International Journal of Clinical Medicine, 2011, 2, 339-345
doi:10.4236/ijcm.2011.23059 Published Online July 2011 (http://www.SciRP.org/journal/ijcm)
339
Prevalence of Anti-Cardiolipin and Anti-β2
Glycoprotein Antibodies in Indian Systemic Lupus
Erythematosus Patients
Vandana Pradhan1, Anjali Rajadhyaksha1, Pranaya Joshi1, Manisha Patwardhan1, Shruti Dighe1,
Kanjaksha Ghosh2
1Department of Autoimmune Disorders, National Institute of Immunohaematology, Indian Council of Medical Research, King Ed-
ward Memorial Hospital, Mumbai, India. 2Department of Medicine, King Edward Memorial Hospital, Mumbai, India.
Received March 15th, 2011; revised April 26th, 2011; accepted May 27th, 2011.
ABSTRACT
Anti-phospholipid antibodies (APA) like anti-cardiolipin antibodies (ACA) and anti-β2glycoprotien (anti-β2 GP) are
important cause of venous and arterial thrombosis and other occlusive vascular diseases. The prevalence of these anti-
bodies in SLE patients at the time of diagnosis is not known in Indian SLE patients. This study was conducted to evalu-
ate the prevalence of ACA and anti-β2 GP autoantibodies in SLE patients and to correlate them with disease activity
and immune parameters such as C3, C4 and CRP levels, where 85 SLE patients referred from Rheumatology Depart-
ment, KEM hospital, Mumbai were studied. SLE disease activity was evaluated by SLE Disease Activity Index (SLEDAI)
score at the time of evaluation. All patients studied were in an active stage of disease of which 37.6% patients had renal
disorders, which were categorized as Lupus Nephritis (LN) and 62.3% patients did not show any renal manifestations
(non-LN). ACA and anti-β2 GP autoantibodies, to IgG and IgM subclasses were tested by ELISA. C3, C4 and CRP lev-
els were detected by nephelometer. It was observed that 12.9% patients were IgG-ACA and IgM-ACA positive and ACA
positivity was noted more among LN group Anti-β2 GP autoantibody positivity was 27.1% for IgG and 31.8% for IgM.,
IgG-anti-β2 GP antibodies were slightly higher in non-LN patients, whereas a higher incidence of IgM-anti-β2 GP an-
tibodies were detected in LN patients. Hence detection both ACA and anti-β2 GP antibodies along with associated im-
mune parameters were helpful to evaluate their possible association with disease severity in SLE patients. A long term
follow up of patients having ACA and anti-β2 GP antibodies without thrombotic event is also needed to detect their pos-
sible thrombotic event in future along with their clinical presentation.
Keywords: Systemic Lupus Erythematosus (SLE), Anti-Cardiolipin Antibodies (ACA), Anti-β2 Glycoprotein Antibodies
(anti-β2 GP), Lupus Nephritis (LN), SLE without Nephritis (Non-LN)
1. Introduction
Antiphospholipid antibody syndrome (APS) is perhaps
one of the most confounding immunologic disorders. It's
an acquired autoimmune disorder defined by the pres-
ence of antibodies against phospholipids. Anti-phos-
pholipid antibodies (APA), namely the lupus anticoagu-
lant (LAC) and the anti-cardiolipin antibodies (ACA) are
a group of antibodies directed against negatively-charged
phospholipid antigens (phosphatidylserine), on endothe-
lial cell membranes and platelets. Previously these anti-
bodies were thought to be recognizing epitopes on ani-
onic phospholipids and a complex of lipid-bound human
prothrombin [1]. Several components including high ti-
tres of APA, β2 GP-I and activation of endothelium or
platelets, are now suspected to encompass the APS [2]. It
seems likely that binding of APA on endothelial cells is
mediated through the cofactor β2 GP-I [3]. The target
antigen for could be a complex of β2 GP-I and anionic
phosphoator lipids.
