Perceived

work-related

stress

and

early

atherosclerotic

changes

in

healthy

employees

Objective

This

study

was

conducted

to

investigate

the

relationship

between

perceived

work-related

stress

and

preclinical

atherosclerosis

Introduction

Stress

can

no

longer

be

recognized

as

a

problem

of

an

individual

only

Due

to

its

versatile

presence

in

every

human

's

life

often

resulting

in

health

complications

stress

has

become

a

social

problem

and

the

role

of

work-related

stress

in

this

puzzle

should

not

be

underestimated

Coronary

heart

disease

-LRB-

CHD

-RRB-

is

on

the

list

of

stress-related

health

problems

Atherosclerosis

the

basis

of

CHD

develops

in

a

long-lasting

multifactorial

and

complex

process

In

the

etiopathogenesis

of

atherosclerosis

apart

from

traditional

factors

like

lipids

carbohydrate

metabolic

disorders

hypertension

and

lifestyle

-LRB-

smoking

alcohol

use

and

limited

physical

exercise

-RRB-

immunological

disorders

as

a

consequence

of

reciprocal

interactions

in

the

psycho-neuro-immunological

system

have

been

recently

brought

up

-LRB-

George

and

Shoenfeld

Bednarska-Makaruk

and

Pasierski

Kiecolt-Glaser

and

Glaser

Amengual

et

al.

Patryka

et

al.

Jędryka-Góral

et

al.

Jędryka-Góral

Dinan

-RRB-

Early

atherosclerosis

can

even

occur

in

young

healthy

people

-LRB-

Pasierski

-RRB-

For

a

long

time

now

occupational

medicine

has

been

interested

in

the

relationship

between

work-related

stress

and

CHD

Studies

undertaken

in

this

field

have

been

based

on

western

as

well

as

eastern

european

populations

-LRB-

Jonsson

et

al.

Hammer

et

al.

Bosma

et

al.

Kristenson

et

al.

Kivimaki

et

al.

Smith

et

al.

Malinauskiene

et

al.

-RRB-

Although

there

is

a

large

body

of

literature

on

clinically

overt

CHD

and

its

relation

to

work-related

stress

there

have

been

very

few

studies

on

preclinical

CHD

in

those

circumstances

-LRB-

Lynch

et

al.

Nordstrom

et

al.

Rosvall

et

al.

Hintsanen

et

al.

-RRB-

The

current

study

aimed

to

fill

this

gap

and

to

assess

the

relationship

between

work-related

stress

and

preclinical

atherosclerotic

changes

in

healthy

employees

We

considered

carotid

artery

intima-media

thickening

and/or

plaque

presence

as

a

surrogate

of

coronary

atherosclerosis

To

detect

these

changes

gold-standard

methodology

i.e.

B-mode

carotid

ultrasound

examination

was

applied

Because

of

the

complex

nature

of

the

pathogenesis

of

CHD

other

contributing

factors

have

not

been

disregarded

Methods

Organization

of

the

study

First

all

participants

took

part

in

a

psychological

study

in

which

the

level

of

stress

and

coping

were

evaluated

with

relevant

questionnaires

-LRB-

see

below

-RRB-

Then

the

participants

consecutively

presented

themselves

for

a

clinical

visit

in

which

a

medical

examination

took

place

and

a

blood

sample

was

taken

Tests

for

biochemical

parameters

-LRB-

see

below

-RRB-

were

performed

on

the

same

day

as

the

blood

sample

was

taken

according

to

routine

laboratory

procedures

Sera

for

immunological

parameters

-LRB-

see

below

-RRB-

were

collected

and

stored

according

to

international

laboratory

standards

then

tested

in

runs

-LRB-

up

to

sera

per

day

-RRB-

to

minimize

day-to-day

variations

Participants

One

hundred

healthy

managers

and

office

workers

-LRB-

F

M

-RRB-

aged

were

studied

All

of

them

were

investigated

for

the

presence

of

individual

-LRB-

age

obesity

hypertension

diabetes

smoking

alcohol

use

and

low

physical

activity

-RRB-

and

family

-LRB-

obesity

hypertension

diabetes

heart

attack

and

stroke

-RRB-

risk

factors

for

atherosclerosis

The

studied

individuals

detailed

characteristics

are

presented

in

Table

Table

of

studied

groupsManagers

-LRB-

n

-RRB-

Office

workers

-LRB-

n

-RRB-

Total

-LRB-

n

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Females

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Mean

-LRB-

years

-RRB-

Individual

risk

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Hypertension

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Alcohol

use

Every

-LRB-

-RRB-

-LRB-

-RRB-

a

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Smoking

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Hormone

replacement

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Physical

activity

a

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

in

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Family

risk

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Hypertension

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Heart

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Instruments

Work-related

stress

was

operationalized

as

perceived

pressure

caused

by

inappropriate

working

conditions

It

was

measured

by

the

Sources

of

pressure

in

your

job

scale

that

is

a

part

of

the

short

version

of

the

Occupational

Stress

Indicator

-LRB-

-RRB-

by

Cooper

et

al.

Widerszal-Bazyl

's

-LRB-

-RRB-

Polish

adaptation

of

was

used

in

the

study

The

scale

consists

of

items

on

potential

sources

of

pressure

at

work

respondents

are

required

to

rate

each

source

on

six-point

response

scales

in

which

it

is

very

definitely

not

a

source

-LRB-

of

pressure

-RRB-

to

it

is

very

definitely

a

source

Those

items

were

divided

into

eight

subscales

concerning

the

following

stress

factors

workload

-LRB-

e.g.

Having

to

work

very

long

hours

Taking

work

home

-RRB-

relationships

-LRB-

e.g.

Inadequate

guidance

and

backup

from

superiors

Feeling

isolated

-RRB-

home

work

balance

-LRB-

e.g.

Pursuing

a

career

at

the

expense

of

home

life

-RRB-

recognition

-LRB-

e.g.

Underpromotion

working

at

a

level

below

my

level

of

ability

-RRB-

organizational

climate

-LRB-

e.g.

Characteristics

of

the

organization

's

structure

and

design

managerial

role

-LRB-

e.g.

Managing

or

supervising

the

work

of

other

people

-RRB-

personal

responsibility

-LRB-

e.g.

Having

to

take

risks

-RRB-

hassle

at

work

-LRB-

e.g.

