hepatic side effects associated with the use of anabolic-androgenic steroids include peliosis hepatis and formation of hepatic tumors. All anabolic-androgenic steroids can cause androgenic side effects, including acne, hirsutism, hair loss, clitoral/phallic enlargement, vocal changes, erectile tissue stimulation, gynecomastia, amenorrhea, and changes in libido and sexual potency.

CONCLUSIONS: As is the case with many anabolic-androgenic steroids, few pharmacokinetic and tolerability studies were performed before oxymetholone's approval in the 1960s. It has proved, however, to be an appropriate treatment choice for selected patients with anemia, if carefully monitored.

Clinical evaluation of anemia in the aged. [Article in Italian]

Pentimone F, Del Corso L, Frustaci G, Gnesi A, Romanelli AM, Sabbatini AR. Istituto Clinica Medica II, Universita di Pisa.

Minerva Med 1992 Jan-Feb;83(1-2):35-9

Of 533 patients over 65 years old (153 males and 380 females), admitted to geriatric units for various medical diseases, 111 (20.8%) were anemic. Among males the prevalence of anemia was 30.1%, among females 17.1%. Three principal causes of anemia were revealed. The most frequent (42.3%) was microcytic, hypochromic anemia, with low levels of serum iron concentrations, related to gastrointestinal diseases (with chronic occult blood loss). 38.7% of anemic elderly people was affected by chronic diseases. In 19.0% a folate (16 case) and iron (5 cases) deficiency was revealed. These results suggest that anemia in the elderly is always pathological; hemoglobin values lower than 12 g/dl should be considered abnormal and investigated.

Effect of zinc supplementation on serum testosterone level in adult male sickle cell anemia subjects.

Prasad AS, Abbasi AA, Rabbani P, DuMouchelle E.

Am J Hematol 1981;10(2):119-27

Previously, we have documented primary testicular failure in adult male subjects with sickle cell anemia. We have also reported the occurrence of zinc deficiency and suggested that androgen deficiency may be related to zinc deficiency in such patients. In this study, we present data with respect to the efferent of oral zinc supplementation on serum testosterone levels in adult male patients with sickle cell anemia. An increase in serum testosterone, neutrophil zinc, and neutrophil alkaline phosphatase activity ws observed in the zinc-supplemented group in comparison with the group on placebo. Additionally, body weight increased and serum lactic dehydrogenase activity decrease in response to zinc supplementation. We conclude that androgen deficiency in adult male subjects with sickle cell anemia is correctable with zinc supplementation and that the determination of neutrophil zinc and alkaline phosphatase activity in the neutrophils may be utilized as good indicators of body zinc status in such subjects.

Serum erythropoietin concentration in anephric patients.

Radtke HW, Erbes PM, Schippers E, Koch KM.

Nephron 1978;22(4-6):361-5

In 13 bilateral nephrectomized patients serum erythropoietin (SEp) activity could be measured quantitatively by use of the highly sensitive fetal mouse liver cell assay. SEp concentration in the majority of the cases was below the mean of normal controls. There was a significant positive correlation between SEp levels and hematocrits, suggesting erythropoietin (Ep) deficiency to be a causative factor in the anemia of the anephric state. Androgen therapy stimulated extrarenal Ep production in all of 5 anephric patients studied.

Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.

Reddi K, Henderson B, Meghji S, Wilson M, Poole S, Hopper C, Harris M, Hodges SJ. Department of Oral and Maxillofacial Surgery, Eastman Dental Institute for Oral Healthcare Sciences, London.

Cytokine 1995 Apr;7(3):287-90

Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones.

Cytokine and natural killing regulation of growth of a hairy cell leukemia-like cell line: the role of interferon-alpha and interleukin-2.

Reiter Z, Ozes ON, Blatt LM, Taylor MW. Department of Biology, Indiana University, Bloomington 47405.