Systemic Lupus Erythematosus (SLE) is a chronic,
multisystem, inflammatory disorder of autoimmune eti-
ology, occurring predominantly in young women in their
child-bearing age. Common manifestations may include
arthralgias and arthritis, malar and other skin rashes,
pleuritis or pericarditis, renal and CNS involvement and
hematologic cytopenias. SLE may be precipitated by
currently unknown environmental triggers that cause
autoimmune reactions in genetically predisposed people
[4,5]. Lupus Nephritis (LN) is histologically evident in

Prevalence of Anti-Cardiolipin and Anti-β2 Glycoprotein Antibodies in Indian Systemic Lupus Erythematosus Patients
340
most patients with SLE with the involvement of varying
degree of renal disease. Autoimmunity plays a major role
in the pathogenesis of LN where autoantibodies form
pathogenic immune complexes that deposit in kidneys.
Glomerular thrombosis is another mechanism that may
play a role in pathogenesis of LN, mainly in patients with
APS and is believed to be the result of antibodies di-
rected against negatively charged phospholipid-protein
complexes [6,7]. APS is classified as primary or secon-
dary depending on its association with other autoimmune
disorders. Primary APS is diagnosed in patients demon-
strating the clinical and laboratory criteria without other
recognized autoimmune disease. Secondary APS is di-
agnosed in patients with other autoimmune disorders
such as SLE. One-third of patients with SLE also have
antiphospholipid antibodies, and approximately one-third
of those with antibodies have clinical signs of antiphos-
pholipid antibody syndrome [8].
Phospholipids such as cardiolipin, β2 glycoprotein and
LAC are responsible for prevention of blood clotting. In
patients with SLE who have bad obstetric history (BOH)
or recurrent pregnancy loss (RPL), both cardiolipin and
lupus anticoagulant antibodies are often present in high
titre [9]. ACA may belong to both IgG and IgM subtypes.
The IgG antibodies seem to be better predictors of fetal
outcome. More recent studies suggest that the antibodies
that really matter are those to β2 GP, the cofactor by
which ACA binds to phospholipid and usually are pre-
sent with ACA [10]. Earlier studies have confirmed that
patients’ positive for ACA are at risk of repeated epi-
sodes of thrombosis, fetal loss and thrombocytopenia.
APA occurs in up to 60% of patients with SLE and may
be of pathogenic significance in LN where the presence
of intra glomerular capillary thrombosis has also been
described [11-14].
Present study was designed to evaluate the prevalence
of ACA and anti-β2 GP autoantibodies in SLE patients
and to correlate them with disease activity and immune
parameters.
2. Materials and Methods
This study was conducted in 85 SLE patients from
Rheumatology department of KEM hospital, Mumbai,
India over the period of 2 years (2008-2010). SLE pa-
tients were diagnosed according to the American College
of Rheumatology (ACR) criteria [15]. This study was
carried out after obtaining the requisite Ethics Committee
approval and a written consent from the patient. The dis-
ease activity was assessed at the time of evaluation using
the Systemic Lupus Erythematosus Disease Activity In-
dex (SLEDAI) [16]. Pregnant and post menapausal
women, smokers, patients with diabetes and patients with
significant hyperlipemia were excluded. After blood col-
lection, sera were stored in aliquots at –80˚C until tested.
Renal biopsies of Lupus Nephritis (LN) cases were ex-
amined by light microscopy using hematoxylin, eosin,
periodic Schiff (PAS) staining. Immunofluorescence
microscopy was done using anti-IgG, anti-IgM, anti-IgA,
anti-C3, anti-C4 and anti-fibrinogen fluorescein isothio-
cyanate conjugate (FITC). In LN patients the renal his-
tology was classified according to WHO criteria [17].
Anti-Cardiolipin antibodies (ACA) to IgG and IgM iso-
types and anti-β2 GP autoantibodies to IgG as well as
IgM isotypes were detected by ELISA using commer-
cially available kits (Euroimmune, Lubeck). C3, C4 and
CRP levels were detected using a Nephelometer (BN
ProSpec, Dade Behring, Germany). The Laboratory was
blinded to the disease status of patients and their visceral
involvement and a double blinded study was conducted
on the autoantibody positive samples.