Attending

meetings

-RRB-

The

scale

made

it

possible

to

assess

the

global

level

of

work-related

stress

-LRB-

the

sum

of

scores

for

all

items

-RRB-

as

well

as

to

assess

the

level

of

a

given

kind

of

work

stress

e.g.

workload

-LRB-

the

sum

of

scores

for

items

related

to

workload

-RRB-

The

reliability

of

the

Polish

version

of

the

total

scale

was

very

high

Cronbach

's

α

It

was

also

satisfactory

for

most

subscales

workload

α

relationships

α

home

work

balance

α

recognition

α

organizational

climate

α

managerial

role

α

personal

responsibility

α

hassle

at

work

α

-LRB-

Widerszal-Bazyl

-RRB-

Coping

was

measured

with

the

How

you

cope

with

the

stress

you

experience

scale

that

is

also

part

of

too

It

consists

of

items

on

potential

coping

strategies

respondents

are

required

to

rate

the

extent

to

which

they

actually

use

them

as

ways

of

coping

with

stress

Answers

are

given

on

six-point

scales

from

I

never

use

it

to

I

use

it

very

extensively

Some

coping

strategies

included

into

the

scale

dealt

with

coping

through

control

-LRB-

e.g.

Effective

time

management

-RRB-

and

some

with

coping

through

social

support

-LRB-

e.g.

Talk

to

understanding

friends

-RRB-

The

reliability

of

the

Polish

version

of

the

total

coping

scale

was

Cronbach

's

α

and

reliability

of

its

subscales

-LRB-

for

coping

through

control

-RRB-

and

-LRB-

for

coping

through

social

support

-RRB-

Therefore

the

total

index

of

coping

was

used

in

the

analysis

as

well

as

the

index

of

coping

through

control

Prior

to

the

study

appropriate

approval

from

the

Local

Ethics

Committee

was

obtained

Participants

were

provided

with

detailed

written

information

on

the

study

's

objectives

and

the

methods

that

were

going

to

be

used

subsequently

they

signed

their

informed

consent

Serum

levels

of

biochemical

-LRB-

total

cholesterol

LDL

HDL

TG

glucose

-RRB-

and

serological

risk

factors

of

atherosclerosis

-LRB-

anticardiolipin

GPI

anti-oxLDL

anti-HSP

and

anti-hsCRP

antibodies

-RRB-

were

evaluated

Anticardiolipin

antibodies

Patients

sera

were

tested

with

ELISA

for

the

presence

of

anticardiolipin

antibodies

according

to

the

modified

Harris

method

-LRB-

Luft

et

al.

-RRB-

The

results

were

presented

as

OD

units

Reference

ranges

of

aCL

were

established

by

studying

sera

from

healthy

donors

The

cut-off

value

was

established

as

OD

x

estimated

for

sera

of

healthy

blood

donors

it

was

for

the

IgG

class

and

for

the

IgM

class

glycoprotein

I

-LRB-

β2

GPI

-RRB-

antibody

levels

were

measured

with

a

commercial

DIASTAM

FBGP

from

Axis-Shield

-LRB-

Cat

No

-RRB-

test

The

results

were

expressed

as

OD

units

Reference

ranges

of

glycoprotein

I

antibodies

were

established

by

studying

sera

from

healthy

Caucasian

donors

-LRB-

Axis-Shield

Diagnostics

Ltd.

examination

-RRB-

The

cut-off

value

was

established

as

OD

Anti-HSP

antibody

levels

-LRB-

IgG

class

-RRB-

were

estimated

with

non-commercial

methodology

after

necessary

modification

according

to

Tsoulfa

et

al.

-LRB-

-RRB-

with

the

use

of

McLean

reagents

The

cut-off

value

was

established

as

x

estimated

for

sera

of

healthy

blood

donors

it

was

OD

The

estimation

of

IgM

and

IgA

class

antibodies

was

performed

in

the

same

manner

Anti-oxLDL

IgG

antibody

levels

were

measured

with

ELISA

with

the

use

of

a

commercial

test

from

OLAB

-LRB-

Cat

No

-RRB-

The

cut-off

value

was

established

as

arbitrary

units

hsCRP

concentration

was

measured

with

ELISA

with

the

use

of

commercial

tests

from

EUCARDIO

Laboratory

Inc.

-LRB-

Cat

No

ZZ

-RRB-

The

cut-off

value

was

established

as

ng/ml

Intima-media

thickness

-LRB-

IMT

-RRB-

and

atherosclerotic

plaque

in

carotid

arteries

were

searched

using

a

computer

analysis

of

B-mode

ultrasound

images

Both

carotid

arteries

were

measured

with

a

linear-array

transducer

part

of

Hewlett

Packard

Sonos

Plaque

was

defined

as

intima-medial

thickening

larger

than

in

comparison

to

the

surround

area

-LRB-

Pignoli

et

al.

-RRB-

Statistical

analysis

of

data

was

performed

with

SPSS

v.

