Journal List Indian J Plast Surg v42Suppl 2009 Oct PMC2825080 Indian J Plast Surg 2009 Oct 42Suppl S51S55 doi 1041030970035857187 PMCID PMC2825080 Syndromes and anomalies associated with cleft R Venkatesh Author information Copyright and License information This article has been cited by other articles in PMC Go to Abstract Orofacial clefts are one of the commonest birth defects and may be associated with other congenital anomalies The majority of these orofacial clefts are nonsyndromic A significant percentage of these clefts both syndromic and nonsyndromic may have associated anomalies Apart from reviewing other studies this article also analyses a study of associated anomalies from a tertiary cleft centre in India Keywords Adult patients Cleft lip Cleft palate Premaxilla Go to INTRODUCTION Every congenital structural defect in the body represents an inborn error in morphogenesis and may affect one or more systems Various authors have reported incidence of associated anomalies varying from as low as 43 1 to as high as 634 2 Organogenesis takes place on Days 2528 of intrauterine life Any insult like environmental developmental or nutritional to the embryo during this period will lead to malformations Associated anomalies are classified according to the organs affected In general most congenital anomalies can be divided into three types a Disruptions A rare anomaly related to breakdown of the original normal foetal developmental process eg craniofacial cleft resulting from amniotic bands b Deformations These occur secondary to mechanical forces leading to anomalies of a lesser degree when compared to disruption eg club foot cleft palate Pierre Robin sequence etc c Malformations A morphologic defect in an organ from an intrinsically abnormal developmental process eg polydactyly congenital heart anomalies cleft lip etc However with the present advancement in embryology and genetics and its correlations the associated anomalies need to be differentiated from syndromes from sequences and associations in patients with multiple congenital anomalies They are generally described in four categories Go to MONOGENIC SYNDROME When the anomalies are aetiologically related and due to a single gene the constellation of associated anomalies constitutes a monogenic syndrome A review by Gorlin described 72 monogenic syndromes involving Oral clefts OCs A followup report by Cohen 3 identified 154 monogenic syndromes and more recently 487 were identified in the 2001 version of the London Dysmorphology database Winter and Baraitser 2001 4 Monogenic syndromes include Van der Woude with most of these cases linked to Chromosome 1q32q41 and Treacher Collins an autosomal dominant syndrome Go to CHROMOSOMAL SYNDROME These syndromes involve a clinically significant structural andor numerical chromosomal abnormality The deletion of Chromosome 22q112 for example causes the Velocardiofacial syndrome Shprintzen syndromeCleft palate cardiac anomalies typical facies and learning disabilities Trisomies 13 and 18 and the 4p are other chromosomal abnormalities leading to different syndromes often found with oral clefts 5 Sequence When the associated anomalies are due to a single known or presumed structural defect they are termed sequence The most common sequence observed with oral clefts is the Pierre Robin sequence which is characterized by mandibular deficiency cleft palate and upper airway obstruction It was named Pierre Robin syndrome anomalad or complex but since it is regarded as a series of events during embryology like micrognathic jaw leading to cleft palate it is now known as a sequence 6 Association The nonrandom occurrence of several morphologic defects not identified as a syndrome or a sequence is an association Oral clefts are frequently associated with congenital heart defects The cause of these associations is unknown This category is also called multiple congenital anomaly 7 However as the genes that cause oral clefts are identified a number of sequences and associations will be reclassified as monogenic syndromes Clinical evaluation The approach in dealing with any given anomaly including clefts is to study the associated defects Due to variation in the timing of the development of abnormalities followup until the child is four or five years of age is essential The general guidelines for the evaluation of individuals with Cleft lip and palate and Cleft palate CLP and CP in order to identify syndromes are Thorough clinical examination preferably by geneticist or dysmorphologist Comprehensive medical history Description of the cleft antenatal history birth history developmental history and family history Physical examination measurement of weight length or height and occipitofrontal circumference identification of anomalies of eyes ears heart extremities and also to look for associated preauricular tags lip pits epicanthal folds Documentation by photographs of all affected individuals and firstdegree relatives Necessary laboratory and radiological evaluations Go to LITERATURE REVIEW Prevalence of associated anomalies with orofacial clefts can differ among different populations At birth black population has lower prevalence of oral clefts compared to whites Sullivan 8 found that oral clefts in the black population are more commonly associated with clubfoot and polydactyly compared to other ethnic population The explanation given is that polydactyly and clubfoot are more prevalent in blacks than in whites 9 Populationbased studies will be more appropriate In addition one should also consider spontaneous abortions elective terminations stillborn foetuses and babies that died shortly after birth to get the true numbers of associated anomalies It is also essential that every child should be thoroughly examined immediately after birth for the associated anomalies because children with severe malformation may not survive long Jensen 10 recognized that and because they did not study stillbirths and early deaths their figure of 45 probably considerably underestimates the true frequency We have mentioned here some important studies from different countries Sweden Populationbased study showed that 1 of patients with oral cleft had associated malformations that either required followup or treatment Associated malformations were more frequent in infants who had both cleft lip and palate 28 than in infants with isolated cleft palate 22 or infants with isolated cleft lip 8 Malformations of the limbs or vertebral column were the most common anomalies and accounted for 33 of all associated defects 24 of associated malformations were of the cardiovascular system and congenital heart disease was the most common isolated associated malformation 15 of all associated malformations were multiple and they were frequently 11 France This study was based on 238942 consecutive births of known outcome registered by the registry of congenital anomalies 367 are reported as having associated malformations These were most frequent in infants with cleft palate only 467 as against infants with cleft lip and palate 368 or infants with cleft lip only 136 Malformations in the central nervous system and in the skeletal system were the anomalies most commonly associated Next in frequency were malformations in the urogenital and cardiovascular systems Although prenatal ultrasonic tests were carried out a success rate of only 316 is reported in diagnosis 12 China In multiple institutionalbased studies from China 7812 patients having cleft lip and or palate were studied for associated malformations Overall 289 of orofacial patients had associated anomalies The frequency of associated malformations in CLP 335 was higher than CL 224 and CP 222 13 Iran 1669 consecutive cases of cleft lip and or palate were analyzed in a referral centre Overall 773 of the cases had associated anomalies of which 45 of CLP children had associated anomalies compared to 31in cases with CP The majority of the associated anomalies were skeletal 