3. Results
A total 85 SLE patients were included in the study of
which 80 were females and remaining 5 were males. The
ages ranged between 16 yrs and 36 yrs with mean age
being 26.8 ± 9.9 yrs. According to the ACR criteria,
clinical manifestation of patients indicated that majority
of these patients (60%) had arthritis followed by rash
(Malar and Discoid) among 38.8% patients. It was ob-
served that renal disorders were seen among 32/85
(37.6%) patients and these patients were categorized as
LN. Remaining 53 patients (62.4%) did not showed renal
manifestation and was categorized as non-LN. Other
manifestations such as photosensitivity (20%), serositis
(24.7%) and neurological disorder (16.5%) were noted
among the study group. Laboratory findings indicated
that all these patients were in active stage of disease
where ANA positivity was noted among all. Hemato-
logical disorders showed anemia (Hb < 7.0 g/dl) and/or
autoimmune hemolytic anemia (AIHA) in 27.1%, leuco-
penia (WBC count < 4.0 × 103/μl) in 16.5%, lym-
phopenia (total lymphocyte count < 2.0 × 103/μl) in
11.8% and thrombocytopenia (platelet count < 150 ×
103/μl) in 25.9% patients. Immunological disorders
showed raised CRP levels (>5 mg/L) in 51.8% patients
where 61.4% patients had previous history of bacteria,
viral or parasitic infections and remaining 38.6% patients
had no history of previous infections. Decreased C3 lev-
els alone (<90 - 180 mg/μl) were detected in 22.4% pa-
tients whereas in 13% patients, a decreased C4 levels
alone (<10 - 40 mg/μl) were noted. Both C3 and C4 lev-
els were reduced in 27.1% patients where as 37.7% pa-
tients had normal C3 as well as C4 levels (Table 1).
As shown in Table 2, it was observed that 12.9% pa-
tients had developed IgG-ACA and IgM-ACA individu
ally each where as 3.5% of patients had developed both

Prevalence of Anti-Cardiolipin and Anti-β2 Glycoprotein Antibodies in Indian Systemic Lupus Erythematosus Patients 341
Table 1. Baseline characteristics of SLE patients according
to ACR criteria (n = 85).
Table 2. Anti-Cardiolipin (ACA) and anti-  2 glycoprotein
(anti--
 2 GP) antibo dies in (n = 85).
SLE type Anti-Cardiolipin antibodies
(ACA) (n = 85)
Anti-β2 glycoprotien
antibodies
(anti-β2 GP) (n = 85)
Total SLE(n = 85)
IgG positive
IgM positive
IgG + IgM positive
IgG negative
IgM negative
11 (12.9%)
11 (12.9%)
3 (3.5%)
74 (87.1%)
74 (87.1%)
23 (27.1%)
27 (31.8%)
9 (10.6%)
62 (72.9%)
58 (68.2%)
LN(n = 32)
IgG positive
IgM positive
IgG + IgM positive
IgG negative
IgM negative
4 (12.5%)
4 (12.5%)
1 (3.1%)
28 (87.5%)
28 (87.5%)
8 (25%)
12 (37.5%)
3 (9.4%)
24 (75%)
20 (62.5%)
Non-LN(n = 53)
IgG positive
IgM positive
IgG + IgM positive
IgG negative
IgM negative
7 (13.2%)
7 (13.2%)
2 (3.8%)
46 (86.8%)
46 (86.8%)
15 (28.3%)
15 (28.3%)
6 (11.3%)
38 (71.7%)
38 (71.7%)
IgG and IgM antibodies to ACA. When these patients
were categorized further into LN and non-LN groups,
ACA positivity for both IgG and IgM autoantibodies was
slightly higher in non-LN group (13.2%) as compared to
12.5% in LN group. Anti-β2 GP positivity was 27.1% for
IgG-β2 GP and 31.8% for IgM-β2 GP where as 10.6% of
the patients developed anti-β2 GP antibodies to both IgG
and IgM subclasses. Among LN and non-LN groups,
IgG-β2 GP positivity revealed a slightly higher incidence
(28.3%) in non-LN patients as compared to LN patients
(25%) where as LN patients showed a higher incidence
for IgM-β2 GP positivity (37.5%) as compared to 28.3%
of patients in non-LN group. The cut off levels for
IgG-ACA was 185 u/ml, IgM-ACA is 186 u/ml, IgG-β2
GP is 156 u/ml and IgM-β2 GP is 290 u/ml as per the
normal individuals tested.