Means

comparisons

were

carried

out

with

a

t

test

for

independent

groups

In

bivariate

correlation

analysis

Pearson

's

r

coefficients

were

calculated

The

level

of

significance

was

set

at

α

Results

Assessment

of

work-related

stress

The

level

of

work-related

stress

measured

with

's

Sources

of

pressure

scale

was

as

follows

managers

mean

-LRB-

σ

-RRB-

for

office

workers

mean

-LRB-

σ

-RRB-

for

both

groups

mean

-LRB-

σ

-RRB-

According

to

Polish

sten

norms

the

sten

scale

-LRB-

sten

stands

for

standard

ten

-RRB-

consists

of

ten

units

Each

unit

equals

of

a

standard

deviation

It

is

assumed

that

stens

five

and

six

means

average

results

stens

seven

to

ten

high

results

and

stens

one

to

four

low

results

-LRB-

Canfield

-RRB-

Developed

for

Polish

managers

-LRB-

Widerszal-Bazyl

-RRB-

the

managers

mean

falls

on

sten

six

whereas

the

office

workers

mean

falls

on

sten

five

-LRB-

Table

-RRB-

As

a

rule

stens

five

and

six

are

interpreted

as

average

results

Table

of

psychological

examinationStudied

groupsWork-related

Assessment

of

coping

The

level

of

coping

measured

with

's

Coping

scale

was

as

follows

managers

mean

office

workers

mean

both

groups

mean

According

to

Polish

sten

norms

the

managers

mean

falls

on

sten

five

for

men

and

on

sten

six

for

women

The

office

workers

mean

falls

on

sten

five

-LRB-

for

both

genders

-RRB-

Thus

it

can

be

said

that

the

coping

results

were

in

the

average

range

Laboratory

findings

The

abnormality

most

frequently

disclosed

in

biochemical

findings

were

elevated

levels

of

total

cholesterol

LDL

and

triglycerides

-LRB-

in

and

of

the

studied

individuals

respectively

-RRB-

Decreased

levels

of

HDL

and

increased

levels

of

glucose

were

less

frequent

and

were

found

in

of

cases

each

Of

the

immunological

parameters

studied

oxLDL

antibodies

were

most

frequently

found

-LRB-

in

of

cases

-RRB-

followed

by

an

elevated

level

of

hsCRP

-LRB-

in

of

cases

-RRB-

In

a

few

cases

antibodies

to

β2

GPI

and

-LRB-

IgG

class

-RRB-

were

found

-LRB-

in

and

of

studied

cases

respectively

-RRB-

of

the

studied

individuals

was

positive

for

aCl

For

six

sera

which

were

borderline

or

positive

for

IgG

class

IgM

and

IgA

class

antibodies

were

searched

Only

in

three

cases

were

the

results

weakly

positive

-LRB-

two

in

IgM

and

one

in

IgA

class

-RRB-

Ultrasound

examination

of

carotid

arteries

Changes

in

the

ultrasound

examination

of

carotid

arteries

confirming

the

presence

of

early

atherosclerosis

are

shown

in

Table

Plaque

was

found

in

-LRB-

-RRB-

cases

in

managers

-LRB-

-RRB-

and

in

office

workers

-LRB-

-RRB-

groups

did

not

differ

statistically

The

distribution

of

the

mean

values

of

the

IMT

measure

was

slightly

skewed

to

the

right

The

mean

values

of

IMT

in

managers

and

office

workers

were

and

mm

respectively

groups

did

not

differ

statistically

Table

of

ultrasound

examination

of

carotid

arteries

in

studied

groupsManagers

-LRB-

n

-RRB-

Office

workers

-LRB-

n

-RRB-

Total

-LRB-

n

-RRB-

Number

of

individuals

without

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Number

of

individuals

with

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Intima-media

measurement

values

Correlation

between

IMT

and

the

presence

of

plaque

in

carotid

arteries

with

atherosclerosis

risk

factors

Positive

correlation

was

found

between

IMT

and

age

-LRB-

r

P

-RRB-

diastolic

blood

pressure

-LRB-

r

P

-RRB-

LDL

-LRB-

r

P

-RRB-

anti-HSP

antibodies

-LRB-

r

P

-RRB-

whereas

negative

correlation

was

revealed

with

aCl

IgG

-LRB-

r

P

-RRB-

and

global

work-related

stress

level

-LRB-

r

P

-RRB-

Among

the

stressors

studied

statistical

significance

was

shown

for

interpersonal

relations

-LRB-

r

P

-RRB-

work

home

balance

-LRB-

r

P

-RRB-

managerial

role

-LRB-

r

P

-RRB-

and

organization

climate

-LRB-

r

P

-RRB-

The

presence

of

plaque

correlated

positively

with

age

-LRB-

r

P

-RRB-

smoking

-LRB-

r

P

-RRB-

LDL

-LRB-

r

P

-RRB-

and

negatively

with

global

work-related

stress

level

-LRB-

r

P

-RRB-

Statistical

significance

was

shown

for

the

following

stressors

work

load

-LRB-

r

P

-RRB-

interpersonal

relations

-LRB-

r

P

-RRB-

work

home

balance

-LRB-

r

P

-RRB-

and

responsibility

-LRB-

r

P

-RRB-

-LRB-

see

Table

-RRB-

Table

between

IMT

and

the

presence

of

plaque

in

carotid

arteries

and

atherosclerosis

risk

factors

-LRB-

Pearson

's

r

-RRB-

Risk

factorIMTPlaqueAge

BMI

Systolic

blood

preasure

Diastolic

blond

preasure

Cigarette

smoking

Physical

activity

HDL

Glucose

hsCRP

aCl

IgG

aCl

IgM

Workload

Relationships

Home

work

balance

Managerial

role

Personal

responsibility

Hassle

at

work

Recognition

Organizational

climate

Total

index

of

coping

Coping

through

control

Global

level

of

stress

Correlation

is

significant

at

-LRB-

-RRB-

Correlation

is

significant

at

-LRB-

-RRB-

Correlation

between

LDL/smoking

and

global

stress

level

Pearson

's

analysis

showed

a

negative

relation

between

LDL

and

global

stress

level

-LRB-

r

P

-RRB-

and

between

smoking

and

global

stress

level

-LRB-

r

P

-RRB-

Work-related

stress

coping

lifestyle

and

IMT

Pearson

's

analysis

was

performed

in

two

triangles

-LRB-

a

-RRB-

work-related

stress

coping

IMT

and

-LRB-

b

-RRB-

work-related

stress

healthy

lifestyle

IMT

No

statistically

significant

relations

were

shown

either

between

work-related

stress

and

coping

or

between

coping

and

IMT

-LRB-

P

-RRB-

or

between

work-related

stress

and

healthy

lifestyle

-LRB-

no

smoking

no

excessive

use

of

alcohol

high

physical

activity

-RRB-

or

between

healthy

lifestyle

and

IMT

-LRB-

P

-RRB-

Discussion

A

multidisciplinary

approach

to

assessing

risk

factors

for

atherosclerosis

was

considered

by

us

in

an

earlier

study

-LRB-

Jędryka

Góral

et

al.

-RRB-

On

the

basis

of

a

deep

multilevel

analysis

we

were

able

to

show

that

in

healthy

individuals

as

in

CHD

patients

individual

and

biochemical

risk

factors

were

likely

to

play

a

leading

role

in

the

development

of

early

atherosclerosis

Psychosocial

stress

should

also

be

considered

however

inflammatory-immunological

factors

have

not

been

found

to

be

an

independent

predictor

As

inflammatory-immunological

factors

antibodies

to

oxLDL

and

hsCRP

as

well

as

anticardiolipin

and

GPI

antibodies

were

considered

In

the

extensive

literature

of

the

subject

these

parameters

are

recognized

as

directly

involved

in

the

pathogenesis

of

atherosclerosis

-LRB-

George

and

Shoenfeld

Kiecolt-Glaser

Glaser

Amengual

et

al.

Patryka

et

al.

Jędryka-Góral

et

al.

