29. The Chemistry of Food – and of Bodies 11
Aqueous (polar) environment
outside cell
Phospholipid
molecule Intrinsic protein
(e.g. sugar carrier,
hormone receptor)
Cholesterol
molecules
Non-polar
(hydrophobic)
region
within
membrane
Aqueous (polar) environment
inside cell
Figure 1.5 Structure of biological membranes in mammalian cells. Cell membranes
and intracellular membranes such as the endoplasmic reticulum are composed of bilayers of phos-
pholipid molecules with their polar head-groups facing the aqueous environment on either side and
their non-polar ‘tails’ facing inwards, forming a hydrophobic center to the membrane. The membrane
also contains intrinsic proteins such as hormone receptors, ion channels, and sugar transporters, and
molecules of cholesterol which reduce the ‘fluidity’ of the membrane. Modern views of cell mem-
brane structure emphasize that there are domains, known as ‘rafts,’ in which functional proteins
co-locate, enabling interactions between them. These lipid rafts are characterized by high concentra-
Frayn KN. Metabolic Regulation. Blackwell Pub; 2010:384.
30. De Caterina R. N Engl J Med 2011
AINES ÁCIDO ARAQUIDÓNICO
31. De Caterina R. N Engl J Med 2011
Coxibs ÁCIDO ARAQUIDÓNICO
32. Nonsteroidal Anti-Inflammatory Drugs 241
F
CHCO2H
CH3
Br
S
F
SO2CH3 Bulky grouping
COX-1 inhibitor
Flurbiprofen
COX-2 inhibitor
DuP697
Intracellular membrane
NSAID binding space
COX-1 COX-2
“Side pocket”
Figure 18.2. Serhan CN, Ward PA, Gilroy DW, editors. Fundamentals of Inflammation. Cambridge Univ Pr; 2010: 234-243.
AINES
Coxibs
33. Inflammationandeccentricexercise•77
Figure 1 Exercise-induced muscle damage and subsequent muscle inflammation and regeneration process
(PMN, polymorphonuclear leucocyte; Mb, myoglobin; CK, creatine kinase; ROS, reactive oxygen species)
PMN
satellite cells
regenerated
muscle fibres
Recovery
• proliferation of satellite cells
• acquisition of protective effect
After exercise
• leukocyte infiltration
• inflammation
During exercise
mechanical damage to muscle
tissue
monocytes
macrophages
growth
factors
cytokines
phagocytosis
cytokines
chemoattractants
priming
damaged
muscle fibres
ROS
enzymes
muscle tissue
fragments
CK
CK
Mb
Mb
muscle tissue
fragments
phagocytosis
adhesion molecules
endothelial cells
blood circulation
Exercise 24 hours after exercise 1 day to 2 weeks after exercise
Inflammationandeccentricexercise•77
Figure 1 Exercise-induced muscle damage and subsequent muscle inflammation and regeneration process
(PMN, polymorphonuclear leucocyte; Mb, myoglobin; CK, creatine kinase; ROS, reactive oxygen species)
PMN
satellite cells
regenerated
muscle fibres
Recovery
• proliferation of satellite cells
• acquisition of protective effect
After exercise
• leukocyte infiltration
• inflammation
During exercise
mechanical damage to muscle
tissue
monocytes
macrophages
growth
factors
cytokines
phagocytosis
cytokines
chemoattractants
priming
damaged
muscle fibres
ROS
enzymes
muscle tissue
fragments
CK
CK
Mb
Mb
muscle tissue
fragments
phagocytosis
adhesion molecules
endothelial cells
blood circulation
Exercise 24 hours after exercise 1 day to 2 weeks after exercise
Peake J, Nosaka K, Suzuki K. Exerc Immunol Rev. 2005;11:64-85
34. fibers, as previously mentioned.
These cells have also been used
genetic disease (such as Duch-
enne muscular dystrophy [DMD]),
skeletal muscle is limited and very
often, fibrotic tissue forms, delay-
Figure 1. Generalized scheme of myogenic differentiation. Other markers are used by different investigators. (Adapted from Deasy
et al., 2001, Blood Cells Mol Dis, 27, 924–933)
MODULATING SKELETAL MUSCLE REPAIR BY MUSCLE DERIVED STEM CELLS AND ANTIFIBROTIC AGENTS 83
Mio D – factor de transcrição responsável
pela activação das células satélite e
subsequente proliferação dos mioblastos
Gharaibeh B, et al. Birth Defects Res C Embryo Today. 2012 Mar;96(1):82-94.
35. 52 • Exercise-induced muscle damage and inflammation
-60
-50
-40
-30
-20
-10
0
10
-24 0 24 48 72 96 120 144 168
Changeinforce-generatingcapacity(%)
Time (hours after exercise)
Mild damage
Moderate damage
Severe damage
Figure 2. Recovery of the force-generating capacity of subjects that have performed heavy
resistance exercise or maximal eccentric exercise (subjects from several studies are com-
bined: (230,248-251), as well as unpublished data). The subjects are organized so that
those who recover their force-generating capacity within 48 hours are represented as mild
Paulsen G, Mikkelsen UR, Raastad T, Peake JM. Exerc Immunol Rev. 2012;18:42-97
36. ü 14 atletas
ü Corrida de 36 Km
ü Indometacina (100 mg) vs Placebo
ü Ingestão: durante 4 dias antes da corrida até à data da
última biópsia
RESULTADOS:
J Appl Physiol 103: 425–431, 2007
38. 40
J Appl Physiol 107: 1600–1611, 2009
200 contrações excêntricas
NSAID numa perna (antes, durante e até 4,5 h depois) e a outra como controlo
Célulassatélite
39. protein accretion seen in eccentric protocols. Other studies,
however, seem to refute whether a reversal of the size
principle actually does occur. An extensive review of the
literature by Chalmers (26) concluded that the preponder-
ance of evidence does not support selective recruitment of
generally less compared with those performed concentri-
cally. This paradox was demonstrated by Grabiner et al. (55),
who found that the maximum EMG of the vastus lateralis
during eccentric knee extension was only 84 6 41% of that
obtained concentrically. Hence, although the potential to
TABLE 1. Summary of human studies investigating the effect of NSAID consumption on satellite cell activity.*
Study Subjects NSAID/dosage Results
Bondesen et al. (16) Rodents SC-560/3 mgÁkg21
Ád21
SC-236 /6 mgÁkg21
Ád21
Significant blunting of satellite cell
activity in NSAID compared
with placebo
Bondesen et al. (17) Rodents SC-236 /6 mgÁkg21
Ád21
Significant blunting of satellite cell
activity in NSAID compared with
placebo
Mackey et al. (91) Humans Indomethacin/100 mg Significant blunting of satellite cell
activity in NSAID compared with
placebo
Mikkelsen et al. (100) Humans Indomethacin/45 mg Significant blunting of satellite cell
activity in NSAID compared with
placebo
Paulsen et al. (117) Humans Celcoxib/400 mg No significant differences in satellite
cell activity between groups
*NSAIDs = nonsteroidal anti-inflammatory drugs.
Exercise-Induced Muscle Damage
Schoenfeld BJ. J Strength Cond Res. 2012 May;26(5):1441-53.
40. Am J Physiol Cell Physiol 287: C475–C483, 2004
Inibidor de
COX-2
Lesão induzida pelo frio
45. ü 24 adultos masculinos
ü RCT com Placebo
ü 10-14 series de 10 rep excéntricas RM
DIMINUIÇÃO (24h): Fractional synthesis rate
Sem efeitos na dor comparado com placebo
Am J Physiol Endocrinol Metab 2002; 282: E551–E556
48. 52
INFLAMAÇÃO AGUDA
INFLAMAÇÃO CRÓNICAREGENERAÇÃO
Ahn KS, Aggarwal BB. Ann N Y Acad Sci. 2005 Nov;1056:218-33
Serhan CN. Annu. Rev. Immunol. 2007. 25:101–37
Roubenoff R. Nutr Rev. 2007 Dec;65(12 Pt 2):S208-12
Tidball JG, Villalta SA. Am J Physiol Regul Integr Comp Physiol 2010; 298: R1173–R1187
Lesão e Dor Crónica
Catabolismo muscular e ósseo
Síndrome de Morte Súbita
Doenças Metabólicas
e Neurodegenativas
49. Chen LC, Ashcroft DM. Pharmacoepidemiol Drug Saf. 2007 Jul;16(7):762-72
50. 54
INFLAMAÇÃO AGUDA
INFLAMAÇÃO CRÓNICAREGENERAÇÃO
Ahn KS, Aggarwal BB. Ann N Y Acad Sci. 2005 Nov;1056:218-33
Serhan CN. Annu. Rev. Immunol. 2007. 25:101–37
Roubenoff R. Nutr Rev. 2007 Dec;65(12 Pt 2):S208-12
Tidball JG, Villalta SA. Am J Physiol Regul Integr Comp Physiol 2010; 298: R1173–R1187
AA
Lesão e Dor Crónica
Catabolismo muscular e ósseo
Síndrome de Morte Súbita
Doenças Metabólicas
e Neurodegenativas
52. 56
ACILGLICERÓIS PODEM TER:
1 ácido gordo (acil):
monoacilglicerol ou monoglicéridos
2 ácidos gordos (acil): díacilglicerol
ou diglicéridos
3 ácidos gordos (acil): Triacilglicerol
ou Triglicéridos
Erasmus U. Fats that heal, fats that kill. Alive Books 1993
53. 57Erasmus U. Fats that heal, fats that kill. Alive Books 1993
Hidrofóbica
Apolar
Hidrofílico
Polar
Ómega
(Metil)
Carboxil
54. 58
ü Cadeia curta: 4-6 carbonos
ü Cadeia média: 8-12 carbonos
ü Cadeia longa: 14-20 carbonos
ü Cadeia muito longa: 22+ carbonos
H H H H H H H H H H H O
I I I I I I I I I I I II
H-C-C-C-C-C-C-C-C-C-C-C-C-OH
I I I I I I I I I I I I
H H H H H H H H H H H H
1
12
Grupo Carboxil
Omega
(Grupo Metil)
Mataix J. Nutrición y Alimentación Humana – Tomo I: Nutrientes y Alimentos. Ergon, 2002.
55. 59
CADA ÁTOMO DE CARBONO TEM 4 UNIÕES
H H H H H H H H H H H O
I I I I I I I I I I I II
H-C-C-C-C-C-C-C-C-C-C-C-C-OH
I I I I I I I I I I I I
H H H H H H H H H H H H
Grupo Carboxil
Ómega
(Grupo Metil)
Mataix J. Nutrición y Alimentación Humana – Tomo I: Nutrientes y Alimentos. Ergon, 2002.