Table 3 gives the correlation of ACA and anti-β2 GP
levels with SLEDAI and other immunological parame-
ters such as CRP, C3 and C4. IgM-β2 GP positive LN
patients had higher SLEDAI scores (mean ± SD; 20 ±
15.8) Out of 23 patients with IgG-anti-β2 GP positivity,
15 (65.2%) patients showed raised CRP levels where
non-LN patients 11/15 (73.3%) had higher CRP levels as
compared to 4/8 (50%) in LN group. Among IgM anti-β2
GP positive patients 17/27 patients (63%) showed re-
duced C3 and C4 levels, where in LN group 10/12 pa-
tients (83.3%) had reduced C3 and C4 levels as com-
pared to 7/15 patients (46.7%) in non-LN group.
The distribution of clinical manifestations according to
the ACR criteria among ACA and anti-β2 GP positive
patients at the time of evaluation was as shown in Table
4. ACA positive patients showed a higher incidence for
clinical manifestations such as malar and discoid rash,
photosensitivity, oral ulcers, vasculitis, alopecia, fever,
arthritis and myositis. A slightly higher incidence for
clinical manifestations such as renal disorders, serositis,
neurological and hematological manifestations such as
leucopenia, thrombocytopenia and autoimmune hemo-
lytic anemia (AIHA) were noted among anti-β2 GP pa-
tients. It was observed that among ACA positive patients,
none of the patient had leucoepenia where as among
anti-β2 GP positive patients having leucopenia, WBC
counts ranged between (2.9 - 3.7) × 103/μl with mean ±
SD value of 3.3 ± 0.6. In a group of ACA positive pa-
tients having thrombocytopenia, platelet counts ranged
between (39 - 71) × 103/μL with a mean ± SD value 5.5 ±
22.6 where as anti-β2 GP patients having thrombocyto-
penia showed platelet counts ranged between (12 – 141)
× 103/μl with a slightly higher mean ± SD value (58.1 ±
48.3). Table 5 shows distribution of clinical severity
categorized into mild, moderate and severe based on the
SLEDAI scores.
4. Discussion
Anti-phospholipid antibodies (APA) are a distinct group
of autoantibodies that appear in a variety of autoimmune
diseases, particularly Systemic Lupus Erythematosus
(SLE). They are associated with clinical events such as
arterial and/or venous thrombosis, and obstetric compli-
cations with a strong association of ACA with thrombo-
sis, thrombocytopenia, recurrent fetal losses and Coombs’
Characteristics:
Sex Ratio (F:M) 16:1
Mean Age (Years ± SD) 26.8 + 9.9
Clinical Manifestations (%)
Rash (Malar or Discoid) 33 (38.8%)
Photosensitivity 17 (20%)
Oral Ulcers 24 (28.2%)
Arthritis 51 (60%)
Serositis 21 (24.7%)
Renal Disorders 32 (37.6 %)
Neurological Disorders 14 (16.5%)
Laboratory Characteristics
Hematological Disorders
Anemia/ AIHA
Leucopenia
Lymphopenia
Thrombocytopenia
23 (27.1%)
14 (16.5%)
10 (11.8%)
22 (25.9%)
Immunological Disorders
↑ CRP
↓ C3 alone
↓ C4 alone
↓ C3 & C4 both
44 (51.8%)
19 (22.4%)
11 (13%)
23 (27.1%)

Prevalence of Anti-Cardiolipin and Anti-β2 Glycoprotein Antibodies in Indian Systemic Lupus Erythematosus Patients
342
Table 3. Correlation of ACA and anti-
 2 GP levels with SLEDAI and other immunological parameters.
Anti-Cardiolipin antibodies (ACA) Anti-  2 glycoprotien antibodies (anti-  2 GP)
SLE type IgG IgM IgG IgM
Total SLE
Range
Mean + SD
SLEDAI
Range
Mean + SD
↑ CRP
↓ C3 alone
↓ C4 alone
↓ C3 & C4 both
11
190 - 451
265.1 ± 89.7
4 - 43
14.6 ± 11.1
11
3
0
1
11
186 - 1232
392.9 ± 299.7
4 - 24
12.1 ± 5.9
9
0
0
3
23
156 - 410
198.1 ± 33.6
4 - 35
14 ± 9.1
15
3
1
3
27
297 - 3000
847 ± 683.2
4 - 42
15.3 ± 10.1
14
0
0
4
LN
Range
Mean ± SD
SLEDAI
Range
Mean ± SD
↑ CRP
↓ C3 alone
↓ C4 alone
↓ C3 & C4 both
4
190 - 451
261.3 ± 126.7
4-19
11.3 ± 7.3
4
0
0
0
4
186 - 459
295.3 ± 117.0
4 - 15
10.8 ± 5.0
2
0
0
1
8
166 - 277
212.3 ± 42.4
10 - 35
16.9 ± 8.6
4
1
1
1
12
338 - 3000
786.1 ± 756.8
8 - 64
20 ± 15.8
6
0
0
2
Non-LN
Range
Mean ± SD
SLEDAI
Range
Mean ± SD
↑ CRP
↓ C3 alone
↓ C4 alone
↓ C3 & C4 both
7
197 - 402
267.3 ± 73.4
4 - 43
16.6 ± 12.9
7
3
0
1
7
210 - 1232
448.7 ± 364.5
4 - 24
12.9 ± 6.6
7
0
0
2
15
156 - 410
203.7 ± 61.5
4 - 43
12.9 ± 9.3
11
2
0
2
15
297 - 2150
895.3 ± 641.2
4 - 42
14.4 ± 10.2
8
0
0
2
Table 4. Distribution of clinical manifestations according to ACR criteria among ACA and anti-  2 GP positive patients.