32 and in the head and neck region 18 14 Tertiary Care centre in India 2600 clefts patients were analyzed in a study from the cleft and craniofacial centre of Sri Ramachandra University Of the 2600 patients 198 had associated anomalies Associated anomalies were more frequent in patients with cleft lip and palate 32 than in patients with cleft lip alone 11 or patients with cleft palate alone 22 The organs most commonly involved with associated anomalies in the order of decreasing incidence are Eye 49 Ear 34 Heart 33 Upper Limb 22 Lower Limb 17 Genitals 22 Mandible 17 Mental retardation 12 Craniofacial clefts 10 Skull 10 Tongue 9 Growth Retardation 2 Skin and A significant percentage of patients 36 72 198 with associated anomalies were syndromic The common syndromes were Van der Woude syndrome Median facial dysplasia syndrome and Pierre Robin Sequence 15 Go to COMMON SYNDROMES ASSOCIATED WITH OROFACIAL CLEFT OCF Van der Woude Syndrome Figure 1 Figure 1 Van der Woude syndrome with lower lip pits It is one of the commonest syndromes associated with oral cleft It is transmitted as an autosomal dominant and lower lip pits are the hallmark These pits are located bilaterally in the lower lip at the junction of dry and wet vermilion and they are either oval or transverse in shape Pits traverse the underlying orbicularis muscle and end in a blind pouch on the buccal side and communicate with minor salivary glands The associated features are hypodontia missing maxillary or mandibular second premolar teeth absent maxillary lateral incisor and ankyloglosia Other extraoral manifestations though rare include accessory nipples congenital 16 Pierre Robin sequence Figure 2 Figure 2 Pierre Robin sequence In 1926 Pierre Robin published a case with a complete syndrome with triad of glossoptosis micrognathia and airway obstruction Although cleft is not included in the triad it is frequently associated and may aggravate the obstruction due to tongue fall Although many theories have been proposed for the sequence the mechanical theory is the most accepted The initial event is mandibular hypoplasia between the seventh and eleventh weeks of gestation which keeps the tongue high in the oral cavity preventing closure of palatal shelves resulting in formation of classic inverted Ushaped cleft palate Oligohydramnios also plays a role because lack 17 18 Velocardiofacial syndrome Figure 3 Figure 3 Velocardiofacial syndrome with typical facies Velocardiofacial syndrome VCFS is an autosomal dominant condition and is associated with Chromosome 22q abnormality as a result of a submicroscopic deletion on the long arm of Chromosome 22 in theq11region deletion22q11 It was described by Dr Robert J Shprintzen It occurs in approximately one in 2000 live births 19 and is the most common submicroscopic deletion syndrome There are more than 100 physical phenotypic features reported as VCFS affects every major system in the body The most common features are cleft palate cardiac anomaly characteristic facial appearance vertical maxillary excess malar flattening relative mandibular retrusion narrow palpebral fissure and small ears minor learning problems speech and feeding problems There is a close association between VCFS and DiGeorge syndrome which includes small or absent thymus tonsils adenoids and hypocalcaemia These children may have medial displacement of the carotid artery over the cervical vertebrae and this should be borne in mind 19 Median facial dysplasia Figure 4 Figure 4 Median facial dysplasia Median facial dysplasia is a unique distinct definable group of patients characterized by midline facial deficiencies in the presence of a unilateral or bilateral cleft lip with or without cleft palate 20 The midline hypoplasia may extend into the midline structure of the brain like corpus callosum If head circumference is 90 of normal these patients may have associated anomalies of the brain especially frontal corpus callosum It is obvious that they will have compromised development of midface resulting in very early dish face Class III occlusion and severe maxillary hypoplasia Early recognition of these subgroups of patients helps to plan the course of treatment Go to CONCLUSION Recognition of the associated syndromes and anomalies with the oral cleft is essential to assess the problem and risk faced by the child and for counselling the parents Proper knowledge and details of anomalies associated with OFC will help to provide necessary treatment and improve survival of these children Proper epidemiology dysmorphology assessment and genetic study may lead researchers to the identification of the causative agent Go to Footnotes Source of Support Nil Conflict of Interest None declared Go to REFERENCES 1 Leth Jensen B Kreiborg S Dahl E FoghAndersen P Cleft lip and palate in Denmark 19761981 epidemiology variability and early somatic development Cleft Palate 1988 25 25869 PubMed 2 Shprintzen RJ SigelSadewitz VL Amato J Goldberg RB Anomalies associated with clefts lip cleft palate or both Am J Med Gent 1985 20 58595 PubMed 3 Cohen MM Jr Syndromes with Cleft lip and cleft palate Cleft Palate J 1978 15 30628 PubMed 4 Winter RM Baraister M London dysmorpholgy Database London neurogenetics database and Dysmorphology photo library on CDROM version 3 Oxford Oxford University press 2001 PubMed 5 Berge SJ Plath H Van de Vondel PT Appel T Niederhagen B Von Lindern JJ et al Fetal cleft lip and palate sonographic diagnosis chromosomal abnormalities associated anomalies and postnatal outcome in 70 fetuses Ultrasound Obstet Gynecol 2001 18 42231 PubMed 6 Latham RA The pathogenesis of cleft palate associated with the Pierre Robin syndrome An analysis of a seventeenweek human foetus Br J Plast Surg 1966 19 20514 PubMed 7 Tolorova MM Cervenka J Classification and birth prevalence of orofacial clefts AM J med Genet 1998 75 12637 PubMed 8 Sullivan WG Cleft lip with or with out cleft palate in blacks An analysis of 81 patients Plast Reconstr Surg 1989 84 4068 PubMed 9 Kromberg JG Jenkins T Common birth defects in South African Blacks S Afr Med J 1982 62 599602 PubMed 10 Jensen BL Kreiborg S Dahl E FoghAndersen P Cleft lip and palate in Denmark 19761981 epidemiology variability and early somatic development Cleft Palate J 1988 25 25869 PubMed 11 Milerad J Larson O PhD D Hagberg C Ideberg M associated malformations in infants with cleft lip and palate a prospective populationbased study Paediatrics 1997 100 1806 PubMed 12 Stoll C Alembik Y Dott B Roth MP Associated malformations in cases with oral clefts Cleft Palate Craniofac J 2000 37 417 PubMed 13 Zhou QJ Shi B Shi ZD Zheng Q Wang Y Survey of the patients with cleft lip or palate in China who were funded for the surgery by the Smile Train program from 20002002 Chin Med J Engl 2006 119 1695700 PubMed 14 Rajabian MH Sherkat M An Epidemiologic study of Oral Clefts in Iran an analysis of 1669 cases Cleft Palate Craniofac J 2000 37 1916 PubMed 15 Cohen MM Jr Cleft lip and palate From origin to treatment New York Oxford University Press 2002 Syndromes with orofacial clefting pp 5365 16 Hercilo M Marcelo R Mario SO Roseli TM Clinical and Genetic Features of Van der Woude Syndromes in Two large families in Brazil Cleft Palate Craniofac J 2007 44 23943 PubMed 17 Pashayan MM Lewis MB Clinical experience with the Robin sequence Cleft Palate J 1984 21 270276 PubMed 18 Robert J ShprintzenThe Implications of the diagnosis of Robin sequence Cleft Palate Craniofac J 1992 29 2059 PubMed 19 Thomas JA Graham JM Jr Chromosomes 22q11 deletion syndrome an update for the primary peditrician Clin Pediatr Phila 1997 36 25366 PubMed 20 Noordhoff MS Huang CS Lo LJ Median facial dysplasia in unilateral and bilateral cleft lip and palate a subgroup of median cerebrofacial malformations Plast Reconstr Surg 1993 91 9961005 PubMed Articles from Indian Journal of Plastic Surgery Official Publication of the Association of Plastic Surgeons of India are provided here courtesy of Medknow Publications