57. 61
AG MONOINSATURADOS
H H H H H H H H H H H H H H H H H O
I I I I I I I I I I I I I I I I I II
H-C-C-C-C-C-C-C-C-C=C-C-C-C-C-C-C-C-C -OH
I I I I I I I I I I I I I I I
H H H H H H H H H H H H H H H
Ácido Oleico = 18:1n-9
1 união dupla
Longitude: 18 carbonos
9 carbonos a partir do ómega
Ómega
(Metil)
Carboxil
Cordain, 2006
60. 64
AG POLINSATURADOS N-6
H H H H H H H H H H H H H H H H H O
I I I I I I I I I I I I I I I I I II
H-C-C-C-C-C-C=C-C-C=C-C-C-C-C-C-C-C-C -OH
I I I I I I I I I I I I I
H H H H H H H H H H H H H
Ácido Linoleico = 18:2n-6
Ómega
(metil)
Carboxil
Cordain, 2006
61. 65
H H H H H H H H H H H H H H H H H O
I I I I I I I I I I I I I I I I I II
H-C-C-C=C-C-C=C-C-C=C-C-C-C-C-C-C-C-C -OH
I I I I I I I I I I I
H H H H H H H H H H H
Ácido α Linolénico = 18:3n-3
Ómega
(metil)
Carboxil
Cordain, 2006
AG POLINSATURADOS N-3
77. DOSES BAIXAS DE ASPIRINA
Chiang N et al. Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial.
PNAS 2004. 101; 42
81. LXA4 INIBE PRODUÇÃO TNF-ALFA!
Kure I, et al. J Pharmacol Exp Ther. 2010 Feb;332(2):541-8
82. LXA4 RESOLVE INFLAMAÇÃO SINOVIAL!
Fiore et al. Prostaglandins, Leukotrienes and Essential Fatty Acids 73 (2005) 189–196
83. EPA & DHA
Calder PC. Biochimie. 2009 Feb 3. [Epub ahead of print]
84. 91
EPA E DHA DIMINUEM
ü IL1-ß
ü IL6
ü TNF-α
Calder PC. Braz J Med Biol Res 36(4) 2003
85. A meta-analysis of the analgesic effects of omega-3 polyunsaturated
fatty acid supplementation for inflammatory joint pain
Robert J. Goldberg a,c
, Joel Katz a,b,c,d,*
a
Department of Psychology, York University, Toronto, ON, Canada
b
School of Kinesiology and Health Science, York University, Toronto, ON, Canada
c
Department of Anesthesia and Pain Management, Toronto General Hospital and Mount Sinai Hospital, Canada
d
Department of Anesthesia, University of Toronto, Canada
Received 1 September 2006; received in revised form 23 December 2006; accepted 22 January 2007
Abstract
Between 40% and 60% of Americans use complementary and alternative medicine to manage medical conditions, prevent disease,
and promote health and well-being. Omega-3 polyunsaturated fatty acids (x-3 PUFAs) have been used to treat joint pain associated
with several inflammatory conditions. We conducted a meta-analysis of 17 randomized, controlled trials assessing the pain relieving
www.elsevier.com/locate/pain
Pain 129 (2007) 210–223
86. showed significant improvements. Improvements in
morning stiffness and NSAID consumption were noted,
stiffness, and SMD: À0.65; 95% CI: À1.40 to 0.09,
p = 0.09 for NSAID consumption). Significant effects
Geusens 1994 19 1.58(0.57) 20 1.75(2.68) 32.18 -0.08 [-0.71, 0.54]
Remans 2004 26 38.00(7.00) 29 38.00(18.00) 45.33 0.00 [-0.53, 0.53]
Total (95% CI) 62 61 100.00 -0.14 [-0.49, 0.22]
Test for heterogeneity: Chi² = 1.14, df = 2 (P = 0.56), I² = 0%
Test for overall effect: Z = 0.76 (P = 0.45)
-4 -2 0 2 4
Favours Omega-3 PUFA Favours Placebo
Review: Omega-3 polyunsaturated fatty acids for pain
Comparison: 02 Omega-3 polyunsaturated fatty acids versus placebo for joint pain: supplementation for 3-4 months
Outcome: 03 Morning Stiffness (minutes)
Study Omega-3 PUFA Placebo SMD (random) Weight SMD (random)
or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI
Kremer 1985 23 56.00(48.00) 21 131.00(142.00) 13.78 -0.71 [-1.32, -0.10]
Cleland 1988 23 25.00(30.00) 23 38.00(45.00) 14.63 -0.33 [-0.92, 0.25]
vanderTempel 1989 14 15.00(18.70) 14 50.00(48.64) 9.83 -0.92 [-1.71, -0.14]
Kremer 1990 17 39.10(75.30) 12 26.30(32.70) 10.68 0.20 [-0.54, 0.94]
Tulleken 1990 13 45.00(35.70) 14 75.00(52.68) 9.98 -0.64 [-1.42, 0.14]
Nielson 1992 27 78.75(41.25) 24 120.00(60.00) 14.91 -0.80 [-1.37, -0.22]
Remans 2004 26 76.00(70.00) 29 71.00(40.00) 16.31 0.09 [-0.44, 0.62]
Berbert 2005 13 21.00(49.00) 13 46.00(47.00) 9.88 -0.50 [-1.29, 0.28]
Total (95% CI) 156 150 100.00 -0.43 [-0.72, -0.15]
Test for heterogeneity: Chi² = 10.77, df = 7 (P = 0.15), I² = 35.0%
Test for overall effect: Z = 2.95 (P = 0.003)
-4 -2 0 2 4
Favours Omega-3 PUFA Favours Placebo
Review: Omega-3 polyunsaturated fatty acids for pain
Comparison: 02 Omega-3 polyunsaturated fatty acids versus placebo for joint pain: supplementation for 3-4 months
Outcome: 04 Number of Painful / Tender Joints
Study Omega-3 PUFA Placebo SMD (random) Weight SMD (random)
or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI
Kremer 1985 23 6.40(5.60) 21 9.00(8.30) 10.40 -0.36 [-0.96, 0.23]
Cleland 1988 23 9.50(7.50) 23 12.00(10.25) 10.98 -0.27 [-0.85, 0.31]
vanderTempel 1989 14 29.00(26.19) 14 42.00(33.67) 6.58 -0.42 [-1.17, 0.33]
Kremer 1990 17 3.00(5.15) 12 6.20(4.15) 6.40 -0.65 [-1.41, 0.11]
Tulleken 1990 13 14.50(12.69) 14 16.50(8.78) 6.47 -0.18 [-0.94, 0.58]
Nielson 1992 27 8.00(3.00) 24 11.00(5.00) 11.44 -0.73 [-1.30, -0.16]
Geusens 1994 19 15.00(8.72) 20 19.00(13.42) 9.25 -0.34 [-0.98, 0.29]
Adam 2003 30 33.60(18.07) 30 36.00(21.91) 14.44 -0.12 [-0.62, 0.39]
Remans 2004 26 10.70(4.10) 29 9.70(5.10) 13.14 0.21 [-0.32, 0.74]
Sundrarjun 2004 23 9.13(6.62) 23 12.30(10.31) 10.90 -0.36 [-0.94, 0.22]
Total (95% CI) 215 210 100.00 -0.29 [-0.48, -0.10]
Test for heterogeneity: Chi² = 7.35, df = 9 (P = 0.60), I² = 0%
Test for overall effect: Z = 2.97 (P = 0.003)
-4 -2 0 2 4
Favours Omega-3 PUFA Favours placebo
Fig. 3. Analysis of data used in overall result assessment from studies providing 3–4 month supplementation of x-3 PUFAs. Conducted using
Cochrane Review Manager 4.2.8. software. SD, standard deviation; SMD, standardized mean difference; CI, confidence interval.
www.elsevier.com/locate/pain
Pain 129 (2007) 210–223
87. ÓMEGA-3 E INFLAMAÇÃO
ü 17 meta-análises de
RCTs testando os
efeitos de Ómega-3 na
AR
ü 3-4 meses: redução da
dor articular, minutos
de rigidez matinal,
número de
articulações com dor
e menor uso de AINES
Goldberg RJ, Katz J. Pain 129 (2007)
88. t
Table 2. Comparison of fish oil with adalimumab (Values are the
standardised mean difference*)
Tender or swollen
joint count Pain
Fish oil - 0.29† - 0.26†
Adalimumab
(Humira)
- 0.52 to - 0.69‡ - 0.27‡
*Hedges’ g was used to calculate the standardised mean difference, which is
the difference between means divided by the pooled standard deviation.
†Goldberg and Katz(4)
.
‡Calculated from data in FDA(67)
.
. James et al.
ProceedingsoftheNutritionSociety
The 3rd International Immunonutrition Workshop was held at Platja D’Aro, Girona, Spain on 21–24 October
3rd International Immunonutrition Workshop
Session 3: Fatty acids and the immune system
Fish oil and rheumatoid arthritis: past, present and future
Michael James*, Susanna Proudman and Les Cleland
Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Meta- and mega-analysis of randomised controlled trials indicate reduction in tender joint
counts and decreased use of non-steroidal anti-inflammatory drugs with fish-oil supplemen-
tation in long-standing rheumatoid arthritis (RA). Since non-steroidal anti-inflammatory drugs
confer cardiovascular risk and there is increased cardiovascular mortality in RA, an additional
benefit of fish oil in RA may be reduced cardiovascular risk via direct mechanisms and
decreased non-steroidal anti-inflammatory drug use. Potential mechanisms for anti-inflammatory
effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and
provision of substrates for synthesis of lipid suppressors of inflammation (resolvins). Future
studies need progress in clinical trial design and need to shift from long-standing disease to
examination of recent-onset RA. We are addressing these issues in a current randomised con-
trolled trial of fish oil in recent-onset RA, where the aim is to intervene before joint damage has
occurred. Unlike previous studies, the trial occurs on a background of drug regimens deter-
mined by an algorithm that is responsive to disease activity and drug intolerance. This allows
drug use to be an outcome measure whereas in previous trial designs, clinical need to alter drug
use was a ‘problem’. Despite evidence for efficacy and plausible biological mechanisms, the
limited clinical use of fish oil indicates there are barriers to its use. These probably include the
pharmaceutical dominance of RA therapies and the perception that fish oil has relatively
modest effects. However, when collateral benefits of fish oil are included within efficacy, the
argument for its adjunctive use in RA is strong.
Rheumatoid arthritis: Fish oil: Pain: Non-steroidal anti-inflammatory drugs
Efficacy: different outcome measures and the evidence
The main reason that patients with rheumatoid arthritis
(RA) seek medical treatment is for alleviation of pain and
discomfort. Meta- and mega-analysis of ten double-blind,
placebo-controlled trials showed that fish oil supplying
2.9– >6 g long-chain n-3 fatty acids daily for 3 months
was associated with decreased number of tender joints and
duration of morning stiffness in patients with RA of 10–11
years’ duration(1,2)
. It was concluded that there was little
difference in the magnitude of effect between 2.9 and
7.1 g/d long-chain n-3 fats(3)
.
