NON COMMUNICABLE DISEASES EPIDEMIOLOGY AND CONTROL

MPH 5204

WEEK TOPIC LECTURES

1 Introduction to Non communicable diseases Scope,aims and roles of NCD

Epidemiology and Control
-The burden of NCD in different
parts of the world and especially
low and middle income countries

2 Life course approach to NCD Use of biological biomarkers

oncological diseases in male and
female

3 Role of infectious agents in the etiology of Different infectious agents causing

NCD and determinants and risk factors of NCD and the risk factors
NCD,Atherosclerosis Epidemiology,determimants and
risk factors , control and prevention
of Atherosclerosis

4 Cardiovascular Diseases Epidemiology,determimants and

risk factors , control and prevention
of Cardiovasular Diseases

5 Cerebrovascular Diseases Epidemiology,determimants and

risk factors , control and prevention
of Cerebrovascular Diseases

6 CAT 1 CAT 1

7 Diabetes Mellitus Epidemiology,determimants,types

and risk factors , control and
prevention of diabetes mellitus

8 Chronic Respiratory Diseases Epidemiology,determimants and

risk factors , control and prevention
of chronic respiratory diseases

9 Cost effective interventions for chronic Alcohol Addiction

illnesses
10 CAT 2 CAT 2

11 Cost effective interventions for chronic Tobacco abuse

illnesses

12 Injuries and Mental Health Epidemiology, types,causes ,risk

factors ,control and prevention of
injuries and Mental Health

13 Genetic Variant Associations Epidemiology of Respiratory

Outcomes

14 Measuring Inequalities in Health Different inequalities in Health

15 Population prevention strategies High risk individual vs population

strategies ,population based
screening
16 End Semester Exam

By Lynette Muthoki
LECTURE 1

INTRODUCTION TO NON COMMUNICABLE DISEASES EPIDEMIOLOGY AND

CONTROL

Non-communicable diseases (NCDs) are the number one cause of death and disability in the
world. The term NCDs refers to a group of conditions that are not mainly caused by an acute
infection, result in long-term health consequences and often create a need for long-term
treatment and care. These conditions include cancers, cardiovascular disease, diabetes and
chronic lung illnesses. Many NCDs can be prevented by reducing common risk factors such as
tobacco use, harmful alcohol use, physical inactivity and eating unhealthy diets.
Many other important conditions are also considered NCDs, including injuries and mental health.

Of the 57 million deaths that occurred globally in 2008, 36 million – almost two thirds – were
due to NCDs, comprising mainly cardiovascular diseases, cancers, diabetes and chronic lung
diseases.1 The combined burden of these diseases is rising fastest among lower-income
countries, populations and communities, where they impose large, avoidable costs in human,
social and economic terms. About one fourth of global NCD-related deaths take place before the
age of 60.

Sub-Saharan Africa is experiencing a rapid epidemiological transition with the growing burden
of non-communicable diseases (NCDs), as a result of the rapid urbanisation and westernisation
of lifestyles, decreasing physical activity, changing dietary habits and increasing longevity of the
population. In developing countries NCDs have now overtaken communicable diseases (CDs) as
the prime cause of mortality (54% compared to 36% . According to the World Bank, mortality
due to NCDs will have risen from 28% in 2008 to 46% by 2030, representing a 64% increase.
This will amount to a 34% increase in healthy years lost, based on Disability Adjusted Life
Years. A recent study conducted jointly by the World Economic Forum and Harvard University
showed that NCDs will cost the world economy $47 trillion over the next 20 years, representing
75% of global gross domestic product (GDP) and surpassing the cost of the global financial
crisis.This is compared to an estimated cost of $11.4 billion a year in low- and middle- income
countries to provide basic packages of cost effective strategies to prevent and treat NCDs. NCDs
and CDs are therefore placing a joint strain on the already fragile health systems of Sub-Saharan
African countries with an expected adverse impact on the health of the people.

The Millennium Development Goals (MDGs) have proved to be a lost opportunity for
addressing NCDs. NCDs strongly contribute to all eight MDGs but omission of NCD indicators
in the MDGs has resulted in failure to secure adequate attention and donor funding for NCDs.
This is linked to the global focus on communicable diseases (CDs), mainly HIV/AIDS, malaria
and TB, which have been prioritized for major funding support over the last decade. In addition,
vertical programming as the main approach to disease control has promoted fragmentation of the
health services and placed additional constraints on the already limited human resources for
health.
In 2010, NCDs were formally recognized at the UN General Assembly as an important missing
element in the Millennium Development Goals (MDGs)
Most NCDs are preventable because they are caused by modifiable risk factors, which include
poor diet, lack of physical activity and tobacco use. Every year, more than 5 million people die
because of direct tobacco use and 2.8 million die from being overweight or obese. High
cholesterol accounts for 2.6 million deaths and 7.5 million die because of elevated blood
pressure.

By 2030, deaths caused by chronic diseases are expected to increase to 52 million while deaths
caused by infectious diseases, maternal and perinatal conditions and nutritional deficiencies are
expected to decline by 7 million over the same time period. Individually, chronic disease lowers
quality of life for those affected, causes premature deaths and negatively impacts the economic
solvency of families, communities and nations.

National economies are foregoing significant national income because of premature deaths
resulting from heart disease, stroke and diabetes caused by heart disease, stroke and diabetes.

By the end of this lecture, you should be able to:

i. Define the aims, scope and roles of non-communicable diseases
epidemiology.
ii. Outline the health indicators.
iii. Appreciate the changing importance of non communicable
diseases as a major public health burden in different parts of
the world and especially in low and middle income countries.

AIMS OF Non communicable diseases is to:-

-To provide an overview of the importance of and trends in non-communicable diseases globally,
including low and middle income countries;
-To generate an appreciation of the drivers of the burden of non-communicable diseases;
-To identify methodological and conceptual issues in identifying causes of non-communicable
diseases and evaluating preventive strategies

Prevention and treatment play an important role in tackilng non communicable diseases.

Health Indicators
Health indicators are measurements. They measure different aspects of health within a
community or group. Each indicator is like a piece of a puzzle
contributing to an overall picture. When indicators are tracked over time, the picture becomes a
movie, allowing us to see how the health story is changing.
There are two main types of indicators:
 Health status indicators measure different aspects of the health of a population. Examples include
life expectancy, infant mortality, disability or chronic disease rates.

Health determinant indicators measure things that influence health. Examples include diet,
smoking, water quality, income and access to health services.
First Nations also consider language, culture and spirituality to be health determinants.

Indicators help to answer important questions, such as:

• How healthy is our community?

• Is our community in balance?
• What things affect health in our community?
• Are our programs, services or policies working?
• Are we moving towards or away from our vision of health?

Data sources:

The main (preferred) data source or data collection methodology is specified for each indicator,
including:

• civil registration and vital statistics systems;

• population-based health surveys;

• facility-generated data that include routine facility information systems and health facility
assessments and surveys;

• administrative data sources such as financial and human resources information systems;

• indicators from other sources, including modelling.

TYPES OF INDICATORS

Mortality by age and sex

• Life expectancy at birth

• Adult mortality rate between 15 and 60 years of age

• Under-five mortality rate

• Infant mortality rate

• Neonatal mortality rate

• Stillbirth rate

Mortality by cause
• Maternal mortality ratio

• TB mortality rate

• AIDS-related mortality rate

• Malaria mortality rate

• Mortality between 30 and 70 years of age from cardiovascular diseases, cancer, diabetes or
chronic respiratory diseases

• Suicide rate

• Mortality rate from road traffic injuries

Fertility

• Adolescent fertility rate

• Total fertility rate

Morbidity

• New cases of vaccine-preventable diseases

• New cases of IHR-notifiable diseases and other notifiable diseases

• HIV incidence rate

• HIV prevalence rate

• Hepatitis B surface antigen prevalence

• Sexually transmitted infections (STIs) incidence rate

• TB incidence rate

• TB notification rate

• TB prevalence rate

• Malaria parasite prevalence among children aged 6−59 months

• Malaria incidence rate

• Cancer incidence, by type of cancer

Activity 1.1

Describe the different expression of the above health indicators.

______________________________________________________________________________
______________________________________________________________________________

NON COMMUNICABLE DISEAESES IN LOW AND MIDDLE INCOME COUNTRIES

Non-communicable diseases in low- and middle-income countries can no longer be ignored or

seen as a distraction from the business of prevention and control of infectious diseases. The case
has been highlighted in recent reports describing the global burden in terms of mortality- and
disability- adjusted life years World Health Organization and also their economic impact. Until
recently, communicable diseases remained virtually the sole priority for global health policy.
However, they do not constitute the major contributor to the burden of disease in terms of
disability-adjusted life years or mortality in any region of the world apart from sub- Saharan
Africa. Non- communicable diseases cause more than half of deaths in adults aged 15–59 in all
regions except South Asia and sub-Saharan Africa, where infectious disease conditions,including
HIV ⁄ AIDS, result in one-third and two-thirds of deaths, respectively. However, non-
communicable diseases are also becoming a significant burden in sub-Saharan Africa. The
Global Burden of Disease Study, conducted in 2001, showed that 20% of deaths in sub-Saharan
Africa were caused by non-communicable diseases . Cardiovascular disease, cancer and injuries
rank consistently as the top three conditions in these countries.