Jędryka-Góral

-RRB-

The

present

study

was

undertaken

to

extend

the

investigation

of

psychosocial

stress

and

atherosclerosis

We

looked

in

depth

for

correlation

between

preclinical

atherosclerosis

and

work-related

stress

correlations

with

other

risk

factors

of

CHD

were

done

in

parallel

As

expected

we

found

correlation

between

IMT

and

age

diastolic

blood

pressure

LDL

and

anti-HSP

antibodies

and

correlation

between

plaque

and

age

smoking

and

LDL

Surprisingly

our

results

revealed

that

early

atherosclerotic

changes

negatively

correlated

with

the

level

of

global

job

strain

and

some

of

its

components

-LRB-

interpersonal

relations

work

home

balance

managerial

role

organization

climate

for

IMT

work

load

interpersonal

relations

work

home

balance

responsibility

for

plaque

-RRB-

Ambiguous

results

have

been

previously

reported

in

other

although

very

few

studies

where

work

psychosocial

factors

and

carotid

atherosclerosis

were

studied

with

ultrasound

Rosvall

et

al.

's

-LRB-

-RRB-

hypothesis

that

work-related

stress

characterized

by

high

psychological

demands

and

low

decision

latitude

was

associated

with

increased

carotid

atherosclerosis

could

not

be

confirmed

either

for

women

or

for

men

On

the

other

hand

Lynch

et

al.

's

-LRB-

-RRB-

prospective

study

showed

that

men

who

experienced

work-related

stress

-LRB-

demanding

work

and

low

economic

rewards

-RRB-

had

significantly

greater

progression

of

carotid

atherosclerosis

than

more

advantaged

men

Hintsanen

et

al.

-LRB-

-RRB-

provided

data

that

job

strain

-LRB-

a

joint

effect

of

job

demands

and

job

control

-RRB-

was

associated

with

increased

IMT

in

men

but

not

in

women

Similarly

Nordstrom

et

al.

-LRB-

-RRB-

showed

that

in

men

with

greater

work-related

stress

-LRB-

workplace

demands

and

intrusion

of

work

concerns

into

home

life

-RRB-

the

risk

of

focal

lesions

or

intima-media

thickness

in

coronary

artery

increased

whereas

in

women

stress

was

not

related

to

the

prevalence

of

early

atherosclerosis

Hlatky

et

al.

-LRB-

-RRB-

disclosed

that

job

strain

-LRB-

high

psychological

demands

and

low

decision

latitude

-RRB-

did

not

correlate

with

the

presence

of

coronary

disease

in

angiography

either

for

men

or

for

women

By

searching

for

a

relationship

between

work-related

stress

and

atherosclerosis

we

wanted

to

prove

that

the

correlation

found

between

early

atherosclerotic

changes

and

LDL

and

smoking

is

at

least

partly

caused

by

a

higher

stress

reaction

in

the

studied

individuals

It

was

assumed

that

individuals

with

a

level

of

high

stress

undertook

unhealthy

behaviour

smoking

or

excessive

food

intake

However

for

both

LDL

and

smoking

the

correlation

with

stress

was

negative

One

should

keep

in

mind

that

only

of

the

studied

individuals

had

elevated

levels

of

LDL

and

reported

smoking

Therefore

these

results

should

be

interpreted

causally

We

explored

in

depth

the

negative

correlation

we

found

between

IMT

and

the

presence

of

plaque

and

the

level

of

work-related

stress

Being

aware

that

measured

perceived

stress

another

hypothesis

was

formulated

persons

with

a

high

level

of

work-related

stress

-LRB-

conscious

stress

-RRB-

undertake

preventive

activities

at

the

level

of

coping

or

healthy

lifestyle

Perceived

work-related

stress

as

a

risk

factor

for

a

clinically

overt

CHD

has

been

investigated

in

multiple

studies

Some

prospective

studies

showed

an

association

of

work-related

stress

with

an

incidence

of

CHD

-LRB-

Bosma

et

al.

Kivimaki

et

al.

Kivimaki

et

al.

-RRB-

whereas

others

did

not

-LRB-

De

Bacquer

et

al.

Rosvall

et

al.

Eaker

et

al.

-RRB-

The

largest

INTERHEART

study

covering

cases

and

controls

from

different

countries

all

over

the

world

confirmed

this

association

with

regard

to

work

home

financial

and

major

life

stress

-LRB-

Rosengren

et

al.

-RRB-

There

are

studies

which

indicated

that

perceived

work-related

stress

had

profound

impact

on

internal

organs

sensual

organs

the

locomotor

system

and

skin

health

problems

-LRB-

Cheng

et

al.

Lindgren

et

al.

-RRB-

In

the

literature

of

the

subject

coping

is

closely

linked

to

stress

The

most

common

meaning

of

coping

is

an

effort

to

solve

problems

and

to

seek

reduction

of

tolerance

to

stress

The

CATS

theory

-LRB-

cognitive

activation

theory

of

stress

-RRB-

offered

a

new

approach

to

coping

-LRB-

Ursin

Eriksen

Eriksen

et

al.

-RRB-

This

theory

assumed

two

cognitive

reformulations

of

the

learning

theory

-LRB-

stimulus

stimulus

learning

classical

conditioning

and

response

learning

instrumental

conditioning

-RRB-

Both

reformulations

are

essential

to

understanding

the

relationship

between

learning

activation

and

relations

between

stress

and

health

The

stress

response

-LRB-

an

alarm

in

the

homeostatic

system

-RRB-

results

in

behaviors

that

aim

to

cope

with

a

situation

The

level

of

alarm

depends

on

what

outcome

of

a

stimulus

is

expected

and

the

specific

responses

available

for

coping

Response

outcome

expectancy

might

be

positive

-LRB-

coping

-RRB-

negative

-LRB-

hopelessness

-RRB-

or

-LRB-

helplessness

-RRB-

Hence

coping

defined

as

acquired

positive

outcome

expectancy

has

some

predictive

value

for

stress

and

health

According

to

Weidner

and

Cain

-LRB-

-RRB-

research

on

how

people

cope

with

stress

situations

disclosed

avoidant

mechanisms

-LRB-

denial

distraction

excessive

alcohol

consumption

-RRB-

in

men

whereas

more

cardioprotective

strategies

-LRB-

depression

asking

for

help

-RRB-

in

females

Stress

management

goes

far

beyond

coping

strategies

Toobert

et

al.