Another symptomatic outcome measure is overall pain
experience, which is measured most commonly in clinical
trials by use of a visual linear analogue scale or categorical
scales. A meta-analysis of fish oil trials that measured
inflammatory joint pain, mainly with RA patients, reported
a beneficial effect of fish oil on patient-reported joint pain
intensity, number of painful or tender joints, duration of
morning stiffness and non-steroidal anti-inflammatory
drug (NSAID) use(4)
. However, another meta-analysis that
examined the effect of fish oil on pain scores in RA
reported that ‘There were no significant effects in twelve
studies’(5)
. However, this latter meta-analysis did not take
Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; DMARD, disease-modifying anti-rheumatic drugs; LOX, lipoxygenase; LTB, leukotriene B;
NSAID, non-steroidal anti-inflammatory drugs; RA, rheumatoid arthritis; RCT, randomised controlled trials.
*Corresponding author: Dr Michael James, fax 61-8-82224139, email michael.james@health.sa.gov.au
Proceedings of the Nutrition Society (2010), 69, 316–323 doi:10.1017/S0029665110001564
g The Authors 2010 First published online 28 May 2010
89. Table 4. Clinical indices of disease activity at baseline and 3 years. Data are mean ± SD unless stated otherwise.
No Fish Oil Fish Oil
Baseline, 3 Years, Baseline, 3 Years,
n = 13 n = 13 n = 18 n = 18
mHAQ 7.1 ± 4.2 3.3 ± 3.2* 6.6 ± 3.2 1.2 ± 1.7*#
Tender joint count 28 8.8 ± 3.6 3.5 ± 3.9* 6.4 ± 6.2 0.7 ± 1.1*#
Swollen joint count 28 6.9 ± 4.7 0.3 ± 0.6* 5.4 ± 5.5 0.9 ± 1.8*
ESR, mm/h, mean (range) 36.5 (4–80) 21.5 (8–46)* 43.1 (1–91) 8.5 (2–34)*#
CRP, mg/l, mean (range) 17.2 (4–34) 6.6 (3–15)* 30.8 (1–140) 4.0 (0.3–19)*
DAS28 5.7 ± 0.9 3.3 ± 1.0* 5.0 ± 1.5 2.1 ± 0.9*#
NSAID Use, %† 86 54 89 22
Remission Rates at 3 years, %†† — 31 — 72
* Significantly different from baseline (p < 0.01, except for ESR in No fish oil group, where p < 0.05).
# Significantly different at 3 years by comparison with the No fish oil group (p < 0.05). † NSAID use at 3 years
defined as any use of NSAID for rescue analgesia within 3rd year of the study. †† Remission rate at 3 years is
based on DAS28 < 2.6 according to EULAR criteria. DAS: Disease Activity Score; mHAQ: modified Health
Assessment Questionnaire.
J Rheumatol 2006;33:1973–9
90. ty acid analyses provide a sound basis for examining
hemical effects of antiinflammatory doses of fish oil
thin the context of structured chemotherapy. The
compliant users constituted the upper quartile for
change in EPA in plasma phospholipids. It is acknowl
that this measure may be influenced by individual diffe
in efficiency of incorporation of ingested n-3 fatty acid
phospholipids. Notwithstanding, the defining value of
Figure 1. A. Arachidonic acid (AA) as a proportion of AA plus competitor n-3 fatty acids (AA+EPA+DPA+DHA)
(mean ± SEM) at 3 years in platelets and peripheral blood mononuclear cells (PBMC). B. Eicosanoid formation in
whole-blood assay at 3 years (mean ± SEM). TXB2 measured in serum (formed through platelet COX-1). PGE2 meas-
ured in supernatants after 24 h incubation of anticoagulated blood with LPS (formed through COX-2). *p < 0.01,
unpaired t test.
Table 3. Lipid cardiovascular risk factors in plasma and erythrocytes from fasting blood samples. RBC Omega-
3 Index (EPA+DHA) is an independent index that correlates inversely with CV risk19. Data represent mean ±
SD.
No Fish Oil Fish Oil
Baseline, 3 Years, Baseline, 3 Years,
n = 11 n = 13 n = 10 n = 18
Total triglycerides 1.4 ± 0.7 1.4 ± 0.5 1.6 ± 0.5 0.6 ± 0.2*#
Total cholesterol 5.4 ± 0.6 5.3 ± 0.9 5.6 ± 1.5 5.3 ± 0.8
HDL 1.2 ± 0.5 1.4 ± 0.4 1.6 ± 0.5 1.9 ± 0.4*#
LDL 3.6 ± 0.7 3.3 ± 1.0 3.4 ± 1.2 3.1 ± 0.9
Total cholesterol/HDL 4.5 ± 2.4 3.5 ± 1.5 3.6 ± 0.8 3.0 ± 0.8*#
RBC omega-3 index — 5.06 ± 0.8 — 13.8 ± 1.8#
(EPA+DHA)
* Significantly different from baseline (p < 0.01, paired t test); # significantly different at 3 years compared with
the No fish oil group (p < 0.05, t test).
J Rheumatol 2006;33:1973–9
91. ÍNDICE Ω3: % EPA & DHA NA MEMBRANA
DOS ERITRÓCITOS.
8% Risco Baixo
4-8% Risco Intermédio
< 4% Risco Alto
Harris WS. Am J Clin Nutr. 2008 Jun;87(6):1997S-2002S
93. VEGANS TÊM NÍVEIS BAIXOS DE AA E DHA
Fokkema et al. Polyunsaturated fatty acid status of Dutch vegans and omnivores. Prostaglandins, Leukotrienes and Essential FattyAcids (2000)
94. 9 vegans saudáveis suplementados com:
ü A: 2.01 g ALA (4 ml óleo de linhaça)
ü B: 1.17 g GLA (6 ml óleo borragem)
ü A+B
95.
96. Blasbalg TL, et al. Am J Clin Nutr. 2011
FIGURE 4. Regression analysis for the availability of linoleic acid (LA)
between 1909 and 1999. The linear relation [LA percentage of energy
(en%) = 2115.4221 + 0.0617 · x] was significant at P , 0.000001 with
FIGUR
supply fr
indicated
line, and n
line. 190
data are
ESSENTIAL FATTY ACID INTAKE IN T
97.
98. Blasbalg TL, et al. Am J Clin Nutr. 2011
lipids (37), presumab
dietary intakes of LA
account for the poten
However, because LA
effects may be nonlin
A randomized trial t
with high LA (6.7% of
FIGURE 8. Omega-3 tissue highly unsaturated fatty acid (HUFA)
predictions over the 20th century. Solid arrows indicate the percentage of
TABLE 12
Sources of docosahexaeno
Food category
Poultry
Shellfish
Eggs
Finfish
Beef
Game
Total
1
NA, not applicable.
99. DIET AND RED BLOOD CELL n–6 AND n–3 FATTY ACIDS
LA diminui
DHA na
membrana
dos
eritrócitos
LA diminui
EPA na
membrana
dos
eritrócitos
Friesen RW, Innis SM. Am J Clin Nutr. 2010 Jan;91(1):23-31.
N= 105
Mulheres
(Canadá)
Grávidas
(com 36
semanas de
gestação)
100. Original Research
Involvement of CYP 2C9 in Mediating the
Proinflammatory Effects of Linoleic Acid in Vascular
Endothelial Cells
Saraswathi Viswanathan PhD, Bruce D. Hammock PhD, John W. Newman, PhD, Purushothaman Meerarani PhD,
Michal Toborek MD, PhD, and Bernhard Hennig PhD, FACN
Molecular and Cell Nutrition Laboratory, College of Agriculture (S.V., P.M., B.H.), Department of Surgery (M.T.), University of
Kentucky, Lexington, KY, 40546-0215, and Department of Entomology and UC Cancer Center (B.D.H., J.W.N.), University of
California, Davis, CA, USA.
Key words: linoleic acid, CYP 2C9, leukotoxin, leukotoxin diol, oxidative stress
Objective: Polyunsaturated fatty acids such as linoleic acid are well known dietary lipids that may be
atherogenic by activating vascular endothelial cells. In the liver, fatty acids can be metabolized by cytochrome
P450 (CYP) enzymes, but little is known about the role of these enzymes in the vascular endothelium. CYP 2C9
is involved in linoleic acid epoxygenation, and the major product of this reaction is leukotoxin (LTX). We
investigated the role of CYP-mediated mechanisms of linoleic acid metabolism in endothelial cell activation by
examining the effects of linoleic acid or its oxidized metabolites such as LTX and leukotoxin diol (LTD).
Methods: The effect of linoleic acid on CYP 2C9 gene expression was studied by RT-PCR. Oxidative stress
was monitored by measuring DCF fluorescence and intracellular glutathione levels, and electrophoretic mobility
shift assay was carried out to study the activation of oxidative stress sensitive transcription factors. Analysis of
oxidized lipids was carried out by liquid chromatography/mass spectrometry.
Results: Linoleic acid treatment for six hours increased the expression of CYP 2C9 in endothelial cells.
Linoleic acid-mediated increase in oxidative stress and activation of AP-1 were blocked by sulfaphenazole, a
specific inhibitor of CYP 2C9. The linoleic acid metabolites LTX and LTD increased oxidative stress and
activation of transcription factors only at high concentrations.
Conclusion: Our data show that CYP 2C9 plays a key role in linoleic acid-induced oxidative stress and
subsequent proinflammatory events in vascular endothelial cells by possibly causing superoxide generation
through uncoupling processes.
INTRODUCTION
Atherosclerosis is believed to be a chronic inflammatory
disease, and the earliest event of coronary atherosclerosis is
characterized by endothelial activation and dysfunction [1].
Several factors are implicated in the initiation of endothelial
dysfunction of which the formation of reactive oxygen species
is believed to play a critical role during this process [2,3].
Endothelial cells are continuously exposed to circulating
lipids (e.g., dietary fatty acids) and to lipids that have accumulated
in sub-endothelial regions. These biologically active lipids play an
important role in the development of atherosclerosis. Polyunsatu-
rated fatty acids and/or their metabolites can have potent biolog-
ical effects in various cell types by functioning as signaling mol-
ecules. Evidence suggests that linoleic acid, a major dietary
unsaturated fatty acid in the American diet, has proinflammatory
and proatherogenic effects by causing endothelial cell activation
[4]. Linoleic acid-induced endothelial activation is considered to
be mediated through oxidative stress [4,5]. However, the precise
mechanism involved in linoleic acid-induced oxidative stress and
Address reprint requests to: Bernhard Hennig, PhD, RD, FACN, Molecular and Cell Nutrition Laboratory, College of Agriculture, 213 Garrigus Building, University of
Kentucky, Lexington, KY 40546-0215. E-mail: bhennig@uky.edu
Saraswathi Viswanathan PhD, Bruce D. Hammock PhD, John W. Newman, PhD, Purushothaman Meerarani PhD,
Michal Toborek MD, PhD, and Bernhard Hennig PhD, FACN
Molecular and Cell Nutrition Laboratory, College of Agriculture (S.V., P.M., B.H.), Department of Surgery (M.T.), University of
Kentucky, Lexington, KY, 40546-0215, and Department of Entomology and UC Cancer Center (B.D.H., J.W.N.), University of
California, Davis, CA, USA.