Chronic conditions kill people at economically and socially productive ages: 80% of chronic
disease deaths occur in low- and middle-income countries, reflecting both the size of these
populations and the epidemiologic transition from infectious to chronic diseases. Cardiovascular
disorders are the second most common causes of adult deaths in sub- Saharan Africa, in addition
to a major cause of chronic illness and disability. Half of cardiovascular disease deaths occur
among people 30–69 years of age, which is 10 or more years younger than in more developed
regions (Baingana & Bos 2006). Recent global and regional burden of disease analyses suggest
that almost half the disease burden in low- and middle-income countries is now from non-
communicable diseases, a rise of 10% in its relative share since 1990. Disease burden per head in
sub-Saharan Africa and the low- and-middle-income countries of Europe and Central Asia
increased between 1990 and 2001. Verbal autopsy studies suggest that estimates for cause of
death within broad categories (e.g. cardiovascular diseases) are accurate when compared with
clinical records.
According to the World Health Organization (2005), from a total of 58 million deaths from all
causes in 2005 globally, chronic diseases accounted for an estimated 35 million or 60% of all
deaths, which is double the number of deaths from all infectious diseases (including HIV⁄AIDS,
tuberculosis and malaria), maternal and perinatal conditions and nutritional deficiencies com-
bined. In low- and middle-income countries, 53.8% of all deaths are attributed to non-
communicable diseases and 36.4% to communicable diseases.

This epidemiological transition – the change from a burden of disease dominated by mortality
from infectious causes to degenerative or chronic causes currently being experienced in low- and
middle-income countries is compressed into a shorter time frame than that experienced
historically in high-income countries. Furthermore, developing countries not only have to deal
with their current burden of infectious diseases and ill-functioning health systems, but also with
the growing burden of chronic diseases a situation that has been described as ‗a race against
time‘.

Decades of research in the developed world have shown that much of the burden of chronic
diseases is attributable to environmental and lifestyle factors, including tobacco consumption and
decreased physical activity. Variation in the risk of non-communicable diseases between high-
income countries and trends over time within countries also indicate that the factors determining
incidence must be modifiable, and therefore, that many non-communicable diseases are
preventable. Despite this wealth of information available in the developed world, it is also clear
that there is an important research gap between developing and developed countries. Much of the
robust evidence for prevention and control of chronic diseases comes from randomised clinical
trials. Such trials tend to study highly selected groups of people, which means that the results
may not be applicable to the broader population, resulting in a conflict between the proof of
concept and generalisability. Trials often fail to take into account whether the intervention, if
found to be effective, would be affordable, nor do they provide information on prospects of
scaling up to achieve broad population coverage.

Divergent trends in countries of the former USSR and other high-income countries indicate that
different environmental factors are driving ischaemic heart disease rates up or down over the
same decade. To understand non-communicable diseases in today‘s low- and middle-income
countries and their growing burden, a contextualisation appropriate to their greatly different
circumstances is needed.

When evaluating the nutritional transition in low- and middle-income countries, relevant
questions for the understanding and contextualisation of the burden of non- communicable
diseases have been posed. ‗Is the experience related to the rapid onset of obesity and nutrition
related non-communicable diseases in low and middle-income countries ... different from what
occurred in Western European countries, the United States and Japan at a similar stage in their
economic develop- ment?‘ The answer leans towards a unique scenario where current
phenomena being experienced in today‘s low- and middle-income countries differ from those
experienced in the past by today‘s developed nations. Of note are the much more rapid rates of
population ageing in low- and middle-income countries than those experienced by high- income
countries, which are attributed to dramatic declines in fertility and mortality resulting in large
increases in the population at risk from non-communicable diseases. Furthermore, the process of
rural out-migration and associated urban- isation and modernisation in today‘s low- and middle-
income countries, in addition to their divergent degrees of economic development, differred from
the developed nations when they started their rise of non-communicable diseases in the late 19th
century. Greater understanding of the roles of these major factors would be helpful in addressing
potential context-specific strategies to prevent and control the growing problem of non-
communicable diseases in low- and middle-income countries.

Some arguments to understand the unique contextual differences between countries affected by
non-communi- cable diseases at different times have been put forward . First, the speed of
change appears unique owing to the timing of the economic, technological and social
transformations. Second, as the problem of under- and over-nutrition arises, finding both under-
and over-nutrition in the same household is indicative of the complexity of different sets of
stresses and societal changes. Third, the political environments differ, as does the capacity of
low- and middle-income countries to address the rapid increase in the prevalence of non-
communicable diseases.

Such analysis must be superimposed on the common realities of today‘s low- and middle-income
countries, a world marked by increased urbanisation with high levels of urban poverty, and the
rural poor increasingly marginalised. Of critical importance to future social inequalities in
chronic disease risk will be the speed with which social patterning of risk factors spread from the
more affluent to affect poorer people. In west Africa, marketing of imported wheat and rice has
supplanted the consumption of local less-refined cereals (millet and sorghum) and even the
pastoral Masai in Tanzania have experienced rapid changes in eating habits associated with rises
in blood cholesterol.

An additional factor is that beyond biological risk factors of lipid and blood pressure profiles,
health behaviours strongly related to non-communicable diseases show different patterns. For
example, smoking patterns are markedly different between countries, and therefore, their
population-attributable risk towards non- communicable diseases and mortality is not the same
throughout the low- and middle-income countries. The strong social patterning of many non-
communicable diseases forces us to consider approaches to their prevention well beyond the
simple risk factor profile of an individual. For example, from a merely economic perspective,
belonging to a lower socioeconomic status confers protection from obesity up to a level of
USD$2500 per capita per year when inequities in obesity start to appear. If obesity is approached
as a social networking issue, an interesting pattern also appears that shows clustering of
individuals with obesity – and increased risks for the development of such condition in
individuals closer to obese ones.

congratulation, you have come to the end of lecture 1 where we have define scope,aims and roles
of non communicable diseases,health indicators and appreciated the public health burden in
different parts of the world especially in low and middle income countries.
 Now take a break and reflect on some of the issues we
have discussed today. After your break, answer the following questions:

1. Define the scope of non communicable diseases.

2. Outline the major aims of non communicable diseases

3. Explain five health indicators

4. Describe the public health burden in low and middle income countries.

Lopez AD. Disease Control Priorities Project: Global Burden of Diseases and Risk Factors.
New York, Washington DC: Oxford University Press; World Bank.2006.

Ebrahim S & Smeeth L (2005) Non-communicable diseases in low and middle-income

countries: a priority or a distraction? International Journal of Epidemiology 34, 961–966.
 LECTURE 2

USE OF BIOLOGICAL MARKERS ON ONCOLOGICAL DISEASES

LECTURE OVERVIEW

Welcome to lecture 2.This lecture will discuss about the use of biological markers on
oncological diseases in both male and female.

By the end of this lecture, you should be able to:

i. Explain the rationale for a life course approach to the etiology of non
communicable diseases.
ii. Appraise the value and limitations of molecular biomarkers in measuring
exposure, susceptibility and disease outcome in epidemiological studies for non
communicable disease

Every cell type has a unique molecular signature, referred to as biomarkers, which are
identifiable characteristics such as levels or activities (the abilities of genes or proteins to
perform their functions) of a myriad of genes, proteins or other molecular features. Biomarkers
are therefore, an objective measure or evaluation of normal biological processes, pathogenic
processes, or pharmacological responses to a therapeutic intervention. This includes all
diagnostic tests, imaging technologies, and any other objective measures of a person‘s health
status. Biomarkers are subject to dynamic modulation, and are expected to enhance our
understanding of drug metabolism, drug action, efficacy, and safety. These can also facilitate
molecular definition of diseases, provide information about the course of disease and predict
response to therapies.

More than 11 million people are diagnosed with cancer every year. It is estimated that there will
be 16 million new cases every year by 2020. Cancer is a cluster of diseases involving alterations
in the status and expression of multiple genes that confer a survival advantage and undiminished
proliferative potential to somatic or germinal cells. Alterations primarily in three main classes of
genes viz., (proto) oncogenes, tumour suppressor genes and DNA repair genes collectively
contribute to the development of cancer genotype and phenotype that resists the natural and
inherent death mechanism(s) embedded in cells (apoptosis and like processes), coupled with
dysregulation of cell proliferation events (Fig.). There is increasing evidence to suggest that
cancer is also driven by ‗epigenetic changes‘ like DNA methylation and altered patterns of
histone modifications, leading to alterations in chromatin condensation status thereby regulating
expression of certain set of specific genes.