J Immunother 1992 Jan;11(1):40-9

Hairy cell leukemia (HCL) is a lymphoproliferative disorder of B-lymphocytes, with pathological manifestations usually including splenomegaly and pancytopenia. Naturally occurring and recombinant interferons (IFNs), specifically of the alpha subtype, have shown a significant anti-tumor effect in HCL patients, with improvement of hematologic parameters within the first few months of treatment. The mechanisms responsible for the beneficial action of IFN-alpha in HCL patients are unclear, but several hypotheses have been suggested. Recently, a continuous line of cells (Eskol) from a patient diagnosed with hairy cell leukemia was established and shown to have several properties of a leukemic hairy cell. In the present study, we investigated the direct effect of IFN-alpha and interleukin (IL-2) on the Eskol cell line, and lymphokine regulation of natural killing (NK) activity against these cells. It was found that IFN-alpha has a direct antiproliferative effect on Eskol cells. Furthermore, Eskol cells were found to be completely resistant to NK-cell mediated cytotoxicity (CMC) but were somewhat sensitive to either IFN-alpha-primed NK or lymphokine-activated killer (LAK) cells-CMC. The resistance of Eskol cells to NK-CMC is due to a low binding ability to effector cells. Moreover, it was found that like IFN, IL-2 can protect Eskol cells from activated NK-CMC. Both cytokines reduced the ability of Eskol cells to induce NK-cytotoxic factor (NKCF) release from NK cells following conjugate formation between Eskol cells and effector cells. Moreover, cycloheximide treatment abolished the protective effect against NK-CMC induced by IFN-alpha or by IL-2. Therefore, it seems that the protective effect against NK-CMC induced by both cytokines is mediated via the same mechanism.

Serum erythropoietin and erythroid activity in vitamin B12 deficiency.

Remacha AF, Bellido M, Garcia-Die F, Marco N, Ubeda J, Gimferrer E. Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Haematologica 1997 Jan-Feb;82(1):67-8

We studied erythropoiesis in 31 patients with vitamin B12 deficiency by measuring serum erythropoietin (s-Epo), serum transferrin receptor (s-TfR, taken as an index of total erythroid activity), reticulocyte count, and the reticulocyte maturation index (RMI). s-Epo and s-TfR were measured with commercial immunoassays, whereas reticulocyte count and RMI were determined by flow cytometry. s-Epo (123 +/- 196 U/L) and s-TfR (4.1 +/- 2 mg/L) levels were increased in patients with vitamin B12 deficiency. The absolute reticulocyte counts were decreased (29 +/- 18 x 10(9)/L) with a relative increase in the most immature fractions (RMI: 29.6 +/- 18%). A significant negative relationship was found between s-Epo and Hb level (r = -0.65, p < 0.0001). On the average, however, s-Epo was inappropriately low for the degree of anemia, since the observed/predicted (O/P) s-Epo ratio was 0.80 +/- 0.28 in vitamin B12 deficiency vs 1.00 +/- 0.16 in a group of patients with iron deficiency anemia. It is concluded that at least a portion of patients with vitamin B12 deficiency have serum erythropoietin levels that are inappropriately low for the degree of anemia.

Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription.

Riehemann K, Behnke B, Schulze-Osthoff K. Department of Internal Medicine I, Medical Clinics, University of Tubingen, Germany.

FEBS Lett 1999 Jan 8;442(1):89-94

Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases and is responsible for the enhanced expression of many proinflammatory gene products. Extracts from leaves of stinging nettle (Urtica dioica) are used as antiinflammatory remedies in rheumatoid arthritis. Standardized preparations of these extracts (IDS23) suppress cytokine production, but their mode of action remains unclear. Here we demonstrate that treatment of different cells with IDS23 potently inhibits NF-kappaB activation. An inhibitory effect was observed in response to several stimuli, suggesting that IDS23 suppressed a common NF-kappaB pathway. Inhibition of NF-kappaB activation by IDS23 was not mediated by a direct modification of DNA binding, but rather by preventing degradation of its inhibitory subunit IkappaB-alpha. Our results suggests that part of the antiinflammatory effect of Urtica extract may be ascribed to its inhibitory effect on NF-kappaB activation.

Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness.

Rodriguez RM, Corwin HL, Gettinger A, Corwin MJ, Gubler D, Pearl RG. Department of Emergency Medicine, Highland General Hospital, Oakland, CA, USA.

J Crit Care 2001 Mar;16(1):36-41

PURPOSE: The purpose of this article was to determine the prevalence of iron, vitamin B12, and folate deficiency and to evaluate the erythropoietin (EPO) response to anemia in a cohort of long-term intensive care unit (ICU) patients.

MATERIALS AND METHODS: All patients admitted to three academic medical center multidisciplinary ICUs were screened for eligibility into a randomized trial of EPO for the treatment of ICU anemia. On their second or third ICU day, patients enrolled in this trial had EPO levels drawn and were screened for iron, B12, and folate deficiency. Weekly EPO levels were obtained throughout patients' ICU stay.

RESULTS: A total of 184 patients were screened for iron, B12, and folate deficiency. Sixteen patients (9%) were iron deficient by study criteria, 4 (2%) wereB12 deficient, and 4 (2%) were folate deficient. Mean hemoglobin and reticulocyte percents of the remaining 160 patients were 10.3 +/- 1.2 g/dL and 1.66 +/- 1.09%, respectively. In most patients, serum iron and total iron binding capacity levels were very low, whereas ferritin levels were very high. Mean and median day 2 EPO levels were 35.2 +/- 35.6 mIU/mL and 22.7 mIU/mL, respectively (normal = 4.2-27.8). Serial EPO levels in most ersistently anemic patients remained within the normal range.

CONCLUSIONS: In this cohort, screening for iron, B12, and folate deficiency identified potentially correctable abnormalities in more than 13% of patients and should be considered in those who are anticipated to have long ICU stays. Even at an early point of critical illness, most patients had iron studies consistent with anemia of chronic disease (ACD), as well as a blunted EPO response that may contribute to this ACD-like anemia of critical illness.

Alteration of tumor necrosis factor-alpha production by macrophages from mice fed diets high in eicosapentaenoic and docosahexaenoic fatty acids.

Somers SD, Erickson KL. Division of Immunology, James N. Gamble Institute of Medical Research, Cincinnati, Ohio 45319.

Cell Immunol 1994 Feb;153(2):287-97

Dietary exposure to n-3 fats found in marine fish oils are known to reduce certain inflammatory conditions. Although depressed prostaglandin E2 (PGE2) production is thought to be a major mechanism of the beneficial effects, the direct effects of n-3 fatty acids on inflammatory macrophage function are not well understood. In this study, production of the inflammatory monokine, tumor necrosis factor-alpha (TNF alpha), by isolated murine macrophages was assessed following a 3-week feeding with diets containing either 10% menhaden fish oil as a source of n-3 fatty acids or, as a control and source of n-6 fatty acids, 10% safflower oil. Cultures of peritoneal macrophages from mice fed diets with n-3 fatty acids had more TNF alpha activity 24 hr after in vitro stimulation with bacterial lipopolysaccharide than did macrophages from mice fed the n-6-containing diet. The onset and maximal synthesis of bioactive TNF alpha and down-regulation of messenger RNA for TNF alpha appeared to be similar for the two diets, suggesting that macrophages from mice fed a diet high in n-6 but not n-3 fatty acids were capable of removing active TNF alpha from culture media. Experiments in which PGE2 was added exogenously indicated that the removal of TNF alpha from culture supernatant by macrophages was induced by lower concentrations of PGE2 than that associated with termination of production, and that n-3 fatty acid diets caused a selective loss in the clearance mechanism. These results demonstrate a specific alteration of PGE2-mediated regulation of macrophage-produced TNF alpha by n-3 fatty acids.

Dietary supplementation with very long-chain n-3 fatty acids in man decreases expression of the interleukin-2 receptor (CD25) on mitogen-stimulated lymphocytes from patients with inflammatory skin diseases.