Key words: linoleic acid, CYP 2C9, leukotoxin, leukotoxin diol, oxidative stress
Objective: Polyunsaturated fatty acids such as linoleic acid are well known dietary lipids that may be
atherogenic by activating vascular endothelial cells. In the liver, fatty acids can be metabolized by cytochrome
P450 (CYP) enzymes, but little is known about the role of these enzymes in the vascular endothelium. CYP 2C9
is involved in linoleic acid epoxygenation, and the major product of this reaction is leukotoxin (LTX). We
investigated the role of CYP-mediated mechanisms of linoleic acid metabolism in endothelial cell activation by
examining the effects of linoleic acid or its oxidized metabolites such as LTX and leukotoxin diol (LTD).
Methods: The effect of linoleic acid on CYP 2C9 gene expression was studied by RT-PCR. Oxidative stress
was monitored by measuring DCF fluorescence and intracellular glutathione levels, and electrophoretic mobility
shift assay was carried out to study the activation of oxidative stress sensitive transcription factors. Analysis of
oxidized lipids was carried out by liquid chromatography/mass spectrometry.
Results: Linoleic acid treatment for six hours increased the expression of CYP 2C9 in endothelial cells.
Linoleic acid-mediated increase in oxidative stress and activation of AP-1 were blocked by sulfaphenazole, a
specific inhibitor of CYP 2C9. The linoleic acid metabolites LTX and LTD increased oxidative stress and
activation of transcription factors only at high concentrations.
Conclusion: Our data show that CYP 2C9 plays a key role in linoleic acid-induced oxidative stress and
subsequent proinflammatory events in vascular endothelial cells by possibly causing superoxide generation
through uncoupling processes.
INTRODUCTION in sub-endothelial regions. These biologically active lipids play an
Journal of the American College of Nutrition, Vol. 22, No. 6, 502–510 (2003)
101. fatty acids may be
To examine if the
o oxidative stress,
Fig. 8. Proposed model for the mechanism of linoleic acid (LA)-
mediated endothelial cell activation. LA treatment results in CYP 2C9
tabolites. Cells were
; upper trace) for 24
ed epoxides and diols
y. These metabolites
without supplemen-
arachidonates were
a not shown). Results
aliquots analyzed by
Journal of the American College of Nutrition, Vol. 22, No. 6, 502–510 (2003)
107. non-‐fatal
myocardial
infarcIon
(MI)
+
CHD
death.
n-6 specific PUFA trials non significantly increased the risk of
non-fatal MI + CHD death by 13%
(risk ratio (RR) 1·13; 95% CI 0·84, 1·53; P=0·427)
108. EPA & DHA por cada 100g peixe
Fedacko. n−3 PUFAs—From dietary supplements to medicines. Pathophysiology 14 (2007) 127–132
111. RÁCIO ÓMEGA 6/ÓMEGA 3 DE ALGUNS ALIMENTOS
Alimento Rácio ω6/ω3
Ovo convencional 19,4
Ovo de Creta 1,3
Carne (músculo) bovina
alimentada com cereais
5,19
Carne (músculo) bovina
alimentada a pasto
2,2
Cordain L et al. European Journal of Clinical Nutrition 2002; 56:181 – 191.
Simopoulos AP. J Nutr. 2001 Nov;131(11 Suppl):3065S-73S. Review
112. ESTIMAÇÃO DA INGESTÃO DE PUFAS
DURANTE O PALEOLÍTICO
Ácidos Gordos
(g)
Dieta Baseada
em Carne
Dieta Baseada em
Peixe e Carne
Dieta Baseada em
Peixe
ALA 7,73 - 13,4 8,63 - 17,4 6,57 - 17,0
EPA 0,14 - 0,59 0,30 – 2,80 1,41 – 6,61
DHA 0,29 – 2,84 0,81 – 8,79 3,93 – 21,7
LA 8,60 – 11,2 7,20 – 12,2 5,53 – 9,96
AA 1,15 – 2,77 1,15 – 4,61 2,14 – 10,7
ALA/LA 0,70 – 1,56 0,93 – 1,75 1,19 – 1,79
(EPA+DHA) / AA 0,49 – 1,41 0,78 – 2,58 2,45 – 2,66
n-6/n-3 0,79 – 1,59 1,01 – 2,01 1,82 – 2,05
Kuipers RS, et al. Br J Nutr. 2010 Dec;104(11):1666-87
113. Time course relativo à incorporação de EPA e DHA
em fosfolipídios de membrana de células mononucleares
Indivíduos saudáveis: 2,1 g EPA + 1,1 g DHA/dia/12 semanas
0 4 8 12 20
0
1
2
3
4
Time (weeks)
EPAinmononuclearcellPL(%)
0 4 8 12 20
1
2
3
4
Time (weeks)
DHAinmononuclearcellPL(%)
Eur. J. Clin. Invest. 30, 260-274, 2000
Eur. J. Clin. Invest. 30, 260-274, 2000
INCORPORAÇÃO DE EPA E DHA NOS
FOSFOLÍPIDOS DE CÉLULAS MONONUCLEARES
129. Resistência à Insulina
é a primeira alteração
metabólica da
Síndrome Metabólica
Ludwig
D.JAMA
2002;287:2414–2423.
130.
131. Síndrome Metabólica em Portugal: Prevalência
e Implicações no Risco Cardiovascular
- Resultados do Estudo VALSIM [107]
MANUELA FIUZA, NUNO CORTEZ-DIAS, SUSANA MARTINS, ADRIANA BELO EM NOME DOS INVESTIGADORES DO ESTUDO VALSIM
Rev Port Cardiol 2008; 27 (12): 1495-1529
ARTIGOS ORIGINAIS
RESUMO
Introdução: A síndrome metabólica (SM) é uma
constelação de factores de risco de origem
metabólica que se associa a risco aumentado de
diabetes mellitus tipo 2 (DM) e doenças
cardiovasculares (DCV). Têm sido realizados
vários estudos regionais para determinação da
prevalência, mas são insuficientes para o
conhecimento da realidade nacional ou para a
caracterização do risco cardiovascular global
em Portugal.
Objectivos: Determinar a prevalência da SM e
de cada um dos seus componentes na
população adulta utente dos Cuidados de Saúde
Primários, em Portugal.
Métodos: Estudo analítico transversal nos
Cuidados de Saúde Primários, envolvendo 719
médicos de família, segundo distribuição
estratificada e proporcional à densidade
populacional de cada região de Portugal
continental e ilhas. Os primeiros dois utentes
adultos de cada dia de consulta foram
convidados a participar, independentemente do
motivo de consulta. Após consentimento
informado, foi utilizado um inquérito para
recolha de dados sócio-demográficos, clínicos e
laboratoriais. Os diagnósticos prévios de doença
ABSTRACT
Metabolic Syndrome in Portugal:
Prevalence and Implications for
Cardiovascular Risk - Results from the
VALSIM Study
Introduction: The metabolic syndrome (MS) is a
constellation of risk factors of metabolic origin
that is associated with increased risk of type 2
diabetes mellitus (DM) and cardiovascular
disease (CVD). Several regional studies have
been conducted to determine its prevalence,
but they are insufficient to determine the
situation nationally or to characterize overall
cardiovascular risk in Portugal.
Objective: To determine the prevalence of MS
and each of its components in adult primary
health care users in Portugal.
Methods: The VALSIM Study, involving 719
general practitioners (GPs), was performed in a
primary care setting, based on stratified
distribution and proportional to the population
density of each region of mainland Portugal and
the islands of Madeira and the Azores. The first
two adult patients scheduled for an appointment
on a given day were invited to participate,
irrespective of the reason for the consultation.
Norte
Northern
28,17%
(H:26,56%; M:29,61%)
(M:26,56%; F:29,61%)
28,79%
(H:27,89%; M:29,61%)
(M:27,89%; F:29,61%)
26,05%
(H:19,5%; M:32,23%)
(M:19,5%; F:32,23%)
25,71%
(H:24,7%; M:26,62%)
(M:24,7%; F:26,62%)
29,38%
(H:25,84%; M:32,33%)
(M:25,84%; F:32,33%)
30,99%
(H:29,68%; M:32,21%)
(M:29,68%; F:32,21%)
24,42%
(H:21,65%; M:27,1%)
(M:21,65%; F:27,1%)
Centro
Central
Açores
Azores
Madeira
Lisboa e
Vale do Tejo
Lisbon and
Tagus Valley
Alentejo
Algarve
Prevalência inferior à mèdia nacional em mais de 10%
Prevalence more than 10% below national average
Prevalência inferior à mèdia nacional em 5 a 10%
Prevalence 5 to 10% below national average
Prevalência inferior à mèdia nacional em até 5%
Prevalence up to 5% below national average
Prevalência superior à mèdia nacional em até 5%
Prevalence up to 5% above national average
Prevalência superior à mèdia nacional em 5a 10%
Prevalence 5 to 10% above national average
Prevalência superior à mèdia nacional em mais de 10%
Prevalence more than 10% above national average
Rev Port Cardiol
Vol. 27 Dezembro 08 / December 08
Prevalência Global
Nacional: 27,50%
O diagnóstico de SM foi efectuado pelos
critérios NCEP-ATP III
134. a strong strength of association between psoriasis
and metabolic syndrome. Importantly, most studies
also reported a high overall prevalence of metabolic
Fig 2. Meta-analysis of the prevalence of metabolic syndrome in the psoriasis patients.
Armstrong AW, Harskamp CT, Armstrong EJ.J Am Acad Dermatol. 2013 Jan 26.
135. ORIGINAL PAPER
Psoriasis increased the risk of diabetes: a meta-analysis
Juan Cheng • Dayu Kuai • Li Zhang •
Xueqin Yang • Bing Qiu
Received: 15 April 2011 / Revised: 30 November 2011 / Accepted: 8 December 2011 / Published online: 1 January 2012
Ó Springer-Verlag 2011
Abstract To evaluate the association between psoriasis
and risk of diabetes, pertinent studies were identified by
searching electronic databases and by reviewing the ref-
erence lists of retrieved articles. We included observational
studies that examined the association between psoriasis and
risk of diabetes. Two reviewers independently assessed
eligibility and used a standardized form to collect data
from published studies. The study quality was assessed by
the Newcastle–Ottawa Scale. A total of 22 eligible studies
that included 3,307,516 participants fulfilled the inclusion
criteria. Compared to individuals without psoriasis,
subjects with psoriasis had a 1.42-fold increased risk of
diabetes (95% CI, 1.40–1.45). Findings from this meta-
analysis suggest that individuals with psoriasis may have a
modestly increased risk of diabetes.
Keywords Diabetes Á Psoriasis Á Meta-analysis
Introduction
Psoriasis is a chronic, inflammatory disease characterized
by erythematous scaly patches that affect the scalp, trunk,
extensor surfaces of the limbs, and the genital area. Pso-
riasis affects about 2 to 3% of the adult population [16, 36]
and is associated with decreased quality of life, even in
patients in whom the affected body surface area is rela-
tively limited [30].