Technologies to recognize and understand the signatures of normal cells and how these become
cancerous, promises to provide important insights into the aetiology of cancer that can be useful
for early detection, diagnosis, and treatment. Biomarkers are therefore invaluable tools for cancer
detection, diagnosis, patient prognosis and treatment selection. These can also be used to localize
the tumour and determine its stage, subtype, and response to therapy. Identification of such
signature in surrounding cells or at more distal and easily sampled sites of the body viz., cells in
the mouth (instead of lung) or urine (instead of urinary tract) can also influence the management
of cancer.

Cancer cells display a broad spectrum of genetic alterations that include gene rearrangements,
point mutations, and gene amplifications, leading to disturbances in molecular pathways
regulating cell growth, survival, and metastasis. When such changes manifest in majority of
patients with a specific type of tumour, these can be used as biomarkers for detection and
developing targeted therapies, besides predicting responses to various treatments.

Genetics, genomics, proteomics, many non invasive imaging techniques and other technologies
allow measurement of several biomarkers. Currently, there is a greater understanding of the
disease pathways, the protein targets and the pharmacologic consequences of drug
administration. Therefore, application of biomarkers in the clinical practice is likely to result in
advanced knowledge leading to a better understanding of the disease process that will facilitate
development of more effective and disease specific drugs with minimal undesired systemic
toxicity. Establishment of biomarkers requires a comprehensive understanding of the molecular
mechanisms and cellular processes underlying the initiation of cancer, especially focusing on
how small changes in only a few regulatory genes or proteins can disrupt a variety of cellular
functions. A major challenge in cancer diagnosis is to establish the exact relationship between
cancer biomarkers and the clinical pathology, as well as, to be able to non invasively detect
tumours at an early stage. Similarly, identification of subtle changes in the genomics and
proteomic status specific to malignant transformation will allow molecular targets to be used for
developing therapeutics. This review is a brief account of the biomarkers employed currently in
clinical oncology for diagnosis and therapy as well as potential ones that particularly hold
promise as targets for therapy.

Diagnostic and prognostic biomarkers are quantifiable traits that help clinical oncologists at the
first interaction with the suspected patients. These particularly aid in (i) identifying who is at
risk, (ii) diagnose at an early stage, (iii) select the best treatment modality, and (iv) monitor
response to treatment. These biomarkers exist in many different forms; traditional biomarkers
include those that can be assessed with radiological techniques viz., mammograms etc., and
circulating levels of tumour specific (related) antigens for example, prostate-specific antigen
(PSA). With the availability of complete human genome sequence, and advancement in key
technologies such as high- throughput DNA sequencing, microarrays, and mass spectrometry,
the plethora of potentially informative cancer biomarkers has expanded dramatically to include
the sequence and expression levels of DNA, RNA, and protein as well as metabolites. Advances
in imaging technologies open up the possibility that pertinent molecular biomarkers (e.g., those
marking response to therapy) can be monitored in cancer patients non invasively.
Genetic and genome based approaches have played significant role in the diagnosis and
prognosis of cancer. Alterations in the DNA content (hyper- and hypo- diploidy) arising on
account of genomic instability during dysregulated proliferation has been extensively used, but
has its limitations. Structural anomalies in chromosomes on the other hand are not a universal
phenomenon. Molecular genetic techniques providing information about the specific and subtle
genetic changes have been quite useful in the identification of certain tumours. With the
introduction of several comparative genetic analysis techniques, the detection of tumours by
analyzing subtle changes in the genetic composition has become more feasible. Analysis of
global gene expression changes provided by the micro-array technology has revolutionized the
genome based approaches for studying biomarkers at large and cancer in particular. These
techniques have in fact been quite successful in clearly dissecting subtle changes between
different stages of tumours as well as resolving similar tumour types, which were otherwise not
easily discernable.

Activity 2.2

Explain different biomarkers in oncological diseases in both male and female.

Cytogenetic and cytokinetic markers

Structural and numerical aberrations in the chromosomes are classical markers of cancer as the
association between chromosomal aberrations and neoplastic transformation has been well
established. While deviations from diploid chromosome number leading both to hyper- and
hypo-diploidy as well as aneuploidy have been noted in malignant tumours11, sister chromatid
exchanges and translocations give rise to structural aberrations that can be easily scored using
various banding techniques. Further, double minutes and homogenously stained regions
(indicative of gene amplification) are also often observed in malignant cells that can serve as
markers. Although, the ploidy changes complement the clinico-pathological findings, a weak
association between ploidy, histological and clinical staging has been noted in many tumours.
Somatic mutations (in reporter genes, oncogenes and tumour suppressor genes) are promising
biomarkers for cancer risk as these can capture genetic events that are associated with malignant
transformation. There is growing evidence that specific polymorphism in certain genes are
associated with cancer risk.

Among other genome based biomarkers, identification of neoplasm from the level of lesion
specific transcriptomes (mRNA of cytokeratin-19, EGFR, MUC 1, etc.) in the blood has been
successfully employed in certain epithelial tumours. Recently a novel transcriptome marker
based on the levels of exon-3 deleted variant isoform of proghrelin (ghrelin is a growth factor
involved in prostate cancer cell proliferation) has been developed that aims at reducing the false
positives in prostrate and other endocrine cancers.
Enhanced cell proliferation is one of the most important hallmarks of cancer, which is easy to
identify using a number of histological, biochemical and flow cytometric analysis. Although
subjective in nature, histological assessment based on evaluating the number of mitotic cells
present within a given sample, is still used as a routine clinical test and even for grading in
certain tumours like breast cancer. Flow cytometric analysis of DNA content, which is
automated, objective and rapid allowing large number of cells (and samples) to be measured, has
been extensively used for the assessment of proliferation status. This complements histological
analysis in most cases, besides allowing analysis of clonal and spatial heterogeneity, two
important hall- marks of highly malignant tumours11. Identification of S-phase cells
(unequivocal marker of proliferation) and analysis of a number of other antigenic determinants
of proliferation (PCNA, Ki67 NOR, etc.) studied using a variety of cell biology techniques have
also been used as complementary markers. Information provided by gene expression analysis has
a distinct advantage over other assessments of proliferation (viz., more quantitative, objective,
and automated) and could form a component of genomic-based clinical diagnostics of cancer.
Proteins encoded by the minichromosome maintenance (MCM) genes have also been proposed
as useful markers of proliferation; with high levels of gene expression indicating poor
prognosis20. All these genes are cell-cycle regulated and are found among the genes associated
with proliferation in tumors.

Genetic biomarkers

Cancer is a genetic disease initiated by alterations in genes, such as oncogenes and tumour
suppressors that regulate cell proliferation, survival, and other homeostatic functions. Gain/ loss
of gene function is predominantly responsible for oncogenic transformation. Several proto-
oncogenes get converted into oncogenes with as little as a point mutation on a chromosome,
thereby altering the amount of its product i.e., protein. Several non-random mutations, and
translocations/ rearrangement within the regulatory region of the gene are also known to be
associated with particular types of malignancy. For example, the ―Philadelphia chromosome‖ is
associated with chronic myelogenous leukaemia due to a translocation between chromosomes 9
and 22. Other examples occur in Burkitt‘s lymphoma and in follicular B-cell lymphomas. These
translocations serve as highly specific tumour markers for unique clinical diagnosis.

Extensive allotyping of breast cancer for gene deletions of loci on multiple chromosomes has
been reported22. Deletion of genomic material is important, because the lost segment of DNA
may contain certain tumour suppressor activity. Gene deletions are discovered by polymerase
chain reaction (PCR) using microsatellite probes to various chromosomes and sites. Tumour-
suppressor genes are thought to play a role in specific tumour e.g., in breast tumour p53, Rb,
DCC, Brush-1, BRCA-1, BRCA-2. In addition, allelic losses with more or less significant breast
carcinoma associations on virtually all chromosomes have been reported23. Unfortunately,
unlike these well defined markers, random chromosomal abnormalities that are not associated
with a particular morphological change give rise to clinical cancer.