Soyland E, Lea T, Sandstad B, Drevon A. Section for Dietary Reasearch, University of Oslo, Norway.

Eur J Clin Invest 1994 Apr;24(4):236-42

T-cell activation and cytokine production play an important role in several chronic inflammatory diseases. Because n-3 fatty acids exert beneficial effects on the clinical state of some of these diseases, we examined the effect of dietary supplementation of n-3 fatty acids on T-cell proliferation, expression of CD25 (interleukin-2 receptor alpha-chain), secretion of interleukin-2, interleukin-6 and tumour necrosis factor from T-cells from patients with psoriasis and atopic dermatitis. During 4 months, 21 patients supplied 6 g of highly concentrated ethyl esters of EPA and DHA in gelatin capsules daily to their diet. In the control group 20 patients supplied 6 g per day of corn oil in gelatin capsules to their diet. Eicosapentaenoic acid (20:5, n-3) of serum phospholipids increased from 14 (min 4-max 42) to 81 (min 59-max 144) mg l-1 (P < 0.01) in patients with atopic dermatitis receiving n-3 fatty acids, and from 25 (min 7-max 66) to 74 (min 46-max 142) mg l-1 (P < 0.01) in patients with psoriasis, whereas docosahexaenoic acid (22:6, n-3) increased from 65 (min 46-max 120) to 92 (min 54-max 121) mg l-1 (P < 0.05) and from 81 (min 38-max 122) to 92 (min 63-max 169) mg l-1 (NS) in atopic and psoriatic patients, respectively. The changes in the serum phospholipid fatty acid profile in the groups receiving n-3 fatty acids, correlate to the dietary intake of corresponding fatty acids. (ABSTRACT TRUNCATED AT 250 WORDS)

Association of humoral markers of inflammation and dehydroepiandrosterone sulfate or cortisol serum levels in patients with chronic inflammatory bowel disease.

Straub RH, Vogl D, Gross V, Lang B, Scholmerich J, Andus T. Department of Internal Medicine I, University Medical Center, Regensburg, Germany.

Am J Gastroenterol 1998 Nov;93(11):2197-202

OBJECTIVES: Dehydroepiandrosterone sulfate (DHEAS) and cortisol are multifunctional adrenal hormones with immunomodulating properties. DHEAS levels were found to be very low in chronic inflammatory diseases. This study aimed to shed more light on the interrelation between DHEAS and cortisol (and humoral markers of inflammation) in chronic inflammatory bowel disease.

METHODS: DHEAS and cortisol serum levels were measured by ELISA in the serum of 66 normal subjects, 115 patients with Crohn's disease (CD) and 64 patients with ulcerative colitis (UC). Humoral markers of inflammation and disease activity scores were assessed by standard techniques.

RESULTS: DHEAS was lower in patients with CD (p < 0.005) and UC (p < 0.005) than in controls, which was, in part, dependent on previous corticosteroid treatment (p < 0.01). In CD patients, z-normalized DHEAS was inversely correlated with blood sedimentation rate (p = 0.017). Z-normalized DHEAS was negatively correlated with interleukin-6 (IL-6) in the form of a trend (p = 0.068), and z-normalized DHEAS was significantly positively correlated with hemoglobin (p = 0.001) but not with the Crohn's disease activity index. Cortisol, however, was positively correlated with blood sedimentation rate (p = 0.034) and C-reactive protein (p = 0.006). In contrast, in UC patients no such correlation of z-normalized DHEAS or cortisol and parameters of humoral inflammatory activity or Rachmilewitz index exist.

CONCLUSIONS: DHEAS as a marker of inflammation was low in CD and UC. In CD patients, low DHEAS and high cortisol serum levels were associated with higher humoral inflammatory activity. With respect to humoral inflammatory activity in CD patients, DHEAS and cortisol seem to be inversely regulated, which may have an impact on several immune functions, such as IL-6 secretion.

Replacement therapy with DHEA plus corticosteroids in patients with chronic inflammatory diseases-substitutes of adrenal and sex hormones.