's

-LRB-

-RRB-

results

disclosed

success

of

a

complex

intervention

program

to

reduce

CHD

risk

which

included

improvement

of

diet

stress

management

social

support

smoking

and

physical

activity

In

our

study

on

preclinical

atherosclerosis

and

work-related

stress

we

were

not

able

to

confirm

the

hypothesis

about

the

above-mentioned

prophylactic

activities

An

analysis

of

correlation

showed

no

significant

relations

between

work-related

stress

and

coping

between

coping

and

IMT

between

work-related

stress

and

healthy

lifestyle

or

between

healthy

lifestyle

and

IMT

A

relatively

novel

conception

was

presented

by

de

Lange

et

al.

-LRB-

-RRB-

who

claimed

that

the

relationship

between

stressful

work

and

psychological

well-being

may

be

reciprocal

Their

results

showed

that

mental

health

might

influence

employees

perceived

work

characteristics

It

is

likely

that

the

employees

in

our

study

had

been

recruited

from

that

part

of

working

society

who

felt

fit

to

undertake

ambitious

tasks

of

managers

and

office

workers

and

who

developed

job

adaptive

mechanisms

over

time

The

most

probable

interpretation

of

the

negative

correlation

between

perceived

work

related

stress

and

preclinical

atherosclerosis

is

that

in

the

case

of

individuals

with

a

low

level

of

perceived

work-related

stress

somatization

of

stress

took

place

i.e.

stress

is

not

perceived

at

the

conscious

level

but

it

leads

to

somatic

effects

-LRB-

e.g.