Loss of heterozygosity as well as mutations within several protooncogenes can lead to

microsatellite instability (MSI)25. Although detection of microsatellite instability/alterations in
pathologic tissue samples require a comparison with normal tissue but it presents a valuable tool
for early detection, occasionally at preneoplastic stage26. MSI can also be used for prognosis and
evaluation for chemotherapeutic response.
Adenomatous polyposis coli (APC) gene: The APC gene normally responsible for suppressing
cancer, is deactivated in many tumours, the altered gene has been found in 92 per cent of patients
diagnosed with oesophageal adenocarcinoma, and in 50 per cent of patients with squamous cell
carcinoma of the oesophagus27. Mutations in the APC gene occur in 60 per cent of patients with
colorectal carcinoma and are thought to be the earliest genetic abnormalities in the progression of
colorectal carcinoma28. Most of these mutations cause the production of an APC protein that is
abnormally short and nonfunctional. This short protein cannot suppress the cellular overgrowth
that leads to the formation of polyps, which could become cancerous. Somatic mutation of the
APC gene has been identified in sporadic colorectal cancer as well as in some cancer of the
stomach, pancreas, thyroid, ovary and other primary sites. Hence, hypermethylated APC gene is
being utilized as a biomarker to determine the stage of oesophageal cancer, detect recurrent
disease, and monitor disease progression or treatment response. A high level of hypermethylated
APC gene in the bloodstream is generally associated with poor survival; conversely, the
prognosis improves dramatically for patients with low or undetectable blood levels of the altered
gene. APC expression is also induced during pregnancy and lactation in the mouse mammary
gland, and APC deficiency results in defective lobule- alveolar development, therefore should be
used with caution. PCR-based tests are widely used to detect these mutations.

Epigenetic biomarkers

In cancer cells, genes and their functional products are either modified by mutations, or through
epigenetic modifications to chromosomes that alter gene- expression patterns. Epigenetic
modifications can occur directly through DNA methylation of genes or indirectly by
methylation, acetylation, or phosphorylation of histones and other proteins around which DNA is
wound to form chromatin. DNA methylation at the cytosine residue is the main epigenetic
modification in humans which occurs in the context of 5‘-CpG-3‘ dinucleotides. In recent years
it has become apparent that epigenetic events are potentially responsible for cancer initiation and
progression as genetic abnormalities, with DNA hypo- and hyper-methylation promoting cancer
development. Several studies have shown that the activity and DNA methyltransferases
(DNMTs), which add methyl groups to DNA at cytosine residues, are altered in tumour cells and
associated with several developmental abnormalities. Genomic hypomethylation may lead to
both genomic instability and stronger gene expression. On the other hand, local promoter CpG
island hypermethylation induces the functional silencing of tumour suppressor genes, mimicking
their genetic mutations. Many genes involved in the process of carcinogenesis are the common
targets for silencing, which includes cell-cycle control and apoptosis genes viz. p14, p15, p16,
Rb, DAPK; DNA repair genes MGMT, hMLH1; adhesion and metastasis genes CDH1, CDH13;
biotransformation genes GSTP1 and signal transduction genes RARβ, APC34. Since, methylation
pattern of many genes are altered in cancer, type specific panels for methylation of different
genes have been suggested, e.g., GSTP1, RARβ, TIG1 and APC for prostate carcinoma; p16,
RASSF1A, FHIT, H-cadherin and RARβ for non small cell lung cancer34; VHL, p16, p14, APC,
RASSF1A and Timp3 for kidney cancer, etc.

Hypermethylation markers may be used for the detection of both primary and metastatic or
recurrent cancer cases. For example, hypermethylation of p16 promoter in the circulating serum
DNA correlate well with recurrent colorectal cancer36. Aberrant methylation of the p16Ink4 and
MGMT promoters can be detected in DNA from the sputum of patients with squamous cell
carcinoma nearly 3 yr before clinical diagnosis while, methylation of p16Ink4, RASSF1A, or
PAX5- beta genes appears to be associated with a 15-fold increase in the relative risk for lung
cancer. Therefore, it has been suggested that alterations in methylation patterns of groups of
genes in sputum samples may be an effective, non invasive approach for identifying smokers at
risk of developing lung cancer. Methylation of the O6-methylguanine-DNA methyltransferase
(MGMT) gene, which encodes a DNA-repair enzyme has been shown to inhibit the killing of
tumour cells by alkylating agents and methylation of the MGMT promoter of malignant glioma
appears to be a useful predictor of the responsiveness to alkylating agents as patients with
silencing of this gene seem to respond better to therapy. Although, research in epigenetics has
led to improved survival of patients with certain forms of lymphoma and leukaemias through the
use of drugs that alter DNA methylation and histone acetylation, proposed methylation markers
need further optimization and large scale clinical trial for further validation. The development of
therapeutics that reverse epigenetic alterations in cancer cells, along with prognostic and
diagnostic assays based on gene- methylation patterns, are promising new avenues for future
improvements in patient care.

Cells as biomarker

In advanced stages of tumours, cells starts appearing in bloodstream where it can be easily
monitored. Advanced clinical practice in certain malignancy have effectively used tumour and
immune cells where it served as a good biomarker of prognosis, while its utility in other cancers
are under evaluation at the present time.

Circulating tumour cells (CTCs): It is simple yet powerful biomarker in the field of oncology.
The presence of CTCs has been shown to predict survival in patients with metastatic breast
cancer at multiple time points throughout the course of therapy39. CTCs provide an early,
reliable indication of disease progression and survival for patients on systemic therapy for
metastatic breast cancer. Elevated CTCs at any time during therapy is a harbinger of progression,
while elimination of CTCs indicates effectiveness of the therapy. Selection of appropriate
therapeutic regime can also be guided by assessment of the presence of the therapeutic target on
the CTCs and, in contrast to CTC scans, the effect of therapy can be measured after the first
cycle of therapy. CTCs are not only potential surrogate endpoint in oncology clinical trials but
may guide the selection of patients into the trials.

CTCs have been shown to be superior to standard tumour markers (e.g., Ca27-29) in predicting
prognosis. Furthermore, the efficacy or benefit to systemic therapy can also be predicted by the
level of CTCs as early as 3-4 wk after initiation of therapy. Patients with persistent CTCs (≥ 5)
demonstrate lack of response to treatment or progressive disease at the time of restaging by
standard imaging modalities, while objective remission have been reported in patients with < 5
CTCs. Available evidences clearly suggest that CTCs can be used as an early predictor of
treatment efficacy and extremely useful in sparing patients from futile therapy early in the course
of their treatment.

T-regulatory cells (CD4+, CD25+ and Foxp3+): A number of mechanisms contribute to the
capacity of the immune system to discriminate self from non-self, facilitating the maintenance of
immunological tolerance to self-antigens and the induction of protective immunity to foreign
antigens. It is becoming increasingly clear that regulatory T cells (T-regs) are equally important
in inducing and maintaining peripheral self-tolerance and thus preventing immune pathologies.
These are subpopulations of CD4 cells, characterized by high CD25 expression along with Fox
P3. They are thought to play a specialized role in controlling both innate and acquired immune
responses. Furthermore, studies in cancer patients suggests that increased T-regs activity may be
associated with poor immune responses to tumour antigens and contribute to immune
dysfunction resulting in tumour growth. High numbers of T-regs have been found in lung,
pancreatic, breast, liver and skin cancer patients, either in the blood or in the tumour itself.
However, levels of T-regs are also elevated in certain infectious diseases52. T-regs are able to
inhibit proliferation and IFN-γ production by CD4+ and CD8+ T cells, as well as natural killer
(NK) cell- mediated cytotoxicity. Studies on ovarian carcinoma patients have demonstrated that
the presence of T-regs, which suppress tumour-specific T-cell immunity inversely correlate with
survival. Recent studies in Ehrlich ascites tumour bearing mice have also shown that higher
numbers of T-regulatory cells are associated with tumour progression. Further, the T-regs levels
were found to be significantly lower in animals that showed complete response (tumour
regression and cure) to a given treatment (a combination of radiation and the glycolytic inhibitor
2-deoxy-D-glucose;2-DG), while an increase was found in those animals that did not respond to
the treatment suggesting a relationship between T regulatory cells and therapeutic response.
Therefore, it appears that although T-regs may serve as a surrogate immune marker of cancer
progression (and perhaps prognosis), it seems to be more useful as a predictor of response to
therapies.

Regulatory T cells (T-regs) are primarily and specifically identified by the experiments of
(transcription factor, FoxP3) using anti FoxP3 antibodies. The presence of FoxP3+ cells within
tumours has been shown to predict the prognosis, invasiveness, and metastatic ability of some
tumours by modulating the ability of the immune system to target tumour cells. Depletion of
regulatory T cells from tumours could lead to the rejection of both early- and late-stage tumours
by the host immune system. These findings suggest that the widespread use of T-regs, and more
importantly its intracellular marker FoxP3, should be explored as a biomarker for human
tumours to enabling better decisions in patient care, as well as prepare the field for novel
therapeutic agents directed at the elimination of regulatory T cells within tumours or in the
peripheral blood.