Diabetes is a serious and growing health problem in the
USA, where it affects about 17 million people and plays
key role in increasing cardiovascular mortality [11, 15, 23,
24]. The association between psoriasis and risk of diabetes
has been examined in numerous epidemiologic studies [1–
3, 8–10, 13, 17, 18, 20–22, 25, 26, 28, 29, 31–33, 37, 41]
and a markedly increased risk for diabetes has been found
in individuals with psoriasis. The adjusted risk ratios for
incident diabetes associated with psoriasis range between
1.08 and 3.61. In contrast, a few studies have suggested
that psoriasis is not associated with an increased risk of
diabetes. The reasons for this difference are not quite clear
but probably due to poor design, inadequate size, the
severity of psoriasis, and consequent lack of power. So a
meta-analysis is valuable in synthesizing the available
evidence [7].We therefore, performed a meta-analysis of
all published data to examine the association between
psoriasis and risk of diabetes.
Methods
Search strategy
J. Cheng (&)
Department of Dermatology,
Beijing 302 Hospital, Beijing, China
e-mail: chengj_2000@126.com
D. Kuai
Department of Digestion, Lu He Hospital, Beijing, China
L. Zhang
Department of Dermatology,
Beijing 307 Hospital, Beijing, China
X. Yang
Department of Dermatology,
Air Force General Hospital, Beijing, China
Arch Dermatol Res (2012) 304:119–125
DOI 10.1007/s00403-011-1200-6
syndrome was significantly more common in psoriatic
diabetes
h psoriasis
Res (2012) 304:119–125 123
138. 5–12(Table2).DuringthefirstyearfollowingRAdiag- increased RRs were observed for all outcomes, except
<49 years 2124 (28.4) 10 571(28.6) N ⁄ S
50–59 years 1898 (25.4) 9548(25.8)
60–69 years 1791 (24.0) 8893(24.0)
70–93 years 1656 (22.2) 8012(21.6)
Yearofstart offollow-upb
1995–1997 895 (12.0) 4457(12.0) N ⁄ S
1998–2001 2547 (34.1) 12 627(34.1)
2002–2006 4027 (53.9) 19 940(53.9)
RFstatusc
Positive 4981 (66.7) N ⁄ A N ⁄ A
Missing 300 (4.0) N ⁄ A
NA = not assessed ⁄ applicable. NS = nonsignificant. a
Interquartile range. b
Follow-up began for the comparator subjects at the
same time as for their matched patient with RA. c
RF status was determined at diagnosis; data on RF status were missing for 300
patientswithRA.
Table 2 Relative risk (RRa
) for incident MI and other IHD events in the Swedish Early RA Register study population of 7469 patients
with incident RA and 37 024 matched controls aged 16 and above and diagnosed with RA within 18 months of symptom onset
between1995andendof2006
Outcomeb
<1 yearsinceRA
diagnosis
1–4 yearssinceRA
diagnosis
5–12 yearssinceRA
diagnosis Entirefollow-up
AcuteMI 1.4(0.9,2.1)34 ⁄ 115 1.6 (1.3,2.0)134 ⁄ 388 1.6(1.2,2.2)65 ⁄ 198 1.6 (1.4,1.9)233 ⁄ 701
AnyIHDc
1.1(0.8,1.5)52 ⁄ 215 1.5 (1.2,1.7)197 ⁄ 650 1.5(1.2,1.9)92 ⁄ 315 1.4 (1.2,1.6)341 ⁄ 1180
FatalMI 1.3(0.6,2.7)9 ⁄ 33 1.1 (0.7,1.8)19 ⁄ 92 1.1(0.6,2.3)10 ⁄ 56 1.1 (0.8,1.6)38⁄ 181
Coronary
revascularisation
1.5(0.7,3.1)10 ⁄ 32 1.4 (1.0,2.0)46 ⁄ 149 2.0(1.3,3.2)27 ⁄ 75 1.6 (1.2,2.1)83⁄ 256
Angina pectoris 0.9(0.5,1.5)16 ⁄ 87 1.3 (1.0,1.8)67 ⁄ 241 1.2(0.8,1.9)29 ⁄ 111 1.2 (1.0,1.5)112 ⁄ 439
RR and 95% confidence interval, including number of RA events ⁄ number of comparator events. a
Cox proportional hazard
regression models. All models were adjusted for the matching factors: sex, year of birth, county of residence and marital status.
b
Defined as the first occurrence of the event following RA diagnosis. c
Defined as first of MI, coronary revascularisation or angina
pectoris.
139. 149
0
0,5
1
1,5
2
2,5
1 2 3 4 5
CRP LDL
INFLAMAÇÃO E ECV!
Quintis de Riesgo Relativo para todos os Acidentes Cardiovasculares!
Ridker PM et al. N Engl J Med 2002;347:1557-65.
140. cause deterioration of fatty
plaque ruptures and comple
may also act synergistically
risk factors in the pathogene
inflammation is associated w
and an adverse lipid profile.
CVD occurs more frequently
tory burden such as RA. Thi
disease severity is associated
and that treatment with p
such as tumour necrosis f
reduces the cardiovascular ri
RA group as well as in the g
Hoorn study, we were un
relationship between inflam
might be due to a type II erro
study CVD risk at different l
be that the cumulative infla
the curve for CRP) over the l
in order to show an associa
CVD risk in patients with R
with RA without tradition
correlation was found bet
Table 2 Prevalence odds ratios (ORs) for cardiovascular disease using
controls as a reference
OR (95% CI) p Value
Model I
Non-diabetic controls 1.00 (reference)
DM2 2.62 (1.29 to 5.32) 0.008
RA 2.81 (1.46 to 5.42) 0.002
Model II
Non-diabetic controls 1.00 (reference)
DM2 2.31 (1.13 to 4.72) 0.022
RA 3.11 (1.59 to 6.08) 0.001
Model III
Non-diabetic controls 1.00 (reference)
DM2 2.01 (0.90 to 4.51) 0.090
RA 2.70 (1.24 to 5.86) 0.012
DM2, diabetes mellitus type 2; RA, rheumatoid arthritis.
Model I, crude associations.
Model II, corrected for age and gender.
Model III, corrected for cardiovascular risk factors (age and gender, systolic blood
pressure, antihypertensive agents, total cholesterol/high-density lipoprotein
cholesterol (TC/HDL) ratio, lipid-lowering drugs, waist circumference, creatinine and
smoking).
Extended report
group.bmon June 11, 2011 - Published byard.bmj.comDownloaded from
141.
142. adjusted f
ment. In
comparin
with RA a
DM relati
ary analy
for the ad
SPSS sof
values les
cant. No
RESULT
Baselin
populatio
jects (24.1
morbidity
their hosp
sentially
Figure 1. Study design. CARRE´ ϭ Cardiovascular Research and
Rheumatoid Arthritis; IFG ϭ impaired fasting glucose; DM2 ϭ
type 2 diabetes mellitus; RA ϭ rheumatoid arthritis.
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 61, No. 11, November 15, 2009, pp 1571–1579!
143. DISCUSS
Our prosp
patients w
general po
creased CV
patients w
vious cross
lar risk fa
did not ex
sequently,
underestim
cating that
RA should
diovascula
den in RA
we did no
between p
due to a laFigure 2. Cardiovascular event–free probability to 3 years among
1576
PROBABILIDADE DE AUSÊNCIA DE ACIDENTE CARDIOVASCULAR
AO FIM DE 3 ANOS
Controlos
DT2
AR sem
Diabetes
144. Biologics:Targets & Therapy 2008:2(4)664
Nakase et al 1997; Gilbert et al 2000, 2002). Furthermore, bone damage in vivo (Joosten et al 1999; Kong et al 1999;
Osteoclast
precursor
Osteoclast
TNF
TNF
TNF
TNF
Bone erosion
and bone loss
RANK
OPG
RANKL
Secretion
+ or =
OPG
+
+
+
Osteoblast
Figure 1 Increasing the balance of receptor activator of nuclear factor κB ligand (RANKL)-receptor activator of nuclear factor κB (RANK) induced by tumor necrosis factor
alpha (TNFα).
Abbreviations: OPG, osteoprotegerin; +, stimulation; O, inhibition.
Biologics: Targets & Therapy 2008:2(4) 663–669!
145. Arthritis Increases the Risk for Fractures —
Results from the Women’s Health Initiative
NICOLE C. WRIGHT, JEFFREY R. LISSE, BRIAN T. WALITT, CHARLES B. EATON, ZHAO CHEN,
and the Women’s Health Initiative Investigators
ABSTRACT. Objective. To examine the relationship between arthritis and fracture.
Methods. Women were classified into 3 self-reported groups at baseline: no arthritis (n = 83,295),
osteoarthritis (OA; n = 63,402), and rheumatoid arthritis (RA; n = 960). Incident fractures were self-
reported throughout followup. Age-adjusted fracture rates by arthritis category were generated, and the
Cox proportional hazards model was used to test the association between arthritis and fracture.
Results. After an average of 7.80 years, 24,137 total fractures were reported including 2559 self-report-
ed clinical spinal fractures and 1698 adjudicated hip fractures. For each fracture type, age-adjusted frac-
ture rates were highest in the RA group and lowest in the nonarthritic group. After adjustment for sev-
eral covariates, report of arthritis was associated with increased risk for spine, hip, and any clinical frac-
tures. Compared to the nonarthritis group, the risk of sustaining any clinical fracture in the OA group
was HR 1.09 (95% CI 1.05, 1.13; p < 0.001) and HR 1.49 (95% CI 1.26, 1.75; p < 0.001) in the RA
group. The risk of sustaining a hip fracture was not statistically increased in the OA group (HR 1.11;
95% CI 0.98, 1.25; p = 0.122) compared to the nonarthritis group; however, the risk of hip fracture
increased significantly (HR 3.03; 95% CI 2.03, 4.51; p < 0.001) in the RA group compared to the
nonarthritis group.
Conclusion. The increase in fracture risk confirms the importance of fracture prevention in patients
with RA and OA. (J Rheumatol First Release May 15 2011; doi:10.3899/jrheum.101196)
Key Indexing Terms:
ARTHRITIS EPIDEMIOLOGY FRACTURE POSTMENOPAUSAL WOMEN
With an increasing number of older adults in our society,
osteoporosis has become a major public health concern.
rates2. Age and bone mineral density (BMD) are the prima
148. ALGUMAS DOENÇAS AUTO-IMUNES
Alopecia Areata Gastrite Auto-Imune
Anemia Aplástica Hepatite Auto-Imune
Anemia Hemolítica auto-imune Lúpus Eritematoso Sistêmico
Artrite Reumatóide Miastenia Gravis
Colite Ulcerosa Neutropenia Auto-Imune
Dermatite Herpetiforme Psoríase
Doença Celíaca Púrpura Trombocitopênica Auto-Imune
Doença de Behcet Síndrome de Sjögren
Doença de Crohn Tiróidite de Hashimoto
Esclerose Múltipla Uveíte
Espondilite Anquilosante Vitiligo
Rose N R, Mackay IR. Prospectus: The Road to Autoimmune Disease.