Straub RH, Scholmerich J, Zietz B. Laboratory of Neuroendocrinoimmunology, Department of Internal Medicine I, University Hospital, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany.

Z Rheumatol 2000;59 Suppl 2:II/108-18

A dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis was found in animal models of chronic inflammatory diseases, and the defect was located in more central portions of the HPA axis. This defect of neuroendocrine regulatory mechanisms contributes to the onset of the model disease. Since these first observations in animal models were made, evidence has accumulated that the possible defect in the HPA axis in humans is more distal to the hypothalamus or pituitary gland: In chronic inflammatory diseases, such as rheumatoid arthritis, an alteration of the HPA stress response results in inappropriately low cortisol secretion in relation to adrenocorticotropic hormone (ACTH) secretion. Furthermore, it has recently been shown that the serum levels of another adrenal hormone, dehydroepiandrosterone (DHEA), were significantly lower after ACTH stimulation in patients with rheumatoid arthritis without prior corticosteroids than in healthy controls. These studies clearly indicate that chronic inflammation alters, particularly, the adrenal response. However, at this point, the reason for the specific alteration of adrenal function in relation to pituitary function remains to be determined. Since one of the down-regulated adrenal hormones, DHEA, is an inhibitor of cytokines due to an inhibition of nuclear factor-kappa B (NF-kappa B) activation, low levels of this hormone may be deleterious in chronic inflammatory diseases. We have recently demonstrated that DHEA is a potent inhibitor of IL-6, which confirmed an earlier study in mice. Since IL-6 is an important factor for B lymphocyte differentiation, the missing down-regulation of this cytokine, and others such as TNF, may be a significant risk factor in rheumatic diseases. Since in these patients, administration of prednisolone or the chronic inflammatory process itself alters adrenal function, endogenous adrenal hormones in relation to proinflammatory cytokines change. Furthermore, these mechanisms may also lead to shifts in steroidogenesis which have been demonstrated in chronic inflammatory diseases. It was repeatedly demonstrated that the serum level of the sulphated form of DHEA (DHEAS) was significantly lower in patients with chronic inflammatory diseases. Since DHEAS is the pool for peripheral sex steroids, such as testosterone and 17 beta-estradiol, lack of this hormone leads to a significant sex hormone deficiency in the periphery. This overview will demonstrate mechanisms why DHEAS is reduced in chronic inflammatory diseases. The importance of DHEAS deficiency will be demonstrated with respect to osteoporosis. As a consequence, we suggest a combined therapy with corticosteroids plus DHEA in chronic inflammatory diseases.

Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence.

Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich J, Falk W, Lang B. Department of Internal Medicine I, University Medical Center, Regensburg, Germany.

J Clin Endocrinol Metab 1998 Jun;83(6):2012-7

Interleukin-6 (IL-6) is one of the pathogenetic elements in inflammatory and age-related diseases such as rheumatoid arthritis, osteoporosis, atherosclerosis, and late-onset B cell neoplasia. In these diseases or during aging, the decrease in production of sex hormones such as dehydroepiandrosterone (DHEA) is thought to play an important role in IL-6-mediated pathogenetic effects in mice. In humans, we investigated the correlation of serum levels of DHEA, DHEA sulfate (DHEAS), or androstenedione (ASD) and IL-6, tumor necrosis factor-alpha, or IL-2 with age in 120 female and male healthy subjects (15-75 yr of age). Serum DHEA, DHEAS, and ASD levels significantly decreased with age (all P < 0.001), whereas serum IL-6 levels significantly increased with age (P < 0.001). DHEA/DHEAS and IL-6 (but not tumor necrosis factor-alpha or IL-2) were inversely correlated (all patients: r = -0.242/-0.312; P = 0.010/0.001). In female and male subjects, DHEA and ASD concentration dependently inhibited IL-6 production from peripheral blood mononuclear cells (P = 0.001). The concentration-response curve for DHEA was U shaped (maximal effective concentration, 1-5 x 10(-8) mol/L), which may be the optimal range for immunomodulation. In summary, the data indicate a functional link between DHEA or ASD and IL-6. It is concluded that the increase in IL-6 production during the process of aging might be due to diminished DHEA and ASD secretion. Immunosenescence may be directly related to endocrinosenescence, which, in turn, may be a significant cofactor for the manifestation of inflammatory and age-related diseases.