Cancer stem cells (CSCs): It has long been recognized that subpopulations of cancer cells exist
within the tumours that resemble the developmental hierarchy of the normal tissue from which
the tumour arose. In recent years, the cancer stem cell model of tumourigenesis has received
increasing attention. This model postulates that tumours are driven and maintained by a minority
subpopulation of cells that have the capacity to self- renew and to generate the more
differentiated progeny which make up the bulk of a tumour. The former population has been
termed cancer stem cells (CSCs), tumourigenic cancer cells, or tumour-initiating cells, by
various investigators, to indicate that only these can give rise to new tumours when transplanted
into immuno-deficient animals.

Evidence for the existence of CSCs initially came from studies of acute myelogenous leukemia
(AML). Presence of CSCs have now been demonstrated in many solid tumours, including
glioblastoma, medulloblastoma, breast cancer, melanoma, and prostate cancer58. The existence
of CSCs has profound implications for cancer biology and therapy because it is likely that
eradication of CSCs is the critical determinant in achieving cure. It has been proposed that CSCs
may be particularly resistant to chemotherapy and radiation therapy as has been shown in a study
with glioblastoma. CD133+ cells were earlier suggested as the tumourigenic population in
primary glioblastoma multiforme specimens; while more recent studies have shown that these
are indeed more radioresistant compared with CD133- tumour cells, as their fraction increase
after irradiation which appears to be mainly responsible for the tumour regrowth. Therefore, it
appears that identifying and characterizing CSCs for every possible tumour is of paramount
importance and will likely lead to new therapeutic avenues. Also, work on radiosensitizers
should begin to focus on preferentially affecting CSCs compared with normal tissues and normal
tissue stem cells.

Viral biomarkers

Among viral induced cancers, hepatocellular carcinoma (HCC) is one of the most common
cancers worldwide and a leading cause of death in developing countries, where nearly 80 per
cent of the cases are reported61. Risk factors include chronic hepatitis infections mainly due to
the endemic hepatitis B virus (HBV) infection, whereas association of hepatitis C virus (HCV)
infection is also reported in a small fraction (12 - 17%) of the HCC cases61. Beside immuno-
inflammatory reactions, HBV can also promote carcinogenesis through genetic instability
generated by its common integration in host DNA. A number of different types of biomarkers
have been used to understand the aetiology and progression of HCC. Perhaps, the most well
known are the serum/plasma markers of HBV or HCV infection62. These markers include
analysis of viral DNA or proteins or antibodies produced against the viral proteins. HBV surface
antigen (HBsAg) is most frequently used to determine chronic infection with high or low viral
replication, while HBeAg is a measure of chronic infection with high viral replication63. The
other major classes of biomarkers used in studies of HCC are analysis of antibodies including
measurement of anti-HBV core antigen, anti-HBe antigen and anti-HBsAg.

Cervical cancer is the second most common cancer and predominant gynaecological cancer in
women, causing most cancer related deaths world over. There are several factors which
contribute to high incidence of this disease are early age of marriage, multiple sexual partners,
multiple pregnancies, poor genital hygiene, smoking and use of oral contraceptives. But the most
predominant aetiological factor for cervical cancer is persistent infection of certain high-risk
types of human papillomaviruses (HR-HPVs), while low risk types are associated with benign
cervical lesions and genital warts. HPV has also been detected in a significant proportion of oral,
oesophageal, anal, vaginal, vulvar, and penile cancer and in a small percentage of lung,
laryngeal, and stomach cancer, as has been shown in some parts of the world. HPV viral load, a
measure of the amount of viral DNA in biopsy specimens, alone or in conjunction with well
characterized HPV serologic assays, has been suggested to delineate the role of HPV among oral
and oropharyngeal cases, while antibodies generated in the subjects against HPV E6 and E7
serve as markers of an invasive HPV- associated malignancy67. Viral load assessment can also
be exploited to distinguish clinically relevant HPV infections in the cervix. Prophylactic
immunization of women who are negative for the HPV16 L1, E6 and E7 oncoprotein markers,
has been reported to eliminate their risk for HPV16-related cervical intraepithelial neoplasia.
Recently, the two new HPV vaccines ―Gardasil‖ and ―Cervarix‖ have been shown to be highly
immunogenic and effective in preventing infection with high-risk HPV types 16 and 18, the two
most common oncogenic types associated with this disease. Papillomaviruses were first
identified, cloned and sequenced from cervical tumour specimens and subsequently established
as important causative agents for development of cervical cancer.
Epstein-Barr virus (EBV) was the first human virus to be directly implicated in carcinogenesis. It
infects more than 90 per cent of the world‘s population, out of which a small proportion develop
tumours. Although herpesviruses are ubiquitous in nature, interestingly humans serve as the only
natural host for EBV and upon infection; the individual remains a lifelong carrier of the virus.
The vast majority of the world‘s population exhibits antibodies to EBV and the infection usually
occurs early in childhood. EBV has been implicated in the pathogenesis of Burkitt‘s lymphoma,
Hodgkin‘s disease, non-Hodgkin‘s lymphoma, nasopharyngeal carcinoma, and lymphomas, as
well as leiomyosarcomas arising in immuno-compromised individuals. EBV infection of B
lymphocytes is thought to occur in the oropharyngeal lymphoid organs, and in normal carriers,
while the virus persists in circulating memory B cells. EBV is a herpesvirus with a 184-kbp long,
double-stranded DNA genome that encodes more than 85 genes. The EBV genome is maintained
in B cells, either as a multicopy circular episome in the host cell or by integrating the viral DNA
into the host genome. The virus thus ensures transmission to cell progeny when B lymphocytes
replicate. EBV DNA in the peripheral blood predicted a high risk of distant metastases.

Detection and quantification of plasma EBV DNA serves as a useful molecular marker for
diagnosis, monitoring, and prediction of relapse in patients with nasopharyngeal carcinoma and
Hodgkin‘s lymphoma.

Thus viral biomarkers seem to have potential application in the diagnosis (particularly staging),
prognosis and predicting as well as monitoring response to therapy.

Cancer antigens (biomolecules) based biomarkers

The cancer proteome contains information on perhaps every biological process that takes place
in cancer cells, cancer tissue microenvironment, and cancer cell-host interaction. Cancer cells
release many proteins and other macromolecules into the extra- cellular fluid through secretion
that can also serve as biomarkers. Some of these products can end up in the bloodstream and
hence serve as potential serum biomarkers.

Prostate specific antigen (PSA), a 33 kDa serine protease belonging to the family of ―Kallikrein
genes‖ and produced by both normal as well as neoplastic prostate epithelial cells is the most
widely studied biomarker in prostate cancer. Among all kallikreins, hK2 and hK3 expression is
highly restricted to the prostate in males and are therefore useful as biomarkers. Being a
protease, it appears to be involved in the initiation and growth of prostate cancer by abnormal
release of growth factors or proteolysis of growth factor binding proteins. It may also have a role
in invasion and metastases through the degradation of collagen and laminin. PSA was first
identified by in 1971 while attempting to find a substance in seminal fluid that would aid in the
investigation of forensic cases. PSA was first measured quantitatively in the blood by Papsidero
and colleagues in 1980, who also reported its clinical use as a marker of prostate cancer. PSA is
present in small quantities in the serum of normal men, and is often elevated in the presence of
prostate cancer and other prostate disorders. However, prostate cancer can also be present in the
complete absence of an elevated PSA level. PSA expression is androgen dependent and therefore
less sensitive in older population. Obesity has been reported to reduce serum PSA levels, while
increase has been found in prostate infection, irritation, benign prostatic hyperplasia (BPH), and
ejaculation. Limitations of PSA as a biomarker for monitoring response to the therapy have been
identified, as increase in serum level not correlating with tumour regression following
radiotherapy has been reported in some instances. A blood test to measure PSA is considered the
most effective test currently available for the early detection of prostate cancer

Metabolic biomarker (glucose metabolism)

Enhanced glucose utilization is a prominent and fundamental change in many tumours

irrespective of their histological origin and the nature of mutatations. Mechanisms underlying
this fundamental alterations in metabolism during carcinogenesis include mutations in the
mitochondrial DNA resulting in functional impairment, oncogenic transformation linked
upregulation of glycolysis, enhanced expression of metabolic enzymes and adaptation to the
hypoxic tumour micro-milieu in case of solid tumours. Based on these observations, a
bioenergetic index of the cell (BEC index) has been suggested that could be used for
classification and prognosis of cancers, besides predicting the response to therapy. Positron
emission tomography (PET), which allows non invasive and quantitative analysis of various
biologic processes, uses a glucose analogue (2-deoxy- D-glucose) labelled with a positron
emitter Fluorine 18; FDG that is partially metabolized and trapped as its phosphate (2-DG-6-P)
in the tumour tissue thus localizing the tumour. The extent of increase in glucose utilization
measured by FDG-PET has been correlated with the degree of malignancy in some of the
tumours. Glucose utilization is also inversely correlated with treatment response in a number of
tumours, while changes in tumour glucose utilization during the first weeks of chemotherapy are
significantly correlated with patient outcome. Therefore, glucose utilization appears to be a
useful metabolic marker for diagnosis, prognosis and prediction of tumour response to a variety
of therapies.