IMT

-RRB-

We

are

aware

of

some

limitations

of

our

study

Firstly

the

results

regarding

work-related

stress

were

based

on

self-reported

data

which

per

se

could

always

be

a

matter

of

some

bias

Secondly

the

number

of

employees

studied

was

limited

to

Voluntary

participation

of

employees

and

fully

unselected

method

of

recruitment

can

guarantee

the

objectivity

of

the

results

Thirdly

it

was

a

cross-sectional

study

A

prospective

type

of

research

on

risk

assessment

is

preferable

nowadays

However

our

study

did

not

aim

to

assess

risk

of

CHD

but

to

find

correlation

between

work-related

stress

and

early

atherosclerosis

so

we

believe

the

measure

taken

for

this

purpose

was

appropriate

We

are

more

than

convinced

that

to

achieve

full

understanding

of

negative

correlation

between

work-related

stress

and

early

atherosclerosis

requires

further

interdisciplinary

studies

and

we

would

be

happy

to

continue

exploration

into

this

intriguing

field

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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Nasal NK/T-cell lymphoma : epidemiology and pathogenesis Nasal NK/T-cell lymphoma -LRB- NKTCL -RRB- is an uncommon disease , but usually shows a highly aggressive clinical course . The disease is much more frequent in Asian and Latin American countries than in Western countries , and is universally associated with Epstein -- Barr virus -LRB- EBV -RRB- infection . Analyses of gene mutations , especially p53 and c-KIT , revealed the different frequencies by district . Epidemiological studies revealed the changes of the disease frequency in Korea during the period from 1977 -- 1989 to 1990 -- 1996 . Case-control study showed that the exposure to pesticides and chemical solvents could be causative of NKTCL . Further studies including HLA antigen typing of patients is necessary to further clarify the disease mechanism . Rapid destruction of the nose and face -LRB- midline -RRB- was firstly described by McBride in 1897 -LSB- 1 -RSB- . Macroscopically the lesions usually looked like necrotic granuloma and the patients showed aggressive and lethal course , therefore the term `` lethal midline granuloma -LRB- LMG -RRB- '' or `` granuloma gangrenescens '' were used for this condition . Later the term LMG is popularly used . It had became evident that the LMG is composed of three different types of histology , i.e. Wegener 's granulomatosis -LRB- WG -RRB- , polymorphic reticulosis -LRB- PR -RRB- or midline malignant reticulosis -LRB- MMR -RRB- , and malignant lymphoma -LSB- 2 , 3 -RSB- . These diseases could be histologically differentiated from each other by taking clinical findings into account . WG is usually characterized by generalized necrotizing vasculitis involving both arteries and veins and the presence of glomerulitis -LSB- 4 -RSB- . Cancer and specific inflammation such as tuberculosis also cause a condition indistinguishable from LMG . PR exhibits a polymorphous pattern of proliferation consisting of large atypical cells with mono - or multinucleus , small lymphocytes , plasma cells , benign-appearing macrophages , neutrophils and much less frequently eosinophils . PR had been considered as a variant of malignant lymphomas because the disease is frequently disseminated -LSB- 2 -RSB- . The nature of proliferating cells in PR had been controversial . Once the disease was termed as nasal T-cell lymphoma because the proliferating cells showed a positive immunoreactivity for polyclonal antibodies against T-cells -LSB- 5 , 6 -RSB- . However , monoclonal rerrangement of the T-cell receptor genes was seldomly found in cases with `` nasal T-cell lymphoma '' -LSB- 7 -RSB- . Later Ng et al. -LSB- 8 -RSB- reported that the tumor cells showed a positive immunoreactivity for natural killer -LRB- NK -RRB- cell marker CD56 . Subsequently it was shown that proliferating cells in PR had large granular lymphocyte morphology -LSB- 9 -RSB- , which is a character of NK cells or cytotoxic T-lymphocytes . There have been accumulating evidences that PR is a neoplasm of activated NK cells -LSB- 10 -- 13 -RSB- : the proliferating cells usually show CD2 + , CD56 + , CD3ε + , CD7 − , CD16 − , cytotoxic granule-associated proteins + and do not exhibit rearrangement of T-cell receptor or immunoglobulin genes -LRB- Fig. 1 -RRB- . Meanwhile rearrangement of T-cell receptor genes was recorded in the rare cases of PR -LSB- 14 , 15 -RSB- . Although the upper respiratory tract , especially nasal region , is the common site of presentation , NK/T-cell lymphoma of nasal type may present in diverse extranodal sites such as gastrointestinal tract , skin , testis , liver , and spleen -LSB- 16 -RSB- . In the World Health Organization classification , NK/T-cell lymphoma encompasses the lymphomas involving nasal area and nonnasal area . Until present , there have been many review articles on the clinical , pathological , immunohistochemical , and immunogenetical aspects of NK/T-cell lymphomas involving upper respiratory tract . This review focuses on the epidemiology and molecular pathogenesis of nasal NK/T-cell lymphoma -LRB- NLTCL -RRB- . Fig. 1HE . Polymorphous pattern of proliferation in the nasal cavity . Large cells show positive immunoreactivity with CD3ε , TIA-1 , and CD56 . ABC method , × 400 Association with Epstein -- Barr virus -LRB- EBV -RRB- The association between EBV and human malignancies , including endemic Burkitt 's lymphoma , Hodgkin lymphoma and non-Hodgkin 's lymphoma -LRB- NHL -RRB- of either B - or T-immunophenotypes , has been reported . Etiological role of EBV for development of NKTCL was firstly reported in 1990 -LSB- 17 -RSB- . Subsequent study revealed the constant association of NKTCL with EBV in the world -LRB- Fig. 2 -RRB- -LRB- Table 1 -RRB- -LSB- 18 -- 23 -RSB- . Sino-nasal lymphomas are immunophenotypically classified into NK/T - -LRB- CD56 + -RRB- , T - , and B-cell type with distinctive clinical features -LSB- 24 -RSB- . CD56 positivity , therefore NKTCL , was closely associated with EBV positivity among sino-nasal lymphomas -LSB- 22 -RSB- . EBV could be subtyped based on the difference in sequence of EBNA2 region , i.e. type A and type B -LSB- 25 -RSB- . Almost all of the NKTCL in Korea and Japan had type A EBV , which is identical with the previous literature reporting that most cases of EBV-associated malignancies of immunocompetent patients in Asia had type A EBV -LSB- 26 -RSB- . Predominance of type A EBV was also found in NKTCL in Malaysia -LSB- 27 -RSB- , indicating the predominance of type A EBV in NKTCL in Asia . Several studies indicated the occurrence of type B EBV in lymphoma of immunocompromised patients -LSB- 28 -RSB- . Borisch et al. -LSB- 29 -RSB- reported that three of six cases of NKTCL in Switzerland had type B EBV , although no findings suggestive of immunodeficiency were found in these patients . These findings suggest a geographic difference in the distribution of EBV subtype in the NKTCL . Fig. 2In situ hybridization with EBER-1 probe reveals positive signals in the nucleus of proliferating cell Table 1EBV in nasal NK/T-cell lymphomaSourceCountryEBV positive rate -LRB- % -RRB- EBV subtype Expression of latent -LSB- 18 -RSB- a France7/7 -LRB- 100 -RRB- NA7/7 LMP + -LSB- 20 -RSB- China21/21 -LRB- 100 -RRB- NA5/21 LMP-1 + -LSB- 21 -RSB- Japan11/12 -LRB- 92 -RRB- 10/11 typeA8/12 LMP-1 + -LSB- 22 -RSB- Korea15/16 -LRB- 94 -RRB- 15/15 typeA7/15 LMP-1 + -LSB- 24 -RSB- Indonesia18/20 -LRB- 90 -RRB- NANAEBV Epstein -- Barr virus , LMP latent membrane