O O O O O O O O O O O O O O O O O O O O O O B O B 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 B 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 B O O O B O O O O O O B 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 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 B 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 B 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 B O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O B 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 B 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 B 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 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 B 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 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 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 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 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 B O O O O B O O O O O O O O B 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 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 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 B 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 B 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 B O O O O O O B 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 B O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O B 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 B 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 B 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 B 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 B O B O O O O O O B O O O O O O O O B O O O O O O B 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 B O O O O B O O O O O O O O O O O O O O O O O B 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 B 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 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 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 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 B 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 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 B O B 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 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 B 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 B O O O O B O O O O O O O O O O O O O O O B O B O O B 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 B 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 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 B 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 B 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 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 B 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 B 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 B 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 B 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 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 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


Paediatr

Child

Health

JulAug

Paediatr

Child

Health

JulAug

PMCID

Language

English

French

Trans

fats

What

physicians

should

know

V

Marchand

Canadian

Paediatric

Society

Nutrition

and

Gastroenterology

Committee

Author

information

Copyright

and

License

information

Cet

article

est

disponible

en

français

Voyez

Les

gras

trans

Ce

que

les

médecins

devraient

savoir

Abstract

Hydrogenation

of

fat

products

is

used

in

the

food

industry

to

extend

their

shelf

life

Trans

fats

are

the

result

of

partial

hydrogenation

of

unsaturated

fat

Trans

fats

increase

lowdensity

lipoprotein

cholesterol

and

decrease

highdensity

lipoprotein

cholesterol

thus

increasing

the

risk

of

cardiovascular

disease

Canadians

have

one

of

the

highest

dietary

intake

of

trans

fat

in

the

world

Health

Canada

has

made

recommendations

to

decrease

the

trans

fat

intake

of

Canadians

Physicians

should

be

able

to

provide

their

patients

with

information

on

trans

fats

and

their

deleterious

effects

on

health

Keywords

Cardiovascular

disease

Cholesterol

Hydrogenation

Saturated

fat

Trans

fat

Unsaturated

fat

Français

en

page

Parents

want

what

is

best

for

their

children

They

want

to

be

able

to

make

the

right

food

choices

not

only

to

ensure

that

their

children

grow

well

but

also

to

prevent

future

illnesses

such

as

coronary

artery

disease

Recently

the

issue

of

trans

fats

has

received

a

lot

of

attention

There

is

a

large

body

of

literature

available

associating

the

consumption

of

trans

fats

with

deleterious

effects

on

health

The

physician

is

in

a

position

to

give

advice

to

parents

on

the

implication

of

trans

fats

on

childrens

health

The

present

practice

point

provides

physicians

with

information

on

trans

fats

Fats

come

in

different

forms

Figure

A

triglyceride

molecule

consists

of

a

glycerol

backbone

to

which

three

fatty

acids

are

attached

These

fatty

acids

are

made

up

of

chains

of

different

numbers

of

carbon

atoms

attached

together

by

simple

or

double

bonds

Figure

Chemical

composition

of

the

different

types

of

fat

A

Saturated

and

unsaturated

fatty

acid

B

Polyunsaturated

fatty

acid

Reproduced

from

references

and

Saturated

fats

are

molecules

of

fat

in

which

the

double

bonds

between

carbon

atoms

have

been

replaced

by

hydrogen

atoms

In

other

words

each

carbon

atom

has

four

other

atoms

attached

to

it

Unsaturated

fats

are

molecules

of

fat

containing

one

or

more

double

bonds

between

two

atoms

of

carbon

at

specific

positions

in

the

chain

Unsaturated

fats

come

in

a

cis

form

and

a

trans

form

according

to

the

arrangement

of

the

carbon

chains

across

one

or

more

double

bonds

Trans

fats

are

unsaturated

fats

with

trans

double

bonds

instead

of

cis

bonds

The

type

of

bond

affects

the

shape

of

the

fatty

acid

chain

A

trans

bond

creates

a

straight

chain

whereas

a

cis

bond

results

in

a

chain

that

is

bent

Trans

fats

may

be

monounsaturated

or

polyunsaturated

The

production

of

trans

fats

is

a

result

of

partial

hydrogenation

The

process

of

hydrogenation

consists

of

chemically

adding

atoms

of

hydrogen

to

cis

unsaturated

fat

eliminating

the

double

bonds

between

carbon

atoms

and

making

them

saturated

Hydrogenation

is

used

by

the

food

industry

to

extend

shelf

life

by

making

fats

less

prone

to

rancidity

a

phenomenon

by

which

free

radicals

attack

the

double

bond

between

carbon

atoms

It

also

increases

the

fats

melting

point

making

the

product

more

suitable

for

frying

However

in

the

process

of

hydrogenation

some

of

the

cis

bonds

in

fatty

acids

are

transformed

to

trans

Unfortunately

trans

fats

have

deleterious

effects

on

human

health

They

not

only

increase

lowdensity

lipoprotein

cholesterol

but

also

decrease

highdensity

lipoprotein

cholesterol

thus

increasing

the

risk

of

cardiovascular

disease

Trans

fats

provide

no

benefits

to

human

health

and

are

not

essential

Therefore

there

is

no

such

thing

as

a

safe

level

of

dietary

trans

fat

Trans

fats

naturally

occur

in

small

amounts

in

the

fat

of

certain

foods

such

as

dairy

and

meat

They

are

also

present

in

breastmilk

in

concentrations

directly

dependent

on

the

mothers

dietary

intake

of

trans

fats

Trans

fats

originating

from

processed

foods

are

by

far

the

largest

dietary

source

of

trans

fats

consumed

According

to

a

survey

performed

in

Canadians

had

one

of

the

highest

dietary

intakes

of

trans

fats

in

the

world

at

gday

This

was

primarily

due

to

the

widespread

use

of

hydrogenated

oils

in

prepackaged

foods

and

for

cooking

in

restaurants

particularly

fast

food

restaurants

In

Health

Canada

introduced

mandatory

nutrition

labelling

of

most

prepackaged

foods

as

well

as

new

and

revised

requirements

for

nutrient

content

claims

The

Nutrition

Facts

table

requires

the

declaration

of

the

content

of

energy

and

nutrients

including

trans

fats

Figure

It

is

important

to

remember

that

to

be

labelled

trans

fat

free

a

food

item

must

contain

less

than

g

of

trans

fat

per

reference

amount

and

per

serving

and

must

be

low

in

saturated

fat

less

than

g

of

saturated

fat

and

trans

fat

combined

per

reference

amount

and

per

serving

Nutrition

labelling

together

with

increased

consumer

awareness

of

trans

fat

have

acted

as

a

driving

force

resulting

in

the

reduction

or

elimination

of

trans

fats

in

many

foods

Since

there

have

also

been

voluntary

guidelines

for

providing

nutrition

information

on

food

sold

in

restaurants

many

Figure

Nutrition

Facts

table

format

Reproduced

from

reference

As

a

result

of

these

measures

intakes

of

trans

fats

decreased

to

gday

in

However

this

level

of

intake

is

still

very

high

and

largely

above

the

WHOs

recommended

intake

of

less

than

of

total

daily

caloric

intake

Further

action

is

still

required

The

Trans

Fat

Task

Force

report

released

in

recommended

that

the

total

amount

of

trans

fats

in

food

should

be

limited

through

regulation

and

that

information

on

healthier

alternatives

should

be

provided

to

the

food

industry

The

proposed

limits

would

decrease

trans

fat

intake

by

approximately

which

would

significantly

improve

the

cardiovascular

health

of

Canadians

In

the

Minister

of

Health

announced

that

Health

Canada

would

adopt

the

Trans

Fat

Task

Forces

recommended

limits

for

trans

fats

in

foods

Those

recommendations

were

to

limit

the

trans

fat

content

of

vegetable

oils

and

soft

spreadable

margarines

to

of

the

total

fat

content

and

to

limit

the

trans

fat

content

for

all

other

foods

to

of

the

total

fat

content

including

ingredients

sold

to

restaurants

Health

Canada

also

announced

that

it

would

develop

regulations

to

enforce

the

limits

if

significant

progress

had

not

been

made

after

a

twoyear

voluntary

reduction

period

Health

Canada

as

part

of

the

Trans

Fat

Monitoring

Program

has

been

analyzing

selected

foods

that

were

significant

sources

of

trans

fats

Results

of

the

analysis

of

prepackaged

foods

and

foods

from

restaurant

and

fast

food

chains

were

released

in

December

in

July

and

in

February

Results

from

all

three

sets

of

data

demonstrate

progress

in

reduction

of

trans

fats

in

different

food

categories

In

many

cases

the

reduction

was

achieved

by

finding

healthier

alternatives

and

not

by

increasing

the

saturated

fat

content

Canadians

are

more

aware

of

the

deleterious

effects

of

trans

fats

on

their

health

With

the

information

that

is

now

available

to

them

they

can

make

better

choices

for

themselves

and

their

children

Physicians

should

be

aware

of

the

negative

impact

that

trans

fats

can

have

on

their

patients

future

health

and

should

be

able

to

provide

parents

with

adequate

information

We

suggest

that

physicians

provide

information

on

trans

fats

when

giving

nutritional

guidance

to

parents

and

patients

Go

to

Acknowledgments

The

author

thanks

Sara

Krenosky

Health

Canada

for

her

assistance

with

the

present

practice

point

Go

to

Footnotes

NUTRITION

AND

GASTROENTEROLOGY

COMMITTEE

Members

Drs

Jeff

Critch

Janeway

Childrens

Health

and

Rehabilitation

Centre

St

Johns

Newfoundland

and

Labrador

Manjula

Gowrishankar

Walter

C

MacKenzie

Health

Sciences

Centre

Edmonton

Alberta

Valérie

Marchand

SainteJustine

University

Hospital

Center

Montreal

Quebec

Chair

Sharon

L

Unger

Mount

Sinai

Hospital

Toronto

Ontario

Robin

C

Williams

Niagara

Region

Public

Health

Unit

Thorold

Ontario

Board

Representative

Liaisons

Ms

Genevieve

Courant

VON

Community

Wellness

Clinic

Sudbury

Ontario

Breastfeeding

Committee

for

Canada

Dr

George

Davidson

BC

Childrens

Hospital

Vancouver

British

Columbia

Human

Milk

Banking

Association

Ms

Tanis

Fenton

Foothills

Hospital

Calgary

Alberta

Dietitians

of

Canada

Dr

Frank

Greer

Madison

Wisconsin

USA

American

Academy

of

Pediatrics

Committee

on

Nutrition

Ms

Jennifer

McCrea

Ottawa

Ontario

Office

of

Nutrition

Policy

and

Promotion

Health

Canada

Ms

Christina

Zehaluk

Ottawa

Ontario

Bureau

of

Nutritional

Sciences

Health

Canada

Consultant

Dr

Jae

Hong

Kim

UCSD

Medical

Center

San

Diego

California

USA

Principal

author

Dr

Valérie

Marchand

SainteJustine

University

Hospital

Center

Montreal

Quebec

The

recommendations

in

this

statement

do

not

indicate

an

exclusive

course

of

treatment

or

procedure

to

be

followed

Variations

taking

into

account

individual

circumstances

may

be

appropriate

All

Canadian

Paediatric

Society

position

statements

are

reviewed

revised

or

retired

as

needed

on

a

regular

basis

Please

consult

the

Position

Statements

section

of

the

CPS

website

wwwcpscaenglishpublicationsstatementsindexhtm

for

the

most

current

version

Articles

from

Paediatrics

Child

Health

are

provided

here

courtesy

of

Pulsus

Group

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paediatr child health
trans fats
hydrogenation