Therapeutic biomarkers

Cytotoxic chemotherapy and radiotherapy remain the most effective treatments for cancer;
however, these can cause serious side effects as these do not often show adequate differential
effect between tumour and normal cells. Advances in understanding the molecular basis of
cancer made possible by the identification and functional analysis of tumour-specific genetic
alterations have opened exciting new opportunities for the design of therapies that specifically
target the molecular pathways involved in promoting tumour cell growth and circumvent death
pathways like apoptosis.

In the past decade, there have been considerable improvements in the way that human tumours
are characterized. Knowledge of cancer at the molecular level has therefore increased greatly,
and has catalyzed a shift towards using targeted therapies for cancer. In principle, ―targeted
therapies‖ display greater selectivity for tumour cells, and indeed several such therapies have
already shown promise in the clinic. These include small molecule drugs that inhibit the activity
of protein tyrosine kinases [e.g., imatinib and erlotinib, targeting ABL and the epidermal growth
factor receptor (EGFR), respectively] and neutralizing antibodies that inhibit trans-membrane
signaling receptors (e.g., trastuzumab, targeting HER2). Other targeted therapies include drugs
that block the activity of molecules in the host microenvironment that support tumour growth
(e.g., the antibody bevacizumab, which targets a growth factor that stimulates tumour blood
vessel growth). To date, many of these therapies have conferred only modest benefits on patient
survival, but refinements in the mode of use of these drugs (e.g., as combination therapies and
with biomarker-guided patient selection) are expected to improve their efficacy. Development of
clinical tools to identify which patients are most likely to benefit from particular targeted
therapies will aid the individualization of molecular targeted therapies thereby enhancing the
efficacy of therapy.

Glycolysis

Enhanced glucose dependency is one of the prominent characteristics of most malignant tumours
and correlate well with resistance to radio- and chemotherapy. Metabolic status linked alterations
in cell signaling related to defense against oxidative stress, redox signaling and damage response
pathways, particularly the downregulation of mitochondrial dependent apoptosis in tumour cells
with enhanced glucose usage and Hexokinase II levels have been observed. Recent observations
in many human tumour cell lines with varying degrees of glycolysis (endogenous and induced)
have shown an inverse relationship between the rate of glycolysis (glucose usage and lactate
production) and manifestation of damage induced by radiation and chemotherapeutic drugs
similar to the correlations between FDG uptake and responses to therapy clinical responses.
These observations have prompted the targeting of this phenotype (elevated glycolysis) as an
attractive proposition for developing therapeutics and adjuvant in cancer therapy.

In vitro and in vivo studies with several murine and human tumour cells have indeed shown that
glycolytic inhibitors like 2-deoxy-D-glucose, 3-bromo-pyruvate etc., are selectively cytotoxic to
tumour cells, inducing both growth inhibition and cell death. Unfortunately, therapies using
pharmacological inhibitors of glycolysis as a primary therapeutic agent have not produced
remarkable results in providing effective local tumour control, besides showing systemic
toxicity, particularly to the central nervous system. A more promising approach for improving
cancer therapy exploiting the inherent differences in glucose metabolism between tumour and
normal cells, employs 2-DG as a differential modifier of cellular responses to the widely used
therapeutic agents such as radiation and/or cytotoxic drugs. The rationale behind this approach is
based on the bioenergetics of cellular damage response pathways including DNA repair, cell
proliferation and cell death on the one hand and enhanced glucose dependency in tumour cells on
the other. Several studies using in vitro and in vivo models of tumours have shown that 2-DG
selectively sensitizes tumour cells to ionizing radiation, while reducing the damage to normal
cells. Since mechanisms underlying cellular responses to damage caused by many anticancer
drugs are similar to radiation, it has been suggested that 2-DG has the potential to enhance the
efficacy of chemotherapy. Indeed, 2-DG has been found to enhance the damage caused by
certain chemotherapeutic drugs in vitr and in vivo

Clinical trials in patients with malignant brain tumours (glioblastoma multiforme) using a
hypofractionted radiotherapy protocol combined with 2-DG have been very encouraging.
Excellent tolerance to the combined treatment, with minimal acute toxicity and late radiation
effects as well as increase in survival and significant improvement in the quality of life has been
reported.

Mammalian target of rapamycin (mTOR)

This is an evolutionarily conserved serine- threonine protein kinase that belongs to the PIKK
[phosphoinositide 3-kinase (PI3K)-related kinase] family, and plays an important role in
regulating cell growth and proliferation148. Upon activation, mTOR increases the
phosphorylation levels of its downstream targets that include p70S6K and 4EBP1, which leads to
increased levels of translation, ribosome biogenesis, and reorganization of the actin cytoskeleton
and inhibition of autophagy. As a result, mTOR activation promotes cell growth and
proliferation, whereas mTOR inhibition stops cell growth and initiates catabolic processes,
including autophagy.

The phosphatidylinositol-3-OH kinase (PI(3) K)–PTEN–mTOR signaling pathway is aberrantly

activated in many tumours, leading to dysregulation of cell growth and proliferation148.
Activation of this pathway can be assessed by biomarkers such as loss of PTEN mRNA or
protein production in tumour tissue.

Biochemical inhibition of mTOR by rapamycin can be assessed by biomarkers such as the

abundance of the phosphorylated form of the ribosomal protein S6, and its therapeutic effects on
tumour cells can be assessed by the proliferation marker Ki-67.

A number of mTOR inhibitors have potent antiproliferative properties which make them useful
for cancer chemotherapy, particularly of advanced solid tumours151. It has surprisingly been
found that S6 40S ribosomal protein (otherwise known as S6) is a useful biomarker which is
predictive of sensitivity of proliferative diseases to treatment with an mTOR inhibitor. In
particular, it has been found that the phosphorylation state of S6 correlates well with sensitivity
to mTOR inhibitors. mTOR inhibitors are more likely to show a significant antiproliferative
effect when used to treat cancer cell lines showing higher levels of expression of phosphorylated
S6. Moreover, the method may be used to select an appropriate dose of an mTOR inhibitor in
order to individualize therapy for each patient.

Telomerase

Telomeres are tracts of repetitive DNA (TTAGGG/ AATCCC for human telomeres) that protect
chromosomes from degradation and loss of essential genes. Under normal circumstances,
telomeres progressively shorten in most human cells with each cycle of cell division and the
length in adult human tissues is approximately half that of the new born. Telomerase belongs to a
class of enzymes known as reverse transcriptases that use RNA as a template for creating DNA
and it contains both RNA and protein components. The enzyme ensures the maintenance of
telomere and thereby protecting the cell from degradation and death. Since telomerase is found
in nearly 90 per cent of human cancers and is responsible for indefinite growth of cancer cells, it
has been a target for anticancer therapeutics that turn-off telomerase and thereby inhibit tumour
growth. The levels of telomerase are also elevated in stem cells allowing unlimited division
necessary for the repair of damaged and worn out tissues. Most human tumours not only express
telomerase but interestingly also have very short telomeres. Telomerase is one of the best
markers for human cancer, associated with only malignant tumours and not the benign lesions
making it a diagnostic marker as well as an ideal target for chemotherapy.

In normal cells, telomerase is sequestered in an area of the cell nucleus called the nucleolus,
away from the chromosomes. The enzyme is released only when needed during cell division, and
then returns quickly to the nucleolus thereafter. In cancer cells, however, telomerase is found
throughout the cell, implying that the telomerase-shuttling system is impaired. Identification and
manipulation of proteins normally involved in telomerase transfer could prove to be useful
targets for anti-telomerase therapies. Currently two clinical trials; one using a vaccine
(GRNVAC1) and the other a lipidated drug (GRN163L) are underway to evaluate the efficacy of
telomerase inhibitors.

The p53 gene is one of the tumour suppressor genes that normally prevent uncontrolled
multiplication of abnormal cells and experimental findings from the last two decades have
established a crucial role for wild-type p53 in intrinsic tumour suppression. Upon stimulation
(e.g., by moderate levels of DNA damage), p53 activates molecular processes that delays the cell
cycle progression of proliferating cells and simultaneously stimulating DNA repair processes. On
the other hand, higher level of damage has been found to activate p53 mediated cell death
pathway (typically apoptosis), a mechanism that is purported to be responsible for the prevention
of carcinogenesis. During malignant transformation p53 or p53-pathway related molecules are
disabled most often and a mutant form of p53 may not only negate the wild type p53 function but
plays additional role in tumour progression. Nearly 50 per cent of all human tumours carry a
mutated p53 gene. Clinical studies in patients with various types of cancer have shown that
certain mutations in the p53 gene are significant predictor of resistance to therapy.