protein , NA not availableaFresh tissue samples were used in the analyses As shown in Table 1 , the proliferating cells in NKTCL frequently express latent membrane protein -LRB- LMP -RRB- as revealed by immunohistochemistry . Latent infection gene products of EBV , EBNA-2 and LMP-1 , serve as target antigens for the elimination of EBV infected cells by host cytotoxic T-lymphocytes -LRB- CTL -RRB- -LSB- 30 -RSB- . Shen et al. -LSB- 31 -RSB- showed that NKTCL cells are able to provide target epitopes of EBV for CTL . In immunocompromised hosts , proliferating cells expressing EBNA-2 and LMP-1 can escape from immune surveillance by the host CTL , which might result in the development of malignant lymphomas -LSB- 32 -RSB- . However , systemic immunosuppression is not noted in patients with NKTCL , thus suggesting an unknown underlying mechanism for escape of LMP-1-expressing tumor cells from the CTL . Several mechanisms such as downregulation of the immunogenic EBV nuclear antigens and preferential selection of the deletion genotype of LMP-1 was reported by Chiang et al. -LSB- 33 , 34 -RSB- and expression of IL-10 , an immunosuppressive cytokine , was reported by Shen et al. -LSB- 31 -RSB- . The cells expressing viral antigens are eliminated primarily by CTL in a MHC-class-I-restricted manner -LSB- 35 -RSB- . Two CTL-epitopes were identified in LMP-1 that are possibly pan A * 02-restricted -LSB- 36 -RSB- . It is possible that NKTCL patients show lower frequencies of A * 02 allele compared with those in the normal population . Indeed high-resolution genetic typing revealed significantly lower frequency of HLA-A * 0201 in NKTCL than in normal population -LSB- 37 -RSB- . These findings suggest that HLA-A * 0201-restricted CTL responses may function in vivo to suppress the development of NKTCL , or in other words , role of EBV for NKTCL development . Genetical changes Lymphoma arises from clonal expansion of lymphoid cells that are transformed by the accumulation of genetic lesions affecting oncogenes and tumor suppressor genes . In general , amount of samples from NKTCL lesions available for genetical analyses is small , and samples usually contain massive necrotic areas . Therefore information for genetical changes in NKTCL has been relatively limited until present . Alterations of tumor suppressor genes and oncogenes Polymerase chain reaction -LRB- PCR -RRB- -- single strand conformation polymorphism -LRB- SSCP -RRB- followed by direct sequence method was employed for analyses of gene alterations in NKTCL . The genes analyzed by this method were p53 , k-ras , c-kit , and β-catenin on the NKTCL cases from Asian countries -LSB- 38 -- 42 -RSB- and Mexico -LSB- 43 -RSB- . p53 is a well-known tumor suppressor gene that causes cells with damaged DNA to arrest at the G1 phase of cell cycle or stimulating expression of the BAX gene , the protein that promotes apoptosis -LSB- 44 -RSB- . In a wide variety of human cancers , p53 gene mutations have been detected mainly in exon 5 through 8 -LSB- 45 -RSB- . K-RAS , c-KIT , and β-catenin genes are oncogenes . Greenblatt et al. -LSB- 46 -RSB- identified 50 studies in which sequencing of the entire coding region of p53 had been reported . Of the 560 mutations reported in those papers , 87 % were found in exons 5 -- 8 , and most of the others were in exon 4 -LRB- 8 % -RRB- . In the studies for NKTCL in Asia , exons 4 -- 8 or exons 5 -- 8 were examined in one institute -LRB- Table 2 -RRB- . The frequency of p53 mutations was various by district : high in Japan and Indonesia and low in Mexico , Korea , and Shenyang . Shenyang situates at north China , which is adjacent to the Korean peninsula , suggesting that environmental and genetical factors might generate the differences in frequency . Transitions -LRB- G : C to A : T -RRB- were the predominant pattern of mutations except for Mexico , in which number of cases with mutations was only five -LSB- 43 -RSB- , thus the data from Mexico seemed to be not conclusive . Predominance of transition mutations suggests that some `` endogenous '' mutagens act in lymphomagenesis . The transition pattern of p53 mutations is known to be more susceptible to spontaneous genetic instability than transversion . While genetic instability as revealed by widespread microsatellite instability was not found in the cases with NKTCL -LSB- 47 -RSB- . Table 2p53 mutations in nasal NK/T-cell lymphomaNumber of cases Exons examinedFrequency of mutations -LRB- % -RRB- Predominance of transition mutationAsia Japan -LSB- 41 -RSB- 584 -- 862 % yes Korea -LSB- 41 -RSB- 424 -- 831 % yes China Beijing , Chengdu -LSB- 38 -RSB- 425 -- 848 % yes Shenyang -LSB- 40 -RSB- 204 -- 840 % yes Indonesia -LSB- 42 -RSB- 274 -- 863 % yesMexico -LSB- 43 -RSB- 215 -- 824 % no Quintanilla-Martinez et al. reported the association of p53 overexpression with poor prognosis , and p53 mutations with large cell morphology and advanced stage -LSB- 43 , 48 -RSB- . However these findings were not confirmed by other studies . -LSB- 15 , 38 -RSB- The c-KIT proto-oncogene encodes a receptor tyrosine kinase , which is involved in normal hematopoiesis , gametogenesis , and melanogenesis via the c-kit receptor-ligand system . -LSB- 49 -RSB- . Because the development of acute leukemia or malignant lymphoma was reported in transgenic mice expressing KIT -LSB- 8 , 14 , 50 -RSB- , NKTCL in Asian countries was examined for the c-kit gene mutations -LSB- 41 -RSB- . Frequency of c-kit mutations was significantly higher in China -LRB- Beijing , Chengdu -RRB- -LRB- 10 of 14 cases : 71.4 % -RRB- -LSB- 39 -RSB- than in Japan -LRB- 9 of 58 cases : 15.5 % -RRB- -LSB- 41 -RSB- , Korea -LRB- 5 of 42 cases : 11.9 % -RRB- -LSB- 41 -RSB- , northeast China -LRB- Shenyang -RRB- -LRB- 2 of 20 cases : 10 % -RRB- -LSB- 40 -RSB- , and Indonesia -LRB- 3 of 27 cases : 11.1 % -RRB- -LSB- 42 -RSB- . These findings suggest that location-specific differences in etiological factors cause specific mutations in c-kit gene . FAS Gene Mutations Fas -LRB- Apo-1 / CD95 -RRB- is a 45 kDa membrane protein belonging to the tumor necrosis factor receptor family , and mediates programmed cell death -LRB- apoptosis -RRB- through binding of FAS ligand -LRB- Fas L -RRB- -LSB- 51 -RSB- . Fas consists of 325 amino acids with a single transmembrane domain , including signal peptide . The 80-amino acid portion in the cytoplasm , designated as a death signaling domain , is essential for the apoptotic signal transduction . FAS gene mutations were reported in about 10 % cases with sporadic non-Hodgkin 's lymphoma -LSB- 52 -RSB- . NKTCL frequently co-express FAS and FAS ligand -LRB- Fas L -RRB- , but the tumor cells seldom undergo apoptosis . Some mechanisms for resistance to FAS/FAS L - induced apoptosis might work in the development of NKTCL , thus FAS gene mutations could be one of the mechanisms . Two reports support this notion : NKTCL cells in 9 of 15 -LRB- 60 % -RRB- cases -LSB- 53 -RSB- and 7 of 14 -LRB- 50 % -RRB- cases -LSB- 54 -RSB- showed mutations of FAS gene . Mouse T-cell lymphoma cells transfected with mutated FAS genes were resistant to apoptosis -LRB- Fig. 3 , Fig. 4 -RRB- -LSB- 54 -RSB- , indicating the mutations to be loss of function mutation . These findings suggest that accumulation of lymphoid cells with FAS mutations provides a basis for the development of NKTCL . Fig. 3Summary of the FAS gene mutations found in patients with nasal NKTCL . The shaded rectangles at the COOH-terminus of the protein represents the small peptide added because of the frameshift in the gene encoding FAS.TM : transmembrane domain Fig. 4The mouse WR19L cell line