Journal List Haematologica v966 2011 Jun PMC3105636 Haematologica 2011 Jun 966 789792 doi 103324haematol2011044628 PMCID PMC3105636 Ring sideroblasts and sideroblastic anemias Mario Cazzola 1 and Rosangela Invernizzi 2 Author information Copyright and License information This article has been cited by other articles in PMC The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia of varying severity and the presence of ring sideroblasts in the bone marrow 1 Ring sideroblasts Ring sideroblasts are erythroblasts with ironloaded mitochondria visualized by Prussian blue staining Perls reaction as a perinuclear ring of blue granules Figures 1D and and2C 2C The International Working Group on Morphology of Myelodysplastic Syndrome IWGMMDS recommended that ring sideroblasts be defined as erythroblasts in which there are a minimum of five siderotic granules covering at least one third of the circumference of the nucleus 2 Ring sideroblasts are found exclusively in pathological conditions and should not be confused with ferritin sideroblasts which are present in normal bone marrow These latter are normal erythroblasts that after Prussian blue staining show a few blue granules scattered in the cytoplasm representing endosomes filled with excess iron not utilized for heme synthesis siderosomes While the iron of ferritin sideroblasts is stored in cytosolic ferritin whose subunits are encoded by the FTH1 and FTL genes the iron of ring sideroblasts is stored in mitochondrial ferritin encoded by the FTMT gene 3 Indeed mitochondrial ferritin is specifically detected in ring sideroblasts as illustrated in Figure 2D Figure 1 Representative peripheral blood and bone marrow smears from a patient with Xlinked sideroblastic anemia A Peripheral blood smear showing many hypochromic and microcytic cells MayGrünwaldGiemsa MGG x1000 B Bone marrow smear showing Figure 2 Representative peripheral blood and bone marrow smears from a patient with refractory anemia with ring sideroblasts A Peripheral blood smear showing dimorphic red cells with a population of macrocytes and a population of hypochromic microcytes MGG Go to Classification of sideroblastic anemias The sideroblastic anemias include both hereditary and acquired conditions and the main disorders are reported in Table 1 Representative peripheral blood and bone marrow smears from a patient with Xlinked sideroblastic anemia XLSA and a patient with refractory anemia with ring sideroblasts RARS are shown in Figures 1 and and2 2 respectively Table 1 Classification of congenital and acquired sideroblastic anemias Go to Xlinked versus autosomal recessive congenital sideroblastic anemias XLSA is caused by germline mutations in the erythroidspecific ALA synthase gene ALAS2 Males with XLSA may present in the first two decades of life with symptoms of anemia or later with manifestations of anemia andor those of parenchymal iron overload 4 However the phenotypic expression of XLSA is highly variable 5 and occasional patients both males and females may present late in life 6 7 Distinctive laboratory features are microcytic anemia with hypochromic red cells increased red cell distribution width and evidence of parenchymal iron overload for a conclusive diagnosis of XLSA however identification of the ALAS2 mutation is required The management of XLSA involves not only treatment of anemia but also prevention and treatment of iron overload family studies to identify additional atrisk individuals and genetic counseling 1 Most patients with XLSA are responsive to some extent to pyridoxine and subjects with iron overload can safely undergo mild phlebotomy programs under pyridoxine supplementation Patients affected with other inherited forms of sideroblastic anemia are not responsive to pyridoxine and the molecular basis of these autosomal recessive disorders has been clarified only recently Camaschella et al 8 studied a middleaged anemic patient with ring sideroblasts and iron overload whose anemia was partially reversed by iron chelation therapy The phenotype of this patient resembled that of the shiraz zebrafish a mutant resulting from a large deletion encompassing the GLRX5 gene 9 In fact sequencing of GLRX5 showed that the patient had a homozygous mutation of this gene GLRX5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts 10 Two years ago Guernsey et al 11 studied three Canadian families each with one child affected by congenital sideroblastic anemia The data available were inconsistent with an Xlinked recessive inheritance while the families derived from a local subpopulation isolate consistent with a possible genetic founder effect A single nucleotide polymorphismbased genomewide scan performed in individuals belonging to these families led to the identification of SLC25A38 as the mutant gene responsible for this type of autosomal recessive pyridoxinerefractory sideroblastic anemia 11 Studies on additional subjects with familial or sporadic congenital sideroblastic anemia without ALAS2 mutations showed multiple additional biallelic SLC25A38 mutations SLC25A38 encodes the erythroid specific mitochondrial carrier protein which is important for the biosynthesis of heme in eukaryotes Following the identification of mutant SLC25A38 as a novel cause of inherited sideroblastic anemia Bergmann et al 12 systematically analyzed a cohort of 60 previously unreported patients with congenital sideroblastic anemia looking for ALAS2 SLC25A38 PUS1 GLRX5 and ABCB7 mutations Twelve probands had biallelic mutations in SLC25A38 while 7 had ALAS2 mutations and one had a novel homozygous null PUS1 mutation In this issue of the journal Kannengiesser et al 13 report on a study of 24 patients with congenital sideroblastic anemia who did not have ALAS2 mutations Eleven patients of several different ancestral origins carried SLC25A38 mutations 9 patients were homozygous and 2 were compound heterozygotes All patients required blood transfusions that inevitably became regular within the first few years of life Two patients underwent allogeneic stem cell transplantation with complete correction of anemia Since the clinical course of congenital sideroblastic anemia associated with SLC25A38 mutations is very similar to that of thalassemia major conservative therapy includes regular red cell transfusion and iron chelation However as in thalassemia major allogeneic stem cell transplantation represents the only curative therapy at present and should therefore be considered for young patients with this congenital sideroblastic anemia Go to Refractory anemia with ring sideroblasts What are the implications of recent advances in our understanding of the molecular basis of congenital sideroblastic anemia for the acquired forms ie refractory anemia with ring sideroblasts RARS and its variant with marked thrombocytosis RARST RARS is a myelodysplastic syndrome characterized by isolated anemia erythroid dysplasia only less than 5 blasts and 15 or more ring sideroblasts in the bone marrow 14 The natural history of RARS is characterized by an initial phase of erythroid hyperplasia and ineffective erythropoiesis which is usually stable for many years but in a proportion of patients may be followed by a phase of marrow failure with or without the later emergence of leukemic blasts 15 16 Since the vast majority of patients with this syndrome have no cytogenetic abnormalities the clonal nature of RARS has been questioned However a few studies of Xchromosome inactivation patterns performed in female patients have suggested that RARS derives from the clonal proliferation