Although p53 is not a typical cancer-specific antigen, its central role in the control of cell growth
and apoptosis and frequent mutations in tumours make p53 a unique target for cancer therapy.
Radiation and many of the anticancer drugs damage the DNA of cancer cells, triggering the
action of the p53 leading to apoptosis. Hence, an intact wild type p53 gene is essentially required
to stimulate programmed cell death of a cancer cell in response to treatment. Investigations in
several types of cancer have shown that the p53 gene is a potentially useful biomarker for
predicting prognosis and patient‘s response to therapy. Experimental evidences show that either
mutation in the gene or overexpression of the p53 protein can be used to predict many aspects of
prognosis and outcome of patients with various type of cancer.

Among the different approaches targeting p53, replacement gene therapies that have been
explored extensively in recent years aims at restoration of p53 function in cancer cells by
introduction of exogenous p53. Various protocols and vectors have been employed, including
retroviruses, adenoviruses and vaccinia- derived vectors166. Recent studies have focused on
adenoviral vectors, with Ad-p53, adenovirus serotype 5 carrying wt p53 genes, as a model
example. Although preliminary results were promising, recent clinical data failed to demonstrate
anti-tumour activity in patients and some trials have indeed been discontinued. New trials aim at
a combination of gene transfer with chemotherapy or radiotherapy. In addition to the strategy of
p53 reactivation in tumours, modulation of p53 activity in normal cells may protect them from
the side effects of chemotherapy or radiotherapy. Several new compounds targeting p53 have
entered clinical trials and therefore, p53-oriented therapy will be one of the major areas of
intense investigations in the coming years. However, the approach of restoring of p53 function in
tumour cells has been nearly questioned after a few contradictory results, which shows that
prostate cancer cells are protected from ionizing radiation-induced DNA damage through
activation of p53168 and cells transformed with oncogenic tyrosine kinase BCR/ABL may
actually benefit from activation of p53 upon DNA damage. These observations have led to the
reexamination of restoring p53 function in tumors as a therapeutic strategy.

Tyrosine kinase
as a therapeutic strategy has been very attractive and results from the recent clinical studies are
indeed quite encouraging. Current approaches include blocking kinase-substrate interaction,
inhibiting the enzyme‘s adenosine triphosphate (ATP) binding site and blocking extracellular
tyrosine kinase receptors on tumour cells. Several tyrosine kinase inhibitors (TKIs) (viz.,
gefitinib and trastuzumab) have already been approved as anti- cancer agents.

Histone deacetylases (HDACs)

Acetylation of proteins orchestra the dynamic interplay between various processes like repair of
DNA damage, cell cycle arrest and apoptosis determining the cellular response to radiation and
various chemotherapeutic drugs. This acetylation is catalyzed by histone acetylases (HATs) that
uses acetyl-CoA as substrate and the acetyl group is transferred to the € amino group of certain
lysine side chains within histones N-terminal tails and other nuclear receptor proteins thereby
regulating chromatin remodeling and gene expression. Chromatin remodeling during the
regulation of gene expression is orchestrated by a concerted action of HATs and HDACs that
condenses and decondenses the chromatin structure by acetylating and deacetylating histones
and other nuclear receptor proteins. Further, HDACs appear to be closely associated with
oncogenesis by regulating the expression of certain tumour suppressor genes leading to excessive
proliferation and tumourogenesis. HDAC have recently been among some of the attractive
targets for cancer therapeutics, and HDAC inhibitors with diversified structures have indeed
shown promising anti-tumour activity (cell cycle arrest, cellular differentiation and apoptosis)
both in vitro and in vivo. Many of the HDAC inhibitors are currently under clinical investigation
in a number of haematological malignancies and solid tumours. Further, HDAC inhibitors are
also being investigated as adjuvant together with other anti-cancer therapeutics. It appears
therefore, that HDAC inhibitors with pleiotropic actions in modulating multiple genes, signaling
pathways and biological features of malignancy are useful in the treatment of cancers with
multiple oncogenic abnormalities targeting the protein acetylation involved in the regulation of
cell signaling.

PIN1

It is well known that the functional status of many proteins is regulated by kinase mediated
phosphorylation Tyrosine kinases are a class of enzymes that regulate multiple cellular processes
by acting primarily as important transducers of extracellular signals influencing diverse functions
such as cell growth, differentiation, migration, and apoptosis that contribute to tumour
development and progression. Many human tumours display aberrant activation of tyrosine
kinases caused by genetic alterations that could be related to the malignant transformation. The
erbB or HER family of transmembrane tyrosine kinase receptors, especially receptors erbB1 (or
EGFR) and erbB2 (or Her2/neu), has been identified as an important therapeutic target in a
number of cancers. Her2/neu, is overexpressed in nearly 30 per cent of patients with aggressive
breast cancer, while EGFR is overexpressed in several solid tumours. Therefore, targeting
protein tyrosine kinases and other post-translational modifications. Recently, regulation of
proteins beyond phosphorylation has been unraveled, which is in the form Cis and Trans
isomerization (a post-phosphorylation event) of phosphoserine/threonine - proline peptide bonds
at selective sites catalyzed by peptidyl-prolyl isomerase (PPIase), Pin1. These conformational
changes can have profound effect on the function of proteins, modulating their activity,
phosphorylation status, protein-protein interactions, subcellular localization and stability.
Overexpression of Pin1 has been reported in human breast cancer cell lines and tissues, and its
expression closely correlates with the level of cyclin D1 (important cyclin required for cell
proliferation) in tumours. Pin1 overexpression not only confers transforming properties on
normal mammary epithelial cells, but also enhances transformed phenotypes of Neu/Ras-
transformed mammary epithelial cells and implicated in mitotic regulation. In contrast, inhibition
of Pin1 suppresses the Neu- and Ras induced transformed phenotypes or induces tumour cells
into mitotic arrest and apoptosis. Pin1 opens a new target for the development of specific
therapeutics and has received greater attention as phosphorylated p53 is among the known
substrates of Pin1184. Inhibition of Pin 1 through various approaches, such as mutations,
deletions or expression of antisense, induces mitotic arrest and apoptosis in tumour cell lines186.
It appears that Pin1 can be used as a diagnostic marker for the detection of the cancer or to stage
the disease, albeit in only certain types of cancers.

Recent studies have shown that treatment of cells with pin1 inhibitor juglone delays the growth
of various tumour cell lines, suggesting that inhibition of pin1 can be used as an approach for
inhibiting tumour growth. We have recently identified potential Pin1 sites on topoisomerase IIα
(a vital nuclear enzyme and mitotic protein) and shown that the two proteins functionally interact
with each other resulting in the activation of topo IIα. Moreover, using inhibitors of topo IIα
(etoposide) and Pin1 (Juglone), we have shown that the combination (etoposide and juglone)
may improve the therapeutic potential. Pin1 appears to be an attractive target for diagnosis and
therapy. Further understanding on the role of Pin1 in tumourigenesis is required before its use as
a target for developing antagonists ensuring specificity, selectivity and safety.

Well done !You have come to the end of lecture 2.You have been able to explain the rational for
life course approach to the etiology of non communicable diseases and appraise the value of
molecular biomarkers on oncological diseases.

Now take a break and reflect on some of the issues we

have discussed today. After your break, answer the following questions:

i. Explain how molecular biomarkers are used in measuring

exposure,susceptibility and disease outcome giving examples.

ii. Highlight the limitations of molecular biomarkers in measuring exposure

,susceptibility and disease outcome in epidemiological studies.
• Srinivas PR, Kramer BS, Srivastava S. Trends in biomarker research for cancer detection.
Lancet Oncol 2001; 2 : 698- 704.

• Cho WSC. Contribution of oncoproteomics to cancer biomarker discovery. Mol Cancer 2007;
6 : 25.
LECTURE 3

ROLE OF INFECTIOUS AGENTS IN THE ETIOLOGY OF NON COMMUNICABLE

DISEASES AND DETERMINANTS AND RISK FACTORS OF NCD

LECTURE OVERVIEW

In the previous lecture you learned about the use of biological biomarkers on oncological
diseases in both male and female. This lecture will look at the role of infectious agents in the
etiology of non communicable diseases and determinants and risk factors of atherosclerosis.

By the end of this lecture, you should be able to:

i.Describe the role of infectious agents in the etiology of non communicable
diseases.
ii.Describe the determinants and risk factors of atherosclerosis

A large percentage of NCDs are preventable through the reduction of their four main behavioural
risk factors: tobacco use, physical inactivity, harmful use of alcohol and unhealthy diet. The
influences of these behavioural risk factors, and other underlying metabolic/physiological causes,
on the global NCD epidemic include:

Tobacco: Almost 6 million people die from tobacco use each year, both from direct tobacco use
and second-hand smoke. By 2020, this number will increase to 7.5 million, accounting for 10%
of all deaths. Smoking is estimated to cause about 71% of lung cancer, 42% of chronic
respiratory disease and nearly 10% of cardiovascular disease. The highest incidence of smoking
among men is in lower-middle-income countries; for total population, smoking prevalence is
highest among upper-middle-income countries.