expressing recombinant human FAS protein with -LRB- T1102C , A978G , 1095 ins A -RRB- or without -LRB- wild type -RRB- mutations were incubated with various concentrations of anti-FAS antibody at 37.0 °C for 16 h. Clones expressing FAS receptor with any mutations -LRB- A978G , 1095 ins A , T1102C -RRB- were resistant to apoptosis induced by the anti-FAS antibody Others Various cytogenetic alterations have been reported , of which deletions of 6q are the common -LSB- 55 -RSB- . Epidemiological features It had been reported that NKTCL seemed to be relatively common among non-Hodgkin 's lymphoma in Hong Kong -LSB- 56 -- 58 -RSB- : malignant lymphomas affecting nose and nasopharyngeal region constituted 7.2 % of extranodal lymphomas -LSB- 56 -RSB- and 45 of 70 cases with malignant lymphomas in the nose , nasopharynx , and larynx had PR morphology -LSB- 57 -RSB- . This disease is occasionally encountered in the hospitals in Japan -LSB- 5 , 59 , 60 -RSB- . When one of the authors -LRB- KA -RRB- visited the USA in 1987 , he noticed that the disease was quite rare in the USA , but they had consultation cases from Peru . Because Japanese and a part of Peruvian belong to Mongolian ethnic group , it was postulated that the Mongolian group might be much more frequently affected by this disease . Then they started to examine the frequency of NKTCL in Japan , Korea -LRB- Seoul -RRB- , and China -LRB- Shanghai -RRB- during the period from 1987 to 1993 . The results are summarized in Table 3 -LSB- 61 -- 63 -RSB- , in which the frequency of each disease constituting LMG is shown as the frequency per 100,000 patients who visited the Ear -- Nose -- Throat -LRB- ENT -RRB- clinic in 37 university hospitals in Japan , Ryukyu University Hospital in Okinawa , Japan , Yonsei University Hospital in Seoul , and Shanghai Medical University Hospital . All of the histological sections were reviewed by one of the authors -LRB- KA -RRB- . Frequency of PR ranged from 8 to 40.8 . That in the Institute of Laryngology and Otology , London -LRB- 1966 -- 1987 -RRB- was four , showing two to ten times higher frequencies of the PR in the east Asian countries -LSB- 61 -RSB- . The disease is rare in the USA -LSB- 64 -RSB- and Europe -LSB- 65 -RSB- . The patients with NKTCL seem to be clustered also in Latin American countries and Indonesia -LSB- 66 , 67 -RSB- . Information from other parts of the world such as Africa , the Middle and Near East , and Rusia is helpful to elucidate the etiology of this disease . Table 3Frequency of lethal midline granuloma in Japan , Korea -LRB- Seoul -RRB- , and China -LRB- Shanghai -RRB- DiseaseNumber of patients -LRB- frequency per 100,000 ENT patients -RRB- Japan other than Okinawa -LRB- 1965 -- 1986 -RRB- Okinawa -LRB- 1973 -- 1991 -RRB- Seoul -LRB- 1979 -- 1989 -RRB- Shanghai -LRB- 1979 -- 1990 -RRB- Wegener 's granulomatosis64 -LRB- 4 -RRB- 1 -LRB- 3 -RRB- 0 -LRB- 0 -RRB- 1 -LRB- 4 -RRB- Polymorphic reticulosis114 -LRB- 8 -RRB- 9 -LRB- 27.4 -RRB- 56 -LRB- 40.8 -RRB- 73 -LRB- 9.8 -RRB- Malignant lymphoma82 -LRB- 6 -RRB- 11 -LRB- 33.5 -RRB- 15 -LRB- 10.9 -RRB- 54 -LRB- 7.2 -RRB- Others42 -LRB- 3 -RRB- 1 -LRB- 3 -RRB- 6 -LRB- 4.4 -RRB- 0 -LRB- 0 -RRB- Total302 -LRB- 21 -RRB- 22 -LRB- 69.9 -RRB- 77 -LRB- 56 -RRB- 128 -LRB- 17 -RRB- At the late 1990s , otorhinolaryngologists in both Korea and Japan had the impression that the frequency of PR appeared to be decreasing . Then the changes in frequency of PR with time among cases from Seoul and 59 university hospitals in Japan were examined -LSB- 68 -RSB- : the frequency rate of PR per 100,000 outpatients of ENT clinics in Seoul decreased from 40 to 20 between the periods of 1977 -- 1989 and 1990 -- 1996 . However , there were no significant changes in Japan during the period studies . Life-style and environmental factors Epidemiological studies have revealed that the NKTCL occurs much more frequently in Asian countries than in Western countries and it is closely associated with EBV infection . There are differences in frequencies of p53 and c-kit gene mutations among patients with NKTCL in Japan , China , and Korea . Recently the first case of familial NKTCL affecting a father and one of his six children was reported -LSB- 69 -RSB- . They used large amounts of pesticide in a green house . An increase in the risk of developing NHL among individuals exposed to pesticides was reported -LSB- 70 , 71 -RSB- . In addition , a correlation of exposure to certain pesticides and organochlorines with increased titers of antibodies to EBV was reported -LSB- 72 -RSB- . All these findings might suggest a causative role for some genetical , environmental and life style factors in the development of NKTCL . Therefore , the epidemiological study to elucidate whether socioenvironmental ambient factors contribute to the development of NKTCL was conducted as a collaborative study of Japan , Korea and China -LRB- Table 4 -RRB- -LSB- 73 -RSB- . The odd ratio -LRB- OR -RRB- of NKTCL was 4.15 -LRB- 95 % confidence interval -LRB- CI -RRB- , 1.74 -- 9.37 -RRB- for farmers , 2.81 -LRB- CI 1.49 -- 5.29 -RRB- for producers of crops , and 4.01 -LRB- CI 1.99 -- 8.09 -RRB- for pesticide users . The ORs for crop producers , who minimized their exposure to pesticides by using gloves and glasses , and sprinkling downwind at the time of pesticide use , were 3.30 -LRB- CI 1.28 -- 8.54 -RRB- , 1.18 -LRB- CI 0.11 -- 12.13 -RRB- , and 2.20 -LRB- CI 0.88 -- 5.53 -RRB- , respectively , which were lower than those for producers who did not take these precautions . Exposures to pesticides and chemical solvents could be causative factors for NKTCL . Previous studies showed the increased risk of NHL in individuals using pesticides , especially phenoxyacetic acid-type herbicides -LSB- 74 -RSB- . Association of pesticides with risk of developing t -LRB- 14 ; 18 -RRB- positive-NHL , but not t -LRB- 14 ; 18 -RRB- negative-NHL , was reported -LSB- 75 -RSB- . Table 4Risk of nasal NK/T-cell lymphoma in relation to cultivation of crops and pesticide useOdds ration -LRB- OR -RRB- a Number of cases N = 88Number of controls N = 30595 % CILowerUpperCultivation of crops At present2 .8127361.495.29 More than 5 years5 .0824192.4710.43 Pesticides Users4 .0123231.998.09 Type of pesticide Herbicide3 .1713161.367.38 Insecticide3 .4520211.677.13 Fungicide6 .051061.9818.46 Precautions Gloves used3 .3010111.288.54 Gloves not used 4.7613121.9311.72 Mask used5 .4414102.2013.47 Mask not used 2.829131.087.37 Glasses used1 .18130.1112.13 Glasses not used4 .5222202.179.42 Sprinkling downward attended2 .209160.885.53 Sprinkling downward not attended8 .451473.0123.70 CI confidence intervalaAdjusted for age -LRB- < 40 , 40 -- 59 , > 60 -RRB- , sex -LRB- male/female -RRB- and country -LRB- Japan , Korea and China -RRB- Conclusions Clinical course of patients with NKTCL is usually highly aggressive . Therefore clarification of risk factors for disease development is especially important to establish a strategy for disease prevention . Because EBV infection and pesticides could be risk factors for NKTCL , investigation on effects of pesticides for EBV activation is needed . Employment of the similar kind of the epidemiological study is desirable in other areas than East Asia . Patients with NKTCL cluster in Asia and Latin American countries , therefore some genetical factors might be involved in the disease development . Further studies including HLA antigen typing of patients is important to further clarify the mechanism for disease development .

O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

nasal lymphoma
nk/t-cell type
epstein–barr virus
c-kit gene