of a multipotent hematopoietic stem cell with the potential for myeloid and lymphoid differentiation 17 Unfortunately none of the candidate genes ie genes mutated in the different types of congenital sideroblastic anemia has been found to be mutated in RARS Of note CD34 cells from patients with RARS have a particular gene expression profile characterized by upregulation of mitochondriarelated genes and in particular genes involved in heme synthesis eg ALAS2 18 and reduced expression of ABCB7 a gene encoding a protein involved in the transport of ironsulfur clusters from mitochondria to the cytoplasm 19 In addition RARS is characterized by overexpression of mitochondrial ferritin Figure 2D encoded by the FTMT gene 3 20 22 RARST is a myelodysplasticmyeloproliferative neoplasm characterized by anemia with ring sideroblasts and marked thrombocytosis 23 Our recent studies suggest that RARST is indeed a myeloid neoplasm with both myelodysplastic and myeloproliferative features at the molecular and clinical levels and that it may develop from RARS through the acquisition of somatic mutations of JAK2 MPL or other asyetunknown genes 24 Thus the available evidence suggests that the clonal hematopoiesis of RARS and RARST is associated with abnormal expression of several genes of heme synthesis and mitochondrial iron processing Identifying the somatic mutations that can be responsible for these abnormalities represents the current challenge in this field Go to Conclusions The two most common forms of congenital sideroblastic anemia ie the Xlinked form due to an ALAS2 mutation and the autosomal recessive form due to SLC25A38 mutations have similar hematologic pictures but completely different clinical courses Overall XLSA is a benign disorder that generally responds to pyridoxine with substantial amelioration of anemia prevention and treatment of iron overload is also important and can be generally achieved through phlebotomy By contrast the congenital autosomal recessive congenital sideroblastic anemia due to SLC25A38 mutations is a severe disease not responsive to pyridoxine and with a clinical course very similar to that of thalassemia major allogeneic stem cell transplantation should therefore be considered in young patients with this disease Go to Supplementary Material Disclosures Click here to view Go to Footnotes Go to References 1 Cazzola M Invernizzi R Sideroblastic anemias In Young NS Gerson SL High KA editors Clinical Hematology Philadelphia Mosby Elsevier 2005 pp 72132 2 Mufti GJ Bennett JM Goasguen J Bain BJ Baumann I Brunning R et al Diagnosis and classification of myelodysplastic syndrome International Working Group on Morphology of myelodysplastic syndrome IWGMMDS consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts Haematologica 2008 93 1117127 PubMed 3 Cazzola M Invernizzi R Bergamaschi G Levi S Corsi B Travaglino E et al Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia Blood 2003 101 519962000 PubMed 4 Cotter PD May A Li L AlSabah AI Fitzsimons EJ Cazzola M et al Four new mutations in the erythroidspecific 5aminolevulinate synthase ALAS2 gene causing Xlinked sideroblastic anemia increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis Blood 1999 93 5175769 PubMed 5 Cazzola M May A Bergamaschi G Cerani P Ferrillo S Bishop DF Absent phenotypic expression of Xlinked sideroblastic anemia in one of 2 brothers with a novel ALAS2 mutation Blood 2002 100 1242368 PubMed 6 Cotter PD May A Fitzsimons EJ Houston T Woodcock BE alSabah AI et al Lateonset Xlinked sideroblastic anemia Missense mutations in the erythroid deltaaminolevulinate synthase ALAS2 gene in two pyridoxineresponsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts J Clin Invest 1995 96 420906 PMC free article PubMed 7 Cazzola M May A Bergamaschi G Cerani P Rosti V Bishop DF Familialskewed Xchromosome inactivation as a predisposing factor for lateonset Xlinked sideroblastic anemia in carrier females Blood 2000 96 1343635 PubMed 8 Camaschella C Campanella A De Falco L Boschetto L Merlini R Silvestri L et al The human counterpart of zebrafish shiraz shows sideroblasticlike microcytic anemia and iron overload Blood 2007 110 413538 PubMed 9 Wingert RA Galloway JL Barut B Foott H Fraenkel P Axe JL et al Deficiency of glutaredoxin 5 reveals FeS clusters are required for vertebrate haem synthesis Nature 2005 436 705310359 PubMed 10 Ye H Jeong SY Ghosh MC Kovtunovych G Silvestri L Ortillo D et al Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts J Clin Invest 2010 120 5174961 PMC free article PubMed 11 Guernsey DL Jiang H Campagna DR Evans SC Ferguson M Kellogg MD et al Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia Nat Genet 2009 41 66513 PubMed 12 Bergmann AK Campagna DR McLoughlin EM Agarwal S Fleming MD Bottomley SS et al Systematic molecular genetic analysis of congenital sideroblastic anemia evidence for genetic heterogeneity and identification of novel mutations Pediatr Blood Cancer 2010 54 22738 PMC free article PubMed 13 Kannengiesser C Sanchez M Sweeney M Hetet G Kerr B Moran E et al Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia Haematologica 2011 96 680813 PMC free article PubMed 14 Brunning RD Orazi A Germing U Le Beau MM Porwit A Bauman I et al Myelodysplastic syndromesneoplasms overview In Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H et al editors WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Lyon IARC 2008 pp 8893 15 Cazzola M Barosi G Gobbi PG Invernizzi R Riccardi A Ascari E Natural history of idiopathic refractory sideroblastic anemia Blood 1988 71 230512 PubMed 16 Malcovati L Porta MG Pascutto C Invernizzi R Boni M Travaglino E et al Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria a basis for clinical decision making J Clin Oncol 2005 23 307594603 PubMed 17 Malcovati L Brisci A Gallì A Bruno F Travaglino E Pellagatti A et al Mutation analysis of TET2 reveals the clonal nature of refractory anemia with ring sideroblasts Blood 2010 116 21776a Abstract 1862 18 Pellagatti A Cazzola M Giagounidis AA Malcovati L Porta MG Killick S et al Gene expression profiles of CD34 cells in myelodysplastic syndromes involvement of interferonstimulated genes and correlation to FAB subtype and karyotype Blood 2006 108 133745 PubMed 19 Boultwood J Pellagatti A Nikpour M Pushkaran B Fidler C Cattan H et al The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts PLoS ONE 2008 3 4e1970 PMC free article PubMed 20 Tehranchi R Invernizzi R Grandien A Zhivotovsky B Fadeel B Forsblom AM et al Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in lowrisk myelodysplastic syndromes Blood 2005 106 124753 PubMed 21 Della Porta MG Malcovati L Invernizzi R Travaglino E Pascutto C Maffioli M et al Flow cytometry evaluation of erythroid dysplasia in patients with myelodysplastic syndrome Leukemia 2006 20 454955 PubMed 22 Nikpour M Pellagatti A Liu A Karimi M Malcovati L Gogvadze V et al Gene expression profiling of erythroblasts from refractory anaemia with ring sideroblasts RARS and effects of GCSF Br J Haematol 2010 149 684454 PubMed 23 Vardiman JW Bennett JM Bain BJ Baumann I Thiele J Orazi A Myelodysplasticmyeloproliferative neoplasms unclassifiable In Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H et al editors WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Lyon IARC 2008 pp 856 24 Malcovati L Della Porta MG Pietra D Boveri E Pellagatti A Galli A et al Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis Blood 2009 114 17353845 PubMed Articles from Haematologica are provided here courtesy of Ferrata Storti Foundation