Clinical presentation ACA positives
(IgG and/or IgM) (n = 19) Anti-
 2 GP positives ( IgG and/or IgM) (n = 41)
Malar Rash &/
Discoid Rash 9 (43.4%) 14 (34.1%)
Photosensitivity 4 (21.1%) 8 (19.5%)
Oral ulcers 7 (36.8%) 11 (26.8 %)
Arthritis 14 (73.7%)
24 (58.5%)
Serositis 6 (31.6%) 14 (34.1%)
Renal Disorders 3 (15.8 %) 8 (19.5%)
Neurological Disorders 2 (10.5%) 8 (19.5%)
Hematological Disorders 1 (5.3%) 5 (12.1%)
Systemic vascular thrombosis 4 (21.0%) 10 (24.4%)
Myositis 7 (36.8%)
10 (24.4%)
Alopecia 8 (42.1%) 16 (39.0%)
Fever 4 (21.1%)
7 (17.1%)

Prevalence of Anti-Cardiolipin and Anti-β2 Glycoprotein Antibodies in Indian Systemic Lupus Erythematosus Patients 343
Table 5. Distribution of clinical severity based on the SLEDAI scores.
Anti-Cardiolipin antibodies (ACA) Anti-  2 glycoprotien antibodies (anti-  2 GP)
IgG IgM IgG IgM
SLE type
(SLEDAI) Pos Neg Pos Neg Pos Neg Pos Neg
Mild
(<8)
Mean ± SD
Range
(4)
5 ± 1.1
4 - 6
(18)
6.6 ± 1.9
3 - 8
(3)
5.3 ± 2.3
4 - 8
(19)
6.4 ± 1.8
3 - 8
(6)
6.3 ± 2
4 - 8
(16)
6.2 ± 1.9
3 - 8
(7)
5.7 ± 1.8
4- 8
(15)
6.5 ± 1.9
3 - 8
Moderate
(8 - 18)
Mean ± SD
Range
(4)
15 ± 2.6
12 - 18
(37)
12.1 ± 2.4
9 - 18
(7)
13.3 ± 2.9
10 - 18
(34)
12.5 ± 2.5
9 - 18
(13)
12.5 ± 2.1
10 - 16
(28)
12.3 ± 2.8
9 - 18
(12)
12.7 ± 2.6
10 - 18
(29)
12.2 ± 2.6
9 - 18
Severe
(>18)
Mean ± SD
Range
(3)
27 ± 13.8
19 - 43
(19)
24.4 ± 7.2
20 - 42
(2)
22 ± 2.8
20 - 24
(20)
25 ± 8.3
19 - 43
(6)
26.2 ± 10.3
19 - 43
(16)
24.2 ± 7.3
18 - 42
(9)
26.2 ± 9.4
18 - 42
(13)
23.7 ± 7.1
19 - 43
positivity in SLE and related autoimmune disorders
[18-22].
Recently Mostafa et al., 2010 had reported an inci-
dence of 16.7% for ACA among SLE patients [23].