In Rose N R, Mackay IR. The auto-immune diseases. Academic Press, 2006, pgs xix-xxv
149. Research
Systemic lupus erythematosus (SLE) is a
chronic autoimmune disease of unclear
etiology, with a prevalence as high as 1 in
2,500 women (Bernatsky et al. 2007). It is
characterized by an overactive immune system
that targets normal tissue in nearly any body
organ. The resulting inflammation causes
dysfunction and damage; involvement of
major organs such as the kidneys can be par-
ticularly devastating and even life-threatening
(Bernatsky et al. 2007).
autoimmunity. Recent data have suggested
that these exposures may be important triggers
of systemic inflammation [for a review, see
U.S. Environmental Protection Agency (EPA)
2004] that could have important effects in
terms of autoimmunity.
Our aim in this study was to evaluate the
potential influence of PM air pollution on
the clinical course of SLE. We have focused
on the effects of variations in levels of fine
ambient PM with median aerodynamic diam-
et al. 1982). Subjects in the cohort completed
an annual evaluation that consisted of a review
of symptoms, medications, physical find-
ings, and laboratory testing. The data were
used to construct validated measures of disease
activity [SLE Disease Activity Index, version
2000 (SLEDAI-2K)] (Gladman et al. 2002)
and damage [Systemic Lupus International
Collaborating Clinics/ACR Damage Index
(SLICC/ACR)] (Gladman et al. 2002).
The SLEDAI-2K is a “weighted” index that
provides a measurement of disease activity
of the organ systems in SLE over a 10-day
period before the annual evaluation. The
index includes central nervous system features,
vascular involvement, kidney disease, musculo-
skeletal disease, dermatological features, serosal
involvement, immune system activity, hema-
tological features, and constitutional symp-
toms (see Appendix). Theoretically, patients
can score a maximum of 105, but in prac-
tice, scores greater than 45 are unusual. In the
present study, we analyzed data collected on
patients who resided on the island of Montreal
from January 2000 through September 2007.
All subjects consented to be included in the
registry, and studies were conducted under
ethical approval from the MUHC.
We studied associations between PM2.5
and the SLEDAI-2K total score. We were
also specifically interested in the presence or
absence of renal tubule cellular casts, which
are a marker for severe kidney inflammation
related to SLE, and the presence or absence
of antibodies against double-stranded DNA
Address correspondence to A. Smargiassi, Institut
Associations between Ambient Fine Particulate Levels and Disease Activity
in Patients with Systemic Lupus Erythematosus (SLE)
Sasha Bernatsky,1,2 Michel Fournier,3 Christian A. Pineau,2 Ann E. Clarke,1,4 Evelyne Vinet,2
and Audrey Smargiassi 5,6
1Division of Clinical Epidemiology and 2Division of Rheumatology, McGill University Health Centre, Montreal, Quebec, Canada; 3Direction
de santé publique de l’Agence de la santé et des services sociaux de Montréal, Montreal, Quebec, Canada; 4Division of Clinical Immunology
and Allergy, McGill University Health Centre, Montreal, Quebec, Canada; 5Département de santé environnementale et de santé au travail,
Université de Montréal, Montreal, Quebec, Canada; 6Institut national de santé publique du Québec, Montréal, Quebec, Canada
BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic disease of unclear etiology,
characterized by an overactive immune system and the production of antibodies that may target nor-
mal tissues of many organ systems, including the kidneys. It can arise at any age and occurs mainly in
women.
OBJECTIVE: Our aim was to evaluate the potential influence of particulate matter (PM) air pollution
on clinical aspects of SLE.
METHODS: We studied a clinic cohort of SLE patients living on the island of Montreal, followed
annually with a structured clinical assessment. We assessed the association between ambient levels of
fine PM [median aerodynamic diameter ≤ 2.5 µm (PM2.5)] measured at fixed-site monitoring stations
and SLE disease activity measured with the SLE Disease Activity Index, version 2000 (SLEDAI-2K),
which includes anti–double-stranded DNA (anti-dsDNA) serum-specific autoantibodies and renal
tubule cellular casts in urine, which reflects serious renal inflammation. We used mixed effects regres-
sion models that we adjusted for daily ambient temperatures and ozone levels.
RESULTS: We assessed 237 patients (223 women) who together had 1,083 clinic visits from 2000
through 2007 (mean age at time of first visit, 41.2 years). PM2.5 levels were associated with anti-dsDNA
and cellular casts. The crude and adjusted odds ratios (reflecting a 10-µg/m3 increase in PM2.5 aver-
aged over the 48 hr prior to clinical assessment) were 1.26 [95% confidence interval (CI), 0.96–1.65]
and 1.34 (95% CI, 1.02–1.77) for anti-dsDNA antibodies and 1.43 (95% CI, 1.05–1.95) and 1.28
(0.92–1.80) for cellular casts. The total SLEDAI-2K scores were not associated with PM2.5 levels.
CONCLUSIONS: We provide novel data that suggest that short-term variations in air pollution may
influence disease activity in established autoimmune rheumatic disease in humans. Our results add
weight to concerns that pollution may be an important trigger of inflammation and autoimmunity.
KEY WORDS: air pollution, antibodies, disease activity, PM2.5, SLE, SLEDAI-2K, systemic lupus
erythematous. Environ Health Perspect 119:45–49 (2011). doi:10.1289/ehp.1002123 [Online
22 September 2010]
150. Original Article
Air pollution and type 1 diabetes in children
Hathout EH, Beeson WL, Ischander M, Rao R and Mace JW. Air pollution
and type 1 diabetes in children.
Pediatric Diabetes 2006: 7: 81–87.
Background: Over the past decade, there has been a worldwide largely
unexplained increase in the incidence of type 1 diabetes in young chil-
dren. This study explores the quantitative role of exposure to specific air
pollutants in the development of type 1 diabetes in children.
Methods: A total of 402 children were retrospectively studied. Zip
code-related, time-specific birth-to-diagnosis exposure to five ambient
air pollutants was obtained for 102 children with type 1 diabetes and
300 healthy children receiving care at a single hospital. Pollution
exposure levels were created by summing up zip code-specific pollution
data and dividing by months of exposure from birth to diagnosis.
Analysis employed w2
, two-tailed independent sample t-test and
unconditional logistic regression.
Results: Odds ratio (OR) was significantly high for cumulative
exposure to ambient ozone (O3) and sulfate (SO4) in cases compared
with controls, OR ¼ 2.89 [95% confidence interval (CI) ¼ 1.80–4.62]
and OR ¼ 1.65 (CI ¼ 1.20–2.28), respectively, even after adjustment
for several potential confounders. Passive smoking was more frequent in
children with diabetes (30 vs. 10%, p ¼ 0.001). Attending day care
and breast feeding in infancy were less frequent in children with diabetes
(14 vs. 23%, p ¼ 0.025; 59 vs. 78%, p ¼ 0.001). Family history of
diabetes, autoimmune disease and drug abuse was more frequent in
cases (p < 0.01).
Conclusion: Cumulative exposure to ozone and sulfate in ambient air
may predispose to the development of type 1 diabetes in children. Early
infant formula feeding and passive smoking in the household may
precipitate or accelerate the onset of type 1 diabetes.
Eba H Hathouta
,
W Lawrence Beesonb
,
Mariam Ischandera
,
Ravindra Raoa
and
John W Macea
a
Department of Pediatrics, Loma Linda
University School of Medicine, Loma
Linda, CA, USA; and b
Department of
Epidemiology and Biostatistics, School of
Public Health Loma Linda University,
Loma Linda, CA, USA
Key words: air pollution – etiology – type
I diabetes
Corresponding author:
Eba H. Hathout, MD, FAAP, Director,
Pediatric Diabetes Center,
Loma Linda University Children’s
Hospital,
11175 Campus Street, CP A1120R,
Loma Linda, CA 92354
USA.
Tel.: þ909 558 4130
fax: þ909 558 0408
e-mail: ehathout@ahs.llumc.edu
Submitted 3 December 2004. Accepted
for publication 15 September 2005
Type1diabetesmellitusreferstoastateofinsulin-deficient
hyperglycemiausuallyattributedtoautoimmunedestruc-
tion of b-cells of the pancreas. The etiology is multifactor-
genetically susceptible individuals progress to develop
thedisease(3).Inaddition,therelativelyshort-timecourse
for the reported increase in incidence is unlikely to be
Pediatric Diabetes 2006: 7: 81–87 # 2006 The Authors. Journal compilation # 2006 Blackwell Munksgaard
All rights reserved
Pediatric Diabetes
151. Traffic Air Pollution and Oxidized LDL
Lotte Jacobs1
, Jan Emmerechts2
, Marc F. Hoylaerts2
, Chantal Mathieu3
, Peter H. Hoet1
, Benoit Nemery1
*,
Tim S. Nawrot1,4
1 Occupational and Environmental Medicine, Unit of Lung Toxicology, Katholieke Universiteit Leuven, Leuven, Belgium, 2 Center for Molecular and Vascular Biology,
Katholieke Universiteit Leuven, Leuven, Belgium, 3 Department of Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium, 4 Centre for Environmental Sciences,
Hasselt University, Diepenbeek, Belgium
Abstract
Background: Epidemiologic studies indirectly suggest that air pollution accelerates atherosclerosis. We hypothesized that
individual exposure to particulate matter (PM) derived from fossil fuel would correlate with plasma concentrations of
oxidized low-density lipoprotein (LDL), taken as a marker of atherosclerosis. We tested this hypothesis in patients with
diabetes, who are at high risk for atherosclerosis.
Methodology/Principal Findings: In a cross-sectional study of non-smoking adult outpatients with diabetes we assessed
individual chronic exposure to PM by measuring the area occupied by carbon in airway macrophages, collected by sputum
induction and by determining the distance from the patient’s residence to a major road, through geocoding. These
exposure indices were regressed against plasma concentrations of oxidized LDL, von Willebrand factor and plasminogen
activator inhibitor 1 (PAI-1). We could assess the carbon load of airway macrophages in 79 subjects (58 percent). Each
doubling in the distance of residence from major roads was associated with a 0.027 mm2
decrease (95% confidence interval
(CI): 20.048 to 20.0051) in the carbon load of airway macrophages. Independently from other covariates, we found that
each increase of 0.25 mm2
[interquartile range (IQR)] in carbon load was associated with an increase of 7.3 U/L (95% CI: 1.3
to 13.3) in plasma oxidized LDL. Each doubling in distance of residence from major roads was associated with a decrease of
22.9 U/L (95% CI: 25.2 to 20.72) in oxidized LDL. Neither the carbon load of macrophages nor the distance from residence
to major roads, were associated with plasma von Willebrand factor or PAI-1.