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Ann

Med

Health

Sci

Res

JulDec

Ann

Med

Health

Sci

Res

JulDec

PMCID

Current

Concepts

in

the

Neurophysiologic

Basis

of

Sleep

a

Review

EB

Ezenwanne

Author

information

Article

notes

Copyright

and

License

information

Abstract

Background

Sleep

is

a

very

vital

physiological

mechanism

which

involves

complex

interactions

in

the

nervous

system

These

interactions

are

not

well

understood

and

have

been

a

subject

of

controversy

in

contemporary

medical

practice

Objectives

To

review

of

the

neurophysiological

factors

in

the

subject

of

sleep

and

recent

research

findings

that

forms

the

basis

for

the

current

knowledge

on

sleep

Methods

Information

sources

consulted

included

published

works

of

past

researchers

current

articles

on

sleep

in

conference

papers

recent

editions

of

textbooks

on

neuroscience

articles

in

seminar

papers

reports

extracted

from

newspaper

and

magazine

articles

on

sleep

reports

accessed

from

the

Internet

using

Google

Search

Engines

and

lecture

notes

Results

It

was

noted

that

emphasis

has

now

shifted

from

the

concept

that

sleep

was

predominantly

the

product

of

activities

in

the

neural

systems

in

phylogenetically

old

reticular

core

of

the

brain

through

withdrawal

of

sensory

input

to

emphasis

on

the

role

of

neurotransmitter

systems

especially

Ach

serotonin

and

GABA

This

review

also

noted

that

among

others

emphasis

is

further

shifting

to

the

PGO

waves

which

is

fast

gaining

prominence

as

the

mechanism

involved

in

the

production

of

REM

sleep

and

dreams

in

particular

Conclusion

It

became

obvious

from

this

review

that

full

knowledge

of

the

neurophysiological

processes

involved

in

sleep

production

appear

generally

to

still

be

more

of

speculative

and

are

yet

far

from

full

understanding

Keywords

Current

concepts

neurophysiological

basis

sleep

Go

to

Introduction

Essentially

sleep

is

a

behavioral

state

It

is

estimated

that

an

individual

spends

approximately

one

third

of

his

lifetime

in

sleep

We

have

knowledge

that

sleep

is

part

of

the

daily

routine

in

everyone

even

when

the

normal

sleep

and

wake

cycle

or

pattern

is

disrupted

by

outside

factors

Sleep

may

be

defined

as

a

state

of

natural

unconsciousness

from

which

an

individual

can

be

aroused

However

in

this

review

paper

on

the

subject

of

sleep

another

definition

regards

sleep

as

a

naturally

recurring

state

of

relatively

suspended

sensory

and

motor

activity

in

the

animal

characterized

by

total

or

partial

Sleep

is

observed

in

all

species

of

animals

including

reptiles

amphibians

fish

and

birds

In

humans

it

is

commonly

regarded

as

a

natural

state

of

bodily

rest

For

example

a

recent

report

observed

that

regular

sleep

is

essential

for

survival

In

one

earlier

report

it

was

similarly

noted

that

sleep

is

a

condition

specifically

required

by

the

body

as

part

of

its

homeostatic

regulatory

and

repair

mechanism

Researchers

have

put

in

much

effort

in

the

quest

for

a

better

understanding

of

the

neurophysiologic

mechanisms

of

sleep

Factors

in

the

mechanisms

of

the

transitions

between

sleep

stages

and

even

dreams

are

subjects

that

have

attracted

intense

research

over

the

years

A

number

of

earlier

workers

believe

that

sleep

is

purely

a

passive

state

in

which

the

brain

is

resting

With

advances

in

scientific

research

however

workers

have

come

to

learn

that

on

the

contrary

sleep

is

not

merely

a

passive

or

static

state

in

which

the

brain

is

resting

It

is

now

known

that

sleep

is

a

dynamic

and

complicated

condition

during

which

the

brain

is

quite

active

It

is

also

now

known

that

normal

sleep

is

made

up

of

complex

series

of

stages

that

repeat

itself

in

a

characteristic

pattern

and

this

aspect

has

helped

to

further

establish

the

Many

workers

have

speculated

on

the

adverse

effects

of

lack

of

sleep

on

the

brain

and

behavior

and

this

is

what

is

often

forgotten

as

society

and

employers

push

workers

to

perform

even

when

they

are

functioning

with

lack

of

sleep

A

recent

report

cited

a

number

of

the

detrimental

effects

of

lack

of

sleep

to

both

the

brain

and

immune

system

In

that

same

report

it

was

noted

that

after

periods

of

extended

reduced

sleep

neurons

begin

to

malfunction

as

sleep

is

needed

to

regenerate

certain

parts

of

the

body

especially

the

brain

Also

in

an

earlier

report

it

was

noted

that

brain

activity

is

visibly

altered

following

sleep

deprivation

in

that

certain

patterns

of

electrical

and

chemical

activity

that

occur

during

sleep

are

interrupted

impeding

the

brains

ability

to

function

normally

Thus

it

is

obvious

that

lack

of

sleep

affects

both

physical

and

mental

health

Lack

of

adequate

sleep

is

fast

becoming

one

of

the

commonest

problems

in

our

society

today

For

example

a

recent

study

carried

out

in

some

tertiary

institutions

in

Nigeria

revealed

that

sleep

deprivation

is

a

significant

pattern

among

medical

students

There

is

no

doubt

that

lack

of

adequate

sleep

can

account

for

poor

performance

at

work

or

study

there

are

obvious

life

threatening

problems

associated

with

human

errors

of

judgment

such

as

traffic

accidents

Sleep

deprivation

obviously

account

for

many

of

the

fatigue

related

decision

making

errors

that

have

been

responsible

for

several

deaths

One

obvious

consequence

of

lack

of

sleep

is

that

it

renders

the

body

and

mental

faculties

less

than

intact

and

functional

On

the

other

hand

it

has

been

noted

that

the

quality

of

sleep

is

as

important

as

its

duration

In

addition

sleep

is

undeniably

one

of

the

greatest

healing

therapies

with

many

benefits

the

effects

of

good

and

adequate

sleep

can

be

seen

in

improved

mental

clarity

boosted

overall

efficiency

at

work

training

and

academic

exercise

etc

Go

to

Methods

A

thorough

search

was

conducted

on

pub

med

and

Google

using

some

of

the

following

key

words

sleep

neurophysiology

of

sleep

current

concepts

in

sleep

physiology

sleep

and

the

hypothalamus

sleep

and

neurotransmitters

etc

Information

sources

consulted

included

published

works

of

past

researchers

current

articles

on

sleep

in

conference

papers

recent

editions

of

textbooks

on

neuroscience

articles

in

seminar

papers

reports

extracted

from

newspaper

and

magazine

articles

on

sleep

reports

accessed

from

the

Internet

using

Search

Engines

lecture

notes

etc

Go

to

Concepts

Originally

sleep

was

regarded

simply

as

the

product

of

activities

in

the

neural

systems

in

phylogenetically

old

reticular

core

of

the

brain

In

those

earlier

concepts

also

it

was

concluded

that

the

preoptic

and

posterior

hypothalamic

areas

are

deeply

involved

in

the

central

regulatory

mechanisms

of

sleep

In

fact

the

earlier

proposals

on

sleep

referred

to

the