Cytokine secretion in whole blood of healthy subjects following oral dministration of Urtica dioica L. plant extract. [Article in German]

Teucher T, Obertreis B, Ruttkowski T, Schmitz H. Strathmann AG & Co., Hamburg.

Arzneimittelforschung 1996 Sep;46(9):906-10

Twenty healthy volunteers ingested for 21 days 2 capsules b.i.d. of an IDS 23/1 containing nettle leaf extract (Rheuma-Hek). Before and after 7 and 21 days the basal and the lipopolysaccharide (LPS) stimulated tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) concentrations were measured ex vivo. In vitro the effects of IDS 23/1 on the release of these cytokines were determined. Additionally basal interleukin-4 (IL-4) and interleukin-10 (IL-10) levels were recorded. Orally taken the test drug has ex vivo no effect on basal levels of TNF-alpha, IL-1 beta, IL-4, IL-6 or IL-10 which were always below detection limits. After 7 and 21 days ingestion ex vivo a decrease of LPS stimulated TNF-alpha release of 14.6 and 24.0%, respectively, was observed. IL-1 beta was reduced for 19.2 and 39.3%. In vitro IDS 23/1 added to whole blood resulted in an exceeded inhibition of LPS stimulated TNF-alpha and IL-1 beta secretion which correlated with the duration of the drug ingestion. Using the highest tested IDS 23/1 concentration the inhibition reached 50.5 (day 0) to 79.5% (day 21) for TNF-alpha and 90.0 (day 0) to 99.2% (day 21) for IL-1 beta, respectively. IDS 23/1 induced a pronounced release of IL-6 in absence of LPS only in vitro. The detected IL-6 concentrations were comparable to those after LPS stimulation, additive effects could not be observed. The absence of detectable IL-6 concentrations in whole blood ex vivo after oral ingestion of the tested drug as well as the differences in the inhibition patterns for TNF-alpha and IL-1 beta ex vivo and ex vivo in vitro suggest that the extract contains different pharmacological effective compounds with varying bioavailabilities.

Dietary docosahexaenoic acid suppresses inflammation and immunoresponses in contact hypersensitivity reaction in mice.

Tomobe YI, Morizawa K, Tsuchida M, Hibino H, Nakano Y, Tanaka Y. Tsukuba Research Laboratory, NOF Corporation, Ibaraki, Japan.

Lipids 2000 Jan;35(1):61-9

This study was designed to examine the immunomodulatory effects of dietary docosahexaenoic acid (DHA) in the absence of eicosapentaenoic acid (EPA). We investigated the effects of feeding dietary DHA ethyl ester (DHA-Et) (97% pure) at levels of 4.8 wt% of the total diet and of feeding EPA ethyl ester (EPA-Et) (99% pure) at 4.8 wt% on the inflammatory response in the challenge phase of the contact hypersensitivity reaction (CHR) in the ears of mice sensitized with 2,4-dinitro-1-fluorobenzene (DNFB). The effect of DHA-Et on T lymphocytes at the CHR site was examined using anti-CD4 antibodies. Furthermore, we examined the cytokines formed at the CHR site on the mRNA level. It was found that 24 h after the challenge, DHA-Et but not EPA-Et reduced the ear swelling. Infiltration of inflammatory cells, in particular, CD4-positive T lymphocytes, into the ears in the challenge phase of CHR was observed. DHA-Et reduced the infiltration of CD4-positive T lymphocytes into the ears. DHA-Et also decreased the expression of interferon-gamma, interleukin (IL)-6, IL-1beta, and IL-2 mRNA in ears. These observations suggest that DHA, but not EPA, may exert an antiinflammatory and immunosuppressive effect. The immunosuppressive ffectiveness of fish oil may be attributed mainly to DHA.

Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin.

Yam D, Peled A, Shinitzky M. Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.

Cancer Chemother Pharmacol 2001;47(1):34-40

PURPOSE: The anticancer activity of omega-3 polyunsaturated fatty acids (omega-3 PUFA) has been shown in a large number of studies. This study was undertaken to analyze the combined effect of omega-3 PUFA and antioxidative vitamins on the level of spontaneous metastatic dissemination. The supportive effect of this dietary combination on chemotherapy with cisplatin (CP) was determined in parallel.

METHODS: C57BL/6J mice bearing the Lewis lung carcinoma 3LL were fed ad libitum one of three isocaloric diets containing 5% soybean oil supplemented with 40 mg/kg alpha-tocopherol acetate (SO diet), or 4% fish oil plus 1% corn oil, and basal amounts of vitamin E (FO diet) or FO diet supplemented with vitamins E and C (FO+E+C diet). These diets were tested in combination with the conventional cytotoxic agent CP in a series of regimens. Tumor growth, feed consumption, body weight, lung metastasis and lung histology were followed.

RESULTS: Both the FO dietary groups showed significantly lower tumor development than the SO group in all examined parameters, indicating that omega-3 PUFA have anticancer activity. However, the FO diet, in comparison with the FO+E+C diet induced a significantly slower rate of tumor growth, and lower metastatic load, as reflected in lung weight. The decrease in the anticancer activity of FO by the addition of vitamins E and C suggests that in situ oxidation of omega-3 PUFA underlies their anticancer action. It is thus proposed that oxidized omega-3 PUFA accumulates in the membranes and the cytosol of tumor cells, reducing their vitality and eventually leading to their death. No signs of anorexia or cachexia were observed in either FO group, in contrast to the SO group. CP treatment with the SO diet had no apparent therapeutic effect, while with the FO diets it reduced the metastatic load. The best regimen of this combined treatment was FO diet followed by CP treatment with FO diet supplemented with vitamins E and C after resection of the primary growth. This regimen could be translated to a combined therapy for human cancer.

CONCLUSIONS: Diets enriched with omega-3 PUFA may have beneficial anticancer effects in particular when containing only basal amounts of antioxidants such as vitamin E or C. Furthermore, the addition of drugs which promote oxidation of omega-3 PUFA, such as ferrous salts (e.g. as prescribed for the treatment of anemia), may further increase these effects. However, the supportive effect of omega-3 PUFA in chemotherapy (e.g. with CP) increases when vitamins E and C are also included.

Folates in human nutrition. Different clinical situations in which folate deficiencies exist. [Article in Spanish]

Zarazaga A, Garcia de Lorenzo A, Montanes P, Culebras JM. Servicio de Cirugia General, Hospital Universitario, La Paz, Madrid.

Nutr Hosp 1991 Jul-Aug;6(4):207-26

The alimentary surveys carried out on various sectors of the population in industrialized countries have shown the existence of chronic clinically silent deficiency in micronutrients. In some cases, as in folates, their lability against conservation techniques, the change in alimentary habits, the abuse of alcohol and the great quantity of frequently used drugs which interfere in their absorption, diminish their content in the diet and their bio-availability. The appearance of macrocytic anemia is a late deficiency sign, and therefore in situations of an increase need and in patients included in the risk groups, a supplemental intake must be given in order to avoid irreversible lesions if it is not possible to monitor the folate levels. There are risk groups in which various etiological factors come into play, acting at a different metabolic level on the folates and making more difficult their dietetic or pharmacological compensation even if supply is considerably increased. We studied these factors independently and in each specific situation (old people, patients with liver disease, alcoholics, pregnant women and nursing mothers, neonates, children, malabsorption syndromes, gastrectomy, AIDS, anaesthesia and patients being treated with antifolic medication), evaluating their mechanisms of action and their potentiation in determined specific situations.

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