|
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. pcc@soton.ac.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. kai-uwe.eckardt@charite.de
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.
Dkelley@whnrc.usda.gov
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.
Loria@gems.vcu.edu
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 &amp; 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.
Rainer.Straub@klinik.uni-regensburg.de
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.
rainer.straub@klinik.uni-regensburg.de
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.
|