posterior

hypothalamus

as

the

waking

area

in

the

brain

The

lateral

hypothalamus

and

the

mammillary

bodies

were

also

linked

with

sleep

regulatory

functions

In

the

wake

of

these

earlier

concepts

the

proposal

that

sleep

was

a

passive

state

initiated

mainly

through

withdrawal

of

Presently

withdrawal

of

sensory

awareness

is

similarly

believed

to

be

a

factor

in

sleep

but

an

active

initiation

mechanism

that

facilitates

brain

withdrawal

has

also

been

recognized

Thus

both

homeostatic

factors

factor

S

and

circadian

factors

factor

C

are

now

believed

to

interact

to

determine

the

timing

and

quality

of

sleep

In

the

sleep

model

as

proposed

by

another

group

of

workers

the

switch

factor

for

sleep

is

considered

to

be

located

in

ventrolateral

preoptic

nucleus

VLPO

of

anterior

hypothalamus

This

area

is

said

to

become

active

during

sleep

and

uses

the

inhibitory

neurotransmitter

Gamma

Amino

Butyric

Acid

GABA

and

galanin

to

initiate

sleep

by

inhibiting

the

arousal

egions

of

the

brain

The

VLPO

is

also

known

to

innervate

and

can

inhibit

the

awakepromoting

regions

of

the

brain

including

the

tuberomammillary

nucleus

lateral

hypothalamus

locus

coeruleus

dorsal

raphe

the

laterodorsal

tegmental

and

pendunculopontine

tegmental

nuclei

Thus

in

the

sleep

model

proposed

by

this

later

group

of

workers

hypocretin

orexin

neurons

in

the

lateral

hypothalamus

are

believed

to

help

to

stabilize

the

switch

when

the

hypocretin

neurons

are

lost

narcolepsy

can

Go

to

Circadian

Sleep

Rhythm

Among

several

intrinsic

body

rhythms

modulated

by

the

hypothalamus

is

the

circadian

sleep

rhythm

It

has

been

observed

that

the

suprachiasmatic

nucleus

sets

the

bodys

clock

to

approximately

hours

with

both

light

exposure

and

schedule

clues

entraining

to

the

hours

cycle

measured

from

awakening

after

one

sleep

period

According

to

report

by

a

group

of

workers

the

physiologic

mechanism

of

the

circadian

rhythm

begins

when

light

strikes

special

cells

within

the

retina

of

the

eye

which

in

turn

causes

the

cells

to

secrete

a

special

hormone

that

causes

the

suprachiasmatic

nucleus

to

signal

the

pineal

body

to

stop

These

workers

also

noted

that

melatonin

reaches

its

highest

level

during

sleep

and

as

the

day

progresses

adenosine

accumulates

within

the

brain

as

the

level

of

melatonin

falls

At

night

fall

the

inhibitory

effects

of

the

retinal

secretions

on

the

pineal

body

are

removed

allowing

the

pineal

to

begin

secreting

melatonin

once

more

Much

later

another

worker

noted

that

it

is

the

presence

of

higher

melatonin

levels

within

the

thalamus

and

hypothalamus

that

controls

the

urge

to

sleep

Most

workers

believe

that

the

nadir

of

the

sleep

rhythm

is

in

the

early

morning

The

downswing

in

circadian

rhythm

prior

to

the

nadir

is

thought

to

assist

the

brain

to

remain

asleep

overnight

for

full

restoration

by

preventing

premature

awakening

The

morning

upswing

then

facilitates

awakening

and

through

the

day

acts

as

a

counterbalance

to

the

progressive

discharge

of

the

awake

neuronal

activity

In

another

observation

it

was

noted

that

after

the

circadian

climax

in

the

early

evening

the

downswing

aids

sleep

initiation

It

should

be

noted

that

the

circadian

rhythm

of

day

and

night

cycle

can

also

serve

as

a

model

that

can

be

employed

to

explore

brain

chemistry

It

is

a

model

that

can

explain

the

relatively

steady

cognitive

function

throughout

wakefulness

Go

to

Neurotransmitter

Systems

Most

of

the

characteristics

of

sleep

are

functions

of

different

brain

activities

and

circuits

For

example

the

extremely

complex

interconnecting

neurons

within

the

brain

stem

and

the

reticular

formation

provoke

EEG

desynchronization

and

arousal

when

stimulated

Further

there

is

experimental

evidence

which

show

that

cells

from

the

reticular

formation

project

to

the

cortex

but

indirectly

Thus

it

should

be

recognized

that

one

of

the

functions

of

the

cells

of

reticular

formation

is

to

maintain

the

state

of

wakefulness

in

the

animal

The

first

stage

upon

falling

asleep

is

the

nonrapideye

movement

sleep

NREM

and

is

thought

to

be

produced

by

the

absence

of

desynchronizing

activity

in

the

ascending

reticular

activating

system

It

has

been

noted

that

serotonin

is

involved

in

the

production

of

NREM

sleep

the

discharge

of

the

serotonin

secreting

neurons

was

linked

with

the

onset

of

NREM

This

observation

was

supported

by

the

report

that

drugs

that

deplete

brain

serotonin

level

such

as

parachlorophenylalanine

caused

insomnia

in

cats

while

administration

of

which

restores

the

serotonin

content

of

the

brain

abolishes

the

effect

The

mechanism

that

trigger

rapideye

movement

sleep

REM

is

believed

to

be

located

in

the

pontine

reticular

formation

but

the

neurotransmitter

substance

involved

in

the

production

of

this

sleep

is

still

far

from

clear

However

it

is

thought

that

the

locus

coeruleus

and

the

norepinephrinesecreting

neurons

emanating

from

it

play

important

role

in

the

phenomenon

of

REM

sleep

In

an

earlier

effort

to

try

to

explain

the

production

of

REM

sleep

a

group

of

workers

postulated

the

existence

of

two

neuronal

systems

that

control

sleep

in

the

brain

stem

each

using

a

different

chemical

to

communicate

one

of

the

neuronal

In

that

proposal

these

workers

maintained

that

acetylcholine

neurons

send

rapid

bursts

of

electrical

signals

to

the

cortex

the

seat

of

higher

thought

and

vision

and

suggested

that

acetylcholine

may

be

the

very

stuff

that

the

REM

sleep

is

made

of

More

recently

a

study

by

a

group

of

researchers

identified

specific

clusters

of

cholinergic

neurons

in

the

pons

believed

to

play

important

role

in

the

activation

of

REM

sleep

These

workers

called

this

region

in

the

pons

the

peribrachial

area

and

argued

that

acetylcholine

cells

in

the

peribrachial

area

are

quite

active

during

REM

sleep

In

that

report

they

maintained

that

the

acetylcholine

cells

start

firing

seconds

before

the

onset

of

REM

sleep

and

noted

further

that

lesions

in

the

peribrachial

area

greatly

reduced

REM

sleep

Neurons

in

the

peribrachial

area

are

known

to

project

directly

to

the

brain

stem

regions

that

control

eye

movements

This

obviously

suggests

that

Ach

cells

in

the

peribrachial

area

might

play

a

part

in

the

mechanism

responsible

for

the

initiation

of

the

fast

scanning

eye

movements

characteristic

of

REM

sleep

It

is

also

suggestive

that

cells

of

the

peribrachial

area

might

be

a

part

of

the

neural

network

in

the

mechanism

responsible

for

the

emotional

aspect

in

dreams

characteristic

of

REM

sleep

stage

From

these

accounts

above

it

is

obvious

that

the

subject

of

the

mechanism

involved

in

the

production

of

REM

sleep

is

still

far

from

clear