Conclusions: The observed positive association, in a susceptible group of the general population, between plasma oxidized
LDL levels and either the carbon load of airway macrophages or the proximity of the subject’s residence to busy roads
suggests a proatherogenic effect of traffic air pollution.
Citation: Jacobs L, Emmerechts J, Hoylaerts MF, Mathieu C, Hoet PH, et al. (2011) Traffic Air Pollution and Oxidized LDL. PLoS ONE 6(1): e16200. doi:10.1371/
journal.pone.0016200
Editor: Sayuri Miyamoto, Instituto de Quı´mica, Universidade de Sa˜o Paulo, Brazil
Received August 21, 2010; Accepted December 15, 2010; Published January 19, 2011
Copyright: ß 2011 Jacobs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The studies of the Flemish Center of Expertise on Environment and Health were commissioned, financed and steered by the Ministry of the Flemish
Community (Department of Economics, Science and Innovation; Flemish Agency for Care and Health; Department of Environment, Nature and Energy). T Nawrot
received a grant of the Flemish Fund for Scientific Research (FWO-Vlaanderen, krediet aan navorsers). The center for Molecular and Vascular Biology is supported
by the ‘‘Excellentie financiering KULeuven’’ (EF/05/13). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of
the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: ben.nemery@med.kuleuven.be
Introduction
Numerous epidemiological studies link various adverse health
roads [8]. These epidemiological observations strongly suggest that
long-term exposure to PM exerts a proatherogenic effect. Studies
in laboratory animals have begun to give experimental plausibility
Figure 1. Traffic related exposure variables and oxidized-LDL. An airway macrophage containing carbo
surface of the macrophage occupied by carbon (in mm2
), in 50 macrophages per person. The carbon load is give
airway macrophages. Pearson correlation between carbon load of airway macrophages and distance from the re
diabetes, who are at high risk for atherosclerosis.
Methodology/Principal Findings: In a cross-sectional study of non-smoking adult outpatients with diabetes we assessed
individual chronic exposure to PM by measuring the area occupied by carbon in airway macrophages, collected by sputum
induction and by determining the distance from the patient’s residence to a major road, through geocoding. These
exposure indices were regressed against plasma concentrations of oxidized LDL, von Willebrand factor and plasminogen
activator inhibitor 1 (PAI-1). We could assess the carbon load of airway macrophages in 79 subjects (58 percent). Each
doubling in the distance of residence from major roads was associated with a 0.027 mm2
decrease (95% confidence interval
(CI): 20.048 to 20.0051) in the carbon load of airway macrophages. Independently from other covariates, we found that
each increase of 0.25 mm2
[interquartile range (IQR)] in carbon load was associated with an increase of 7.3 U/L (95% CI: 1.3
to 13.3) in plasma oxidized LDL. Each doubling in distance of residence from major roads was associated with a decrease of
22.9 U/L (95% CI: 25.2 to 20.72) in oxidized LDL. Neither the carbon load of macrophages nor the distance from residence
to major roads, were associated with plasma von Willebrand factor or PAI-1.
Conclusions: The observed positive association, in a susceptible group of the general population, between plasma oxidized
LDL levels and either the carbon load of airway macrophages or the proximity of the subject’s residence to busy roads
suggests a proatherogenic effect of traffic air pollution.
Citation: Jacobs L, Emmerechts J, Hoylaerts MF, Mathieu C, Hoet PH, et al. (2011) Traffic Air Pollution and Oxidized LDL. PLoS ONE 6(1): e16200. doi:10.1371/
journal.pone.0016200
Editor: Sayuri Miyamoto, Instituto de Quı´mica, Universidade de Sa˜o Paulo, Brazil
Received August 21, 2010; Accepted December 15, 2010; Published January 19, 2011
Copyright: ß 2011 Jacobs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The studies of the Flemish Center of Expertise on Environment and Health were commissioned, financed and steered by the Ministry of the Flemish
Community (Department of Economics, Science and Innovation; Flemish Agency for Care and Health; Department of Environment, Nature and Energy). T Nawrot
received a grant of the Flemish Fund for Scientific Research (FWO-Vlaanderen, krediet aan navorsers). The center for Molecular and Vascular Biology is supported
by the ‘‘Excellentie financiering KULeuven’’ (EF/05/13). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of
the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: ben.nemery@med.kuleuven.be
Introduction
Numerous epidemiological studies link various adverse health
outcomes with air pollution, especially that caused by particulate
matter (PM), which to a considerable extent is caused by traffic
[1,2]. One of the important recent discoveries has been that
exposure to PM is not only harmful to the lungs, but also to the
heart and blood vessels [3–6]. This is undoubtedly true for short-
term increases in PM, which are triggers for acute cardiovascular
events [7], but probably also for long-lasting exposure to urban
PM, which increases the risk of cardiovascular mortality and
morbidity [4,6], possibly by accelerating atherosclerosis [8–10]. A
cross-sectional study in Los Angeles [9] suggested a role of air
pollution in intima-media thickening of the carotid artery and a
follow-up study described an association between traffic proximity
and the progression of intima-media thickness [10]. In a German
study of more than 4000 subjects a strong relation was found
between coronary artery calcification and living close to major
roads [8]. These epidemiological observations strongly suggest that
long-term exposure to PM exerts a proatherogenic effect. Studies
in laboratory animals have begun to give experimental plausibility
to these epidemiological observations [11,12]. However, so far,
only few studies have provided mechanistic evidence for an effect
of chronic exposure to traffic air pollution on the development of
atherosclerosis in human subjects.
It is well established that persons with diabetes have a higher
risk of developing cardiovascular diseases. A population-based
study showed that persons with diabetes, without previous
myocardial infarction, have the same risk of developing myocar-
dial infarction as nondiabetic patients with previous myocardial
infarction [13]. The metabolic abnormalities caused by diabetes
induce vascular dysfunction that predispose these patients to
developing atherosclerosis [14]. There is also evidence that
persons with diabetes and cardiovascular disease are more
sensitive to the effects of PM air pollution [15]. So it is relevant
– and also probably easier – to study the effects of air pollution in
PLoS ONE | www.plosone.org 1 January 2011 | Volume 6 | Issue 1 | e16200
153. ynoviocytes is augmented by IL-1 , IL-17, IL-18 or
NF [55]. Furthermore, Th17 cells express CC chemokine
ceptor (CCR) 6, a receptor for CCL20 [56]. Therefore,
smoke exposure appeared to induce AhR activation in
in AhR/DRE-dependent reporter gene transgenic mice [6
ig. (1). A possible mechanism of cigarette smoke contribution to the induction and development of RA. Cigarette smoke ind
roinflammatory cytokines and chemokines, including IL-1 , IL-1 , IL-6, IL-8 and CCR20 from synovial fibroblast-like cells (SFC), w
partially mediated by aromatic hydrocarbon receptor (AhR) stimulated with polycyclic aromatic hydrocarbons (PAHs) contained in
moke. IL-1 and IL-6 induce the differentiation and development of Th17. PAHs also accelerate the development of Th17 via AhR. CC
cruits Th17 into the synovium, and IL-1 activates Th17 for production of IL-17. IL-17 then induces IL-1, IL-6 and TNF production f
acrophages. The acute inflammation leads to chronic inflammation under the influence of sex hormones and genetic factors, which lead
A.
Onozaki K. Etiological and biological aspects of cigarette smoking in rheumatoid arthritis. Inflamm Allergy Drug Targets. 2009 Dec;8(5):364-8"
154. CLINICAL STUDY
Smoking and thyroid disorders – a meta-analysis
Peter Vestergaard
The Osteoporosis Clinic, Aarhus Amtssygehus, Aarhus University Hospital, Tage Hansens Gade 2, DK-8000 Aarhus C, Denmark
(Correspondence should be addressed to Peter Vestergaard; Email: p-vest@post4.tele.dk)
Abstract
Background: Smoking has been associated with Graves’ disease, but it remains unclear if the
association is present in other thyroid disorders.
Outcome variables: Graves’ disease, Graves’ ophthalmopathy, toxic nodular goitre, non-toxic goitre,
post-partum thyroid disease, Hashimoto’s thyroiditis, or hypothyroidism.
Material and methods: A search of MEDLINE identified 25 studies on the association between smoking
and thyroid diseases.
Results: In Graves’ disease eight studies were available showing an odds ratio (OR) of 3.30 (95% con-
fidence interval (CI): 2.09–5.22) in current smokers compared with never smokers. In ex-smokers
there was no significant excess risk of Graves’ disease (OR à 1:41; 95% CI: 0.77–2.58). The OR
associated with ever smoking in Graves’ ophthalmopathy (4.40, 95% CI: 2.88–6.73, six studies)
was significantly higher than in Graves’ disease (1.90, 95% CI: 1.42–2.55, two-sided P-value
, 0:01). Ever smoking was not associated with toxic nodular goitre (OR à 1:27; 95% CI: 0.69–
2.33, three studies), while there was an increased risk of non-toxic goitre in smokers if men were
excluded (OR à 1:29; 95% CI: 1.01–1.65, eight studies). The risk associated with smoking was sig-
nificantly lower in men than in women for both Graves’ disease and non-toxic goitre. Hashimoto’s
thyroiditis and post-partum thyroid dysfunction were also associated with smoking while the associ-
ation with hypothyroidism did not reach statistical significance.
Conclusions: Cessation of smoking seems associated with a lower risk of Graves’ disease than current
smoking. Smoking increases the risk of Graves’ ophthalmopathy beyond the risk associated with
Graves’ disease alone. Smoking cessation may lead to a decrease in morbidity from Graves’ disease,
especially in women.
European Journal of Endocrinology 146 153–161
Introduction
Previous studies have associated smoking with Graves’
disease (GD) (1–8) and with Graves’ ophthalmopathy
(GO – also termed endocrine ophthalmopathy) (1,
4–7, 9–15), whereas the studies on the association
between smoking and other forms of thyroid disease
are limited. As smoking is frequent in some countries
(16) even a limited association between smoking and
non-smokers? (3) Are other types of thyroid disorders
(toxic nodular goitre (TNG), non-toxic goitre (NTG),
autoimmune hypothyroidism (AIH), Hashimoto’s thy-
roiditis (HT), and post-partum thyroid dysfunction
(PPTD)) linked to smoking?
In GD, hyperthyroidism is linked to immunological
factors whereas this is not the case in TNG (18). If
smoking was linked to GD but not TNG, it would
suggest that smoking only modulates immunological
European Journal of Endocrinology (2002) 146 153–161 ISSN 0804-4643
155. Introducción. Diversos estudios epidemiológicos demuestran
que en la esclerosis múltiple (EM) existe un factor genético de sus-
ceptibilidad, así como que los factores ambientales juegan un papel
prominente en el desarrollo de la misma. Entre los factores ambien-
tales estudiados se encuentra el tabaco. De hecho, varios estudios
establecen relación entre fumar y EM, pero la mayoría de ellos no
hallaron resultados significativos o éstos fueron contradictorios.