Similar incidence was found in our study where
IgG-ACA and IgM-ACA positivity was 12.9% each
which was lower than anti-β2 GP autoantibody positivity
(IgG-β2GP: 27.1% and IgM-β2 GP: 31.8%). Other stud-
ies such as Petri et al., 2010 reported 47% ACA and
32.5% anti-β2 GP autoantibodies in SLE, Biggioggero et
al., 2010 had reported 16.5% IgG-ACA and 9.4% of
IgM-ACA and an incidence of 4.7% IgG-β2 GP and
5.9% for IgM-β2 GP antibodies, Jallouli et al., 2008 had
reported 71.6% for ACA and Descloux et al., 2008 had
reported an incidence of 49% ACA [24,25,13,14]. In a
study on South African SLE patients, Gould et al., 2006
had reported a very high incidence of 53% and 84% for
ACA and anti-β2 GP antibodies where as Al Arfaj et al.,
2009 had reported an incidence of 49.7% and 33.5% for
IgG-ACA and IgM-ACA respectively among Saudi Ara-
bian SLE patients [26,27]. Recently Woo et al., 2010 had
reported an incidence of 18.2% and 31.8% for IgG-ACA
and IgM-ACA respectively and 5.7% for anti-β2 GP to
IgG and IgM isotypes in Korean SLE patients. Shrivastav
et al., 2001 had reported 51% IgG-ACA and 44.7%
IgG-β2 GP autoantibodies [28,29].
Thrombosis varies in SLE patients from 7.2 to 12%.
Sarabi et al., 2005 reported that the most frequent causes
of death in active SLE are infection and thrombosis [30].
The risk of thrombosis for SLE patients reported to be
significantly higher and due to the increased incidence of
traditional cardiovascular and nontraditional lupus-related
thrombosis risk factors, SLE patients are at significantly
increased risk of premature atherosclerosis and/or throm-
bosis. The prevalence of vascular events in SLE patients
ranges between 10% and 30%, for symptomatic coronary
artery disease 6% - 20%, stroke 2% - 15%, and subclini-
cal coronary artery disease 30% - 40% [31]. Our study
showed a higher incidence of systemic vascular throm-
bosis in anti-β2 GP positive patients as compared to
ACA positive patients with an equal distribution for ve-
nous and arterial thrombosis in both the groups.
Recurrent pregnancy loss (RPL) has been associated
with APA including ACA and lupus anticoagulant. It had
been reported that the risk of fetal loss is found to be
increased in patients with hypertension, active SLE, LN,
or abnormally low complement levels. Risk also in-
creased for patients with APA: from 6% to 24% of pa-
tients with SLE are positive for LAC and 40% are posi-
tive for ACA [32-34]. In our study two patients had RPL
and other two had BOH, but they did not show the pres-
ence of ACA or anti-β2 GP antibodies. Shrivastav et al.,
2001 reported that incidence of neurological disorders
such as seizures were noted in 9.4% SLE patients which
was significantly associated with the presence of ACA
and anti-β2 GP antibodies [29]. Neurological disorders
were seen more in anti-β2 GP positive patients than in
ACA positive patients in our study.
Zheng H et al., 2009 reported that LN patients had
elevated SLEDAI as compared to non-LN having ele-
vated renal tissue injury, high serum creatinine, BUN and
proteinuria levels with lower serum C3 levels [9]. Bhan-
dari et al., 1998 had reported a significant reduction in
C3 and C4 levels in ACA positive patients, with a strong
relationship to disease activity/severity at presentation
when compared with changes in ACA negative patients
(p < 0.0%) where renal function at presentation was
worse in patients with ACA positivity [35] It was sug-
gested that ACA is a strong predictor for the presence of
intra glomerular thrombi in patients with LN indicating
the worse long term renal outcome in these patients. Our
findings showed more complement consumption in

Prevalence of Anti-Cardiolipin and Anti-β2 Glycoprotein Antibodies in Indian Systemic Lupus Erythematosus Patients
344
anti-β2 GP positive patients than ACA positives. Hence
detection both ACA and anti-β2 GP antibodies along
with associated immune parameters were found to be
helpful parameters to evaluate their possible association
with disease severity in SLE patients. A long term follow
up of patients having ACA and anti-β2 GP antibodies
without thrombotic event is required to detect their pos-
sible thrombotic event in future along with their clinical
presentation.
5. Acknowledgements
We are grateful to Prof. Yehuda Shoenfeld, MD, Head,
Department of Medicine at the Tel Aviv University, and
Ramat Aviv, Israel for his inputs in correcting this manu-
script and giving his valuable suggestions to modify it.
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