as

no

neurotransmitter

agent

has

been

earmarked

with

certainty

Go

to

The

PontoGeniculoOccipital

PGO

Waves

Very

recently

a

group

of

workers

noted

that

the

first

sign

of

REM

sleep

is

the

presence

of

pontogeniculooccipital

PGO

waves

which

are

bursts

of

phasic

electrical

activity

that

originate

in

the

pons

runs

through

the

lateral

geniculate

nucleus

and

ending

in

the

occipital

primary

visual

cortex

That

report

noted

that

the

PGO

waves

occur

shortly

before

the

onset

of

REM

sleep

and

they

argued

that

it

is

indicative

that

the

PGO

areas

might

be

responsible

for

the

roving

eye

movements

in

REM

sleep

They

further

concluded

that

the

PGO

waves

areas

are

probably

involved

in

the

mechanism

for

the

visual

processing

of

information

in

dreams

at

least

as

byproduct

of

the

PGO

waves

One

fascinating

aspect

of

REM

sleep

is

the

fact

that

we

often

experience

dreams

during

this

stage

of

sleep

It

is

possible

that

the

roving

eye

movements

during

REM

sleep

are

related

to

the

scanning

of

the

visual

scene

of

a

dream

In

other

words

we

are

looking

at

the

surroundings

in

the

dream

the

same

way

we

do

to

the

surroundings

when

we

are

awake

Furthermore

it

is

possible

that

activation

of

the

brain

areas

involved

in

the

control

of

eye

movements

signal

whatever

mechanisms

that

are

responsible

for

the

visual

scenery

visual

information

during

REM

sleep

created

by

This

observation

can

also

be

taken

as

indicative

that

the

PGO

waves

probably

play

major

role

in

the

mechanism

for

the

rapid

roving

eye

movements

and

the

vivid

visual

experiences

in

dreams

characteristic

of

REM

sleep

stage

Finally

the

report

also

noted

that

in

REM

sleep

deprived

individuals

the

PGO

activity

take

place

in

the

earlier

stages

of

sleep

and

this

was

further

proof

that

the

PGO

waves

have

physiological

relevance

in

sleep

Go

to

Theories

A

number

of

theories

were

put

forward

by

workers

mostly

in

the

recent

past

Surprisingly

the

proposals

on

the

subject

of

sleep

by

these

workers

were

not

necessarily

in

any

effort

to

explain

or

examine

such

issues

as

neural

processes

involved

in

the

production

of

sleep

Instead

the

bulk

of

proposals

put

forward

by

these

workers

were

more

of

speculations

on

the

benefits

of

sleep

they

were

more

concerned

about

the

vital

role

of

sleep

to

our

daily

lives

speculations

on

the

possible

risks

in

sleep

and

how

the

benefits

outweigh

the

risks

etc

Only

three

of

these

theories

are

Go

to

Restorative

Theory

The

Restorative

Theory

was

put

forward

in

during

which

a

group

of

workers

argued

that

sleep

served

as

a

behavioral

state

of

the

body

to

save

energy

by

lowering

our

body

metabolism

The

workers

sought

to

explain

that

the

purpose

of

sleep

was

to

reorganize

and

store

information

arguing

that

the

cortical

neurons

that

are

involved

in

memory

and

attentive

learning

needed

to

rest

in

sleep

especially

during

REM

sleep

The

workers

noted

that

this

probably

explains

why

we

feel

mentally

sharper

after

a

good

nights

sleep

as

compared

to

how

we

feel

after

staying

awake

all

night

long

Thus

in

Restorative

Theory

it

was

hypothesized

that

REM

sleep

plays

a

vital

role

in

memory

retention

and

consolidation

removal

of

trivial

or

unwanted

information

and

storage

of

important

data

from

memory

all

Another

group

of

workers

hypothesized

that

slow

wave

sleep

also

has

some

restorative

effect

since

it

appears

to

be

a

period

of

rest

for

the

brain

They

noted

that

the

brain

areas

that

are

very

active

during

wakefulness

show

an

increase

in

slow

wave

sleep

As

it

has

been

stated

that

sleep

is

generally

a

time

of

growth

and

repair

these

workers

also

noted

that

there

is

a

rise

in

certain

growth

hormones

that

have

been

shown

to

increase

during

period

of

slow

wave

sleep

Go

to

Developmental

Theory

Some

group

of

workers

proposed

the

Developmental

Theory

during

which

they

put

forward

the

idea

that

sleep

especially

the

REM

sleep

play

important

role

in

the

development

of

the

brain

In

support

of

this

proposal

the

workers

further

observed

that

REM

sleep

is

a

major

component

of

sleep

for

babies

in

utero

and

infants

It

was

hypothesized

that

REM

sleep

activates

the

visual

motor

and

sensory

areas

of

the

brain

In

the

brain

of

babies

it

is

be

lieved

that

REM

sleep

increases

the

ability

of

neurons

to

function

properly

and

to

make

the

correct

connections

Observation

from

lamb

fetuses

through

Plexiglas

windows

implanted

on

the

uterine

walls

showed

that

during

REM

sleep

fetuses

as

a

result

of

not

having

air

to

breathe

nevertheless

move

their

chest

as

if

they

were

breathing

According

to

these

workers

this

suggests

that

REM

sleep

plays

a

role

in

preparing

the

infant

on

how

to

behave

in

the

Go

to

Preservation

Theory

In

an

overview

sleep

was

noted

to

be

so

essential

that

long

periods

of

sleep

deprivation

eventually

results

in

stress

related

deaths

In

the

Preservation

Theory

it

was

stated

that

sleep

and

the

desire

to

sleep

at

night

or

under

conditions

resembling

night

are

the

result

of

the

evolutionary

process

to

keep

us

away

from

trouble

Thus

the

theory

proposes

that

sleep

is

an

adaptive

behavior

to

keep

us

away

from

night

and

darkness

when

predator

species

enjoy

advantage

in

vision

and

stealth

Workers

further

argued

that

over

time

the

sleep

when

it

is

dark

and

work

in

the

day

Since

the

classical

hypnotoxin

experiments

of

Legendre

and

Pieron

in

the

existence

of

some

sleepregulating

substances

was

proposed

and

a

number

of

endogenous

factors

were

actually

listed

Most

of

the

listed

substances

were

prostaglandins

or

their

synthesis

inhibitors

and

these

factors

were

believed

to

be

present

in

the

cerebrospinal

fluid

It

was

believed

that

these

multiple

endogenous

factors

are

functionally

linked

such

that

sleep

regulation

involves

a

complicated

mutual

interference

mechanism

among

them

The

time

of

that

report

heralded

the

period

of

more

intense

efforts

in

the

search

for

a

better

understanding

of

the

neurophysiologic

factors

in

sleep

In

view

of

the

growing

number

of

proposed

and

suspected

neurotransmitter

agents

in

the

mechanism

of

sleep

regulation

it

has

become

obvious

that

full

knowledge

of

the

neural

processes

in

the

mechanism

of

sleep

is

still

far

from

clear

Recent

reports

in

the

proposed

neural

mechanisms

of

sleep

appear

to

speculate

more

on

the

possible

roles

of

the

PGO

waves

in

REM

sleep

On

the

whole

the

actual

neural

processes

involved

in

the

production

of

REM

sleep

appear

to

be

still

far

from

very

clear

Thus

it

can

be

stated

that

the

actual

factors

in

the

neurophysiologic

mechanisms

of

sleep

Go

to

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