Objetivo. Evaluar la influencia del hábito tabáquico en el riesgo
de padecer EM.
Material y métodos: Estudio caso-control pareado con 138 pacien-
tes diagnosticados de EM según los criterios de McDonald y el mismo
número de controles del mismo sexo, residentes en el mismo municipio
y la misma edad ±2 años. Se recogieron los datos demográficos, status
de fumar, escala de discapacidad de Kurtzke (EDSS) y tipo de EM.
Resultados. De los 138 pacientes (93 mujeres, 43 hombres), 110
presentaban EM remitente recurrente, 20 EM secundariamente pro-
gresiva y 7 EM primariamente progresiva. La mayoría de los pacien-
tes resultaron ser fumadores y exfumadores (63%) frente al (41,3%)
de los controles. Asimismo, la edad de inicio en el hábito de fumar fue
más precoz en los casos que en los controles.
Conclusión. Ser fumador/exfumador implica un 27 % más de
tant role in their development. Smoking is among the environ-
ment factors studied. In fact, several studies have established a
relationship between smoking and multiple sclerosis, although
most of them did not find significant results or found that these
were contradictory.
Objective. To evaluate the influence of the smoking habit on
the risk of suffering MS.
Methods. This was a case-control matched study with 138
patients diagnosed of MS according to the McDonald criteria who
were paired with the same number of controls of the same gen-
der, residents in the same city and having the same age ±2 years.
Demographic data, smoking status (never, always smokers, ex-
smokers), Kurtzke disability status scale (EDSS) and type of MS
were collected.
Results. Out of a total of 138 MS patients (93 women, 43 men),
110 had relapsing-remitting MS, 20 secondary progressive MS and
7 primary progressive MS. Most of the patients were smokers
and ex-smokers (63%). In the control group, only the 41,3% were
smokers/ex-smokers. Moreover, the age of onset for smoking was
earlier in the case group.
Originales
Estudio de casos y controles
sobre la influencia del hábito tabáquico
en la esclerosis múltiple
A. Rodríguez Regal1
M. del Campo Amigo1
J. Paz-Esquete2
A. Martínez Feijoo3
E. Cebrián1
P. Suárez Gil1
M. A. Mouriño1
Servicios de 1 Neurología, 2 Medicina Preventiva
y 3 Urgencias del Complejo Hospitalario
de Pontevedra (CHOP)
Introducción. Diversos estudios epidemiológicos demuestran
que en la esclerosis múltiple (EM) existe un factor genético de sus-
ceptibilidad, así como que los factores ambientales juegan un papel
prominente en el desarrollo de la misma. Entre los factores ambien-
tales estudiados se encuentra el tabaco. De hecho, varios estudios
establecen relación entre fumar y EM, pero la mayoría de ellos no
hallaron resultados significativos o éstos fueron contradictorios.
Objetivo. Evaluar la influencia del hábito tabáquico en el riesgo
de padecer EM.
Material y métodos: Estudio caso-control pareado con 138 pacien-
tes diagnosticados de EM según los criterios de McDonald y el mismo
número de controles del mismo sexo, residentes en el mismo municipio
y la misma edad ±2 años. Se recogieron los datos demográficos, status
de fumar, escala de discapacidad de Kurtzke (EDSS) y tipo de EM.
Resultados. De los 138 pacientes (93 mujeres, 43 hombres), 110
presentaban EM remitente recurrente, 20 EM secundariamente pro-
gresiva y 7 EM primariamente progresiva. La mayoría de los pacien-
tes resultaron ser fumadores y exfumadores (63%) frente al (41,3%)
de los controles. Asimismo, la edad de inicio en el hábito de fumar fue
más precoz en los casos que en los controles.
Conclusión. Ser fumador/exfumador implica un 27 % más de
riesgo de desarrollar EM frente a los nunca fumadores. Este riesgo es
estadísticamente significativo en mujeres y no en varones, probable-
mente debido al bajo número de los mismos en el total de la muestra.
Palabras clave:
Esclerosis múltiple. Tabaco. Epidemiología. Factor de riesgo. Estudio caso-control.
Neurología 2009;24(3):177-180
tant role in their developm
ment factors studied. In f
relationship between smo
most of them did not find
were contradictory.
Objective. To evaluate
the risk of suffering MS.
Methods. This was a
patients diagnosed of MS a
were paired with the same
der, residents in the same c
Demographic data, smokin
smokers), Kurtzke disabilit
were collected.
Results. Out of a total o
110 had relapsing-remitting
7 primary progressive MS
and ex-smokers (63%). In
smokers/ex-smokers. More
earlier in the case group.
Conclusion. Being a s
ter risk of developing MS
smoked. This risk is statisti
men due to the low numbe
Key words:
Multiple sclerosis; tobacco; epidemiolo
INTRODUCCIÓN
Ser fumador/exfumador implica
un 27% más de riesgo de
desarrollar EM frente a los nunca
fumadores.
156. Cigarette Smoking, Alcohol Consumption, and Risk of
Systemic Lupus Erythematosus: A Case-control Study
in a Japanese Population
CHIKAKO KIYOHARA, MASAKAZU WASHIO, TAKAHIKO HORIUCHI, TOYOKO ASAMI, SABURO IDE,
TATSUYA ATSUMI, GEN KOBASHI, YOSHIFUMI TADA, HIROKI TAKAHASHI, and the Kyushu Sapporo SLE
(KYSS) Study Group
ABSTRACT. Objective. Cigarette smoking may be associated with increased risk of systemic lupus erythematosus
(SLE), whereas the role of alcohol consumption is unknown. We examined the association between
SLE risk and smoking or drinking.
Methods. We investigated the relationship of smoking and drinking compared to SLE risk among 171
SLE cases and 492 healthy controls in female Japanese subjects. Unconditional logistic regression was
used to compute OR and 95% CI, with adjustments for several covariates.
Results. Compared with nonsmoking, current smoking was significantly associated with increased risk
of SLE (OR 3.06, 95% CI 1.86–5.03). The higher the level of exposure to cigarette smoke, the higher
the risk of SLE. Inhalation was also associated with increased SLE risk (OR 3.73, 95% CI 1.46–9.94
for moderate inhalation; OR 3.06, 95% CI 1.81–5.15 for deep inhalation). In contrast, light/moderate
alcohol consumption had a protective effect on SLE risk (OR 0.38, 95% CI 0.19–0.76). As for beer, the
risks for non-beer drinkers and beer drinkers were similar. This also applies to alcoholic beverages other
than beer.
Conclusion. Our results suggest that smoking was positively associated with increased SLE risk where-
as light/moderate alcohol consumption was inversely associated with SLE risk, irrespective of the type
of alcoholic beverage. Additional studies are warranted to confirm these findings. (First Release May
15 2012; J Rheumatol 2012;39:1363–70; doi:10.3899/jrheum.111609)
Key Indexing Terms:
ALCOHOL CONSUMPTION EPIDEMIOLOGY JAPAN RISK FACTOR
SYSTEMIC LUPUS ERYTHEMATOSUS SMOKING
From the Department of Preventive Medicine, Graduate School of
Medical Sciences, Kyushu University, Fukuoka; Department of
Community Health and Clinical Epidemiology, St. Mary’s College,
Kurume; Department of Medicine and Biosystemic Science, Graduate
School of Medical Sciences, Kyushu University, Fukuoka; Rehabilitation
Center, Saga University Hospital, Saga; Department of Medicine II,
Hokkaido University Graduate School of Medicine, Sapporo; Molecular
Biostatistics Research Team, Research Center for Charged Particle
Therapy, National Institute of Radiological Science, Chiba; Department of
Clinical Epidemiology, St. Mary’s College; T. Horiuchi, PhD, Associate
Professor, Department of Medicine and Biosystemic Science, Graduate
School of Medical Sciences, Kyushu University; T. Asami, PhD, Professor,
Rehabilitation Center, Saga Medical School Hospital; S. Ide, PhD,
Professor, Department of Community Health and Clinical Epidemiology,
St. Mary’s College; T. Atsumi, PhD, Associate Professor, Department of
Medicine II, Hokkaido University Graduate School of Medicine;
G. Kobashi, PhD, Team Leader, Molecular Biostatistics Research Team,
Research Center for Charged Particle Therapy, National Institute of
Despite intensive research, the etiology of systemic lupus ery-
thematosus (SLE) remains unclear. Many environmental
exposures, including smoking, ultraviolet light, medications,
infectious agents, hair dyes, and dietary factors have been
hypothesized to be associated with the development of
SLE1,2,3,4,5, although the strength of the evidence implicating
each of these factors varies. Studies of twin concordance are
commonly used in epidemiology to estimate the role of genet-
ics and the influence of environmental factors on disease sus-
ceptibility. Disease concordance is much higher in monozy-
gotic twins (24%–57%) than in dizygotic twins (2%–5%),
suggesting a genetic component to SLE6,7,8. However, identi-
fication of these genetic factors has been slow. The genetic
basis of SLE is very complex, and it is difficult to predict how
a Japanese Population
AKO KIYOHARA, MASAKAZU WASHIO, TAKAHIKO HORIUCHI, TOYOKO ASAMI, SABURO IDE,
UYA ATSUMI, GEN KOBASHI, YOSHIFUMI TADA, HIROKI TAKAHASHI, and the Kyushu Sapporo SLE
) Study Group
STRACT. Objective. Cigarette smoking may be associated with increased risk of systemic lupus erythematosus
(SLE), whereas the role of alcohol consumption is unknown. We examined the association between
SLE risk and smoking or drinking.
Methods. We investigated the relationship of smoking and drinking compared to SLE risk among 171
SLE cases and 492 healthy controls in female Japanese subjects. Unconditional logistic regression was
used to compute OR and 95% CI, with adjustments for several covariates.
Results. Compared with nonsmoking, current smoking was significantly associated with increased risk
of SLE (OR 3.06, 95% CI 1.86–5.03). The higher the level of exposure to cigarette smoke, the higher
the risk of SLE. Inhalation was also associated with increased SLE risk (OR 3.73, 95% CI 1.46–9.94
for moderate inhalation; OR 3.06, 95% CI 1.81–5.15 for deep inhalation). In contrast, light/moderate
alcohol consumption had a protective effect on SLE risk (OR 0.38, 95% CI 0.19–0.76). As for beer, the
risks for non-beer drinkers and beer drinkers were similar. This also applies to alcoholic beverages other
than beer.
Conclusion. Our results suggest that smoking was positively associated with increased SLE risk where-
as light/moderate alcohol consumption was inversely associated with SLE risk, irrespective of the type
of alcoholic beverage. Additional studies are warranted to confirm these findings. (First Release May
15 2012; J Rheumatol 2012;39:1363–70; doi:10.3899/jrheum.111609)
Key Indexing Terms:
ALCOHOL CONSUMPTION EPIDEMIOLOGY JAPAN RISK FACTOR
SYSTEMIC LUPUS ERYTHEMATOSUS SMOKING