Insufficient physical activity: Approximately 3.2 million people die each year due to physical
inactivity. People who are insufficiently physically active have a 20% to 30% increased risk of
all-cause mortality. Regular physical activity reduces the risk of cardiovascular disease including
high blood pressure, diabetes.
breast and colon cancer, and depression. Insufficient physical activity is highest in high-income
countries, but very high levels are now also seen in some middle-income countries especially
among women.

Harmful use of alcohol: Approximately 2.3 million die each year from the harmful use of
alcohol, accounting for about 3.8% of all deaths in the world. More than half of these deaths
occur from NCDs including cancers, cardiovascular disease and liver cirrhosis. While adult per
capita consumption is highest in high-income countries, it is nearly as high in the populous
upper-middle-income countries.

Unhealthy diet: Adequate consumption of fruit and vegetables reduces the risk for
cardiovascular diseases, stomach cancer and colorectal cancer. Most populations consume much
higher levels of salt than recommended by WHO for disease prevention; high salt consumption is
an important determinant of high blood pressure and cardiovascular risk. High consumption of
saturated fats and trans-fatty acids is linked to heart disease. Unhealthy diet is rising quickly in
lower-resource settings. Available data suggest that fat intake has been rising rapidly in lower-
middle-income countries since the 1980s.

Raised blood pressure: Raised blood pressure is estimated to cause 7.5 million deaths, about
12.8% of all deaths. It is a major risk factor for cardiovascular disease. The prevalence of raised
blood pressure is similar across all income groups, though it is generally lowest in high-income
populations.

Overweight and obesity: At least 2.8 million people die each year as a result of being
overweight or obese. Risks of heart disease, strokes and diabetes increase steadily with
increasing body mass index (BMI). Raised BMI also increases the risk of certain cancers. The
prevalence of overweight is highest in upper-middle-income countries but very high levels are
also reported from some lower-middle income countries. In the WHO European Region, the
Eastern Mediterranean Region and the Region of the Americas, over 50% of women are
overweight. The highest prevalence of overweight among infants and young children is in upper-
middle-income populations, while the fastest rise in overweight is in the lower-middle-income
group.

Raised cholesterol: Raised cholesterol is estimated to cause 2.6 million deaths annually; it
increases the risks of heart disease and stroke. Raised cholesterol is highest in high-income
countries.

Cancer-associated infections: At least 2 million cancer cases per year, 18% of the global cancer
burden, are attributable to a few specific chronic infections, and this fraction is substantially
larger in low-income countries. The principal infectious agents are human papillomavirus,
Hepatitis B virus, Hepatitis C virus and Helicobacter pylori. These infections are largely
preventable through vaccinations and measures to avoid transmission, or treatable. For example,
transmission of Hepatitis C virus has been largely stopped among high-income populations, but
not in many low-resource countries.
Discuss the role of infectious agents in the etiology of non communicable diseases.

______________________________________________________________________________
______________________________________________________________________________
_________________________________________________________

ATHEROSCELEROSIS

Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol,

in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk
factors for atherosclerosis, the process of atherogenesis has been considered by many to consist
largely of the accumulation of lipids within the artery wall; however, it is much more than that.
Despite changes in lifestyle and the use of new phar- macologic approaches to lower plasma
cholesterol concentrations, cardiovascular disease continues to be the principal cause of death. In
fact, the lesions of atherosclerosis represent a series of highly specific cellular and molecular
responses that can best be described, in aggregate, as an inflammatory disease.

The lesions of atherosclerosis occur principally in large and medium-sized elastic and muscular
arteries and can lead to ischemia of the heart, brain, or extremities, resulting in infarction. They
may be present throughout a person‘s lifetime. In fact, the earliest type of lesion, the so-called
fatty streak, which is common in infants and young children is a pure inflammatory lesion,
consisting only of monocyte-derived macrophages and T lymphocytes. In persons with
hypercholesterolemia, the influx of these cells is preceded by the extracellular deposition of
amorphous and membranous lipids.

FACTORS THAT INDUCE AND PROMOTE INFLAMMATION OR

ATHEROGENESIS

Numerous pathophysiologic observations in humans and animals led to the formulation of the
response-to-injury hypothesis of atherosclerosis, which initially proposed that endothelial
denudation was the first step in atherosclerosis. Possible causes of endothelial dysfunction
leading to atherosclerosis include elevated and modified LDL; free radicals caused by cigarette
smoking, hypertension, and diabetes mellitus; genetic alterations; elevated plasma homocysteine
concentrations; infectious microorganisms such as herpesviruses or Chlamydia pneumoniae; and
combinations of these or other factors. Regardless of the cause of endothelial dysfunction,
atherosclerosis is a highly character- istic response of particular arteries.

The endothelial dysfunction that results from the injury leads to compensatory responses that
alter the normal homeostatic properties of the endothelium. Thus, the different forms of injury
increase the adhesiveness of the endothelium with respect to leukocytes or platelets, as well as its
permeability. The injury also induces the endothelium to have procoagulant instead of
anticoagulant properties and to form vasoactive molecules, cytokines, and growth factors. If the
inflammatory response does not effectively neutralize or remove the offending agents, it can
continue indefinitely. In doing so, the inflammatory response stimulates migration and
proliferation of smooth muscle cells that become intermixed with the area of inflammation to
form an intermediate lesion. If these responses continue unabated, they can thicken the artery
wall, which compensates by gradual dilation, so that up to a point, the lumen remains unaltered,
a phenomenon termed ―remodeling.‖ As for the inflammatory cells, granulocytes are rarely
present during any phase of atherogenesis. Instead, the response is mediated by monocyte
derived macrophages and specific subtypes of T lymphocytes at every stage of the disease.

Continued inflammation results in increased numbers of macrophages and lymphocytes, which

both emigrate from the blood and multiply within the lesion. Activation of these cells leads to the
release of hydrolytic enzymes, cytokines, chemokines, and growth factors, which can induce
further damage and eventually lead to focal necrosis. Thus, cycles of accumulation of
mononuclear cells, migration and proliferation of smooth-muscle cells, and formation of fibrous
tissue lead to further enlargement and re- structuring of the lesion, so that it becomes covered by
a fibrous cap that overlies a core of lipid and necrotic tissue a so-called advanced, complicated
lesion. At some point, the artery can no longer compensate by dilation; the lesion may then
intrude into the lumen and alter the flow of blood.

Among the diseases in the western world, atherosclerosis is overwhelmingly the prime disorder
leading to death and serious morbidity. Despite recent reduction in mortality of coronary heart
diseases (CHD) about 50% of all deaths in US are still attributable to atherosclerosis related
diseases. The developing countries such as India, Singapore, Malaysia and Sri Lanka are
catching up and registering a steady increase in the mortality rates due to atherosclerotic heart
diseases.In India coronary heart disease accounts for 10-15% of all cardiovascular diseases.

The exact global incidence of atherosclerosis is impossible to calculate because it can exist
without producing any symptoms or signs. These asymptomatic cases can be diagnosed only if
an autopsy is done, in all cases of death due to any cause. However, the magnitude of the
problem can be assessed by looking at the mortality rates in different countries due to
atherosclerotic heart disease. In a survey conducted in males in the 45 to 54 years age group,the
mortality rates due to atherosclerotic heart disease in different countries are lowest in Japan (8%)
and highest in Finland (41%). In U.K., U.S.A., and Canada the average mortality rate is 36%.
The disease is increasing in countries undergoing industrialization.

Unfortunately, in India there are no statistics giving the national incidence of this
disorder.However, Padmavathi and associates, gave the average incidence of atherosclerotic
heart disease in seven different states during 1958-59 as 0.51% per 1,000 population. In another
study conducted at All India Institute of Medical sciences, New Delhi, with the help of autopsy
studies and taking atherogenic index as an indicator, the incidence of coronary heart disease is
given as 35.5% in males and in females as 14%.5

Although global incidence, a wide range of variation in the prevalence and severity of
atherosclerosis has been shown to exist in different geographic population.
PREVENTION

Remaining totally free of atherosclerosis is impossible for anyone over the age of 50. However,
there is a great deal that you can do to reduce the risk of significant atherosclerosis, with all of
the consequences that follow from it.

For most people, lifestyle choices contribute strongly to the development—or reduction—of
atherosclerosis. One of the most important single factors is stopping smoking. This is a difficult
task for most smokers, but can give immediate and long-lasting benefits. Stopping smoking
reduces the risk of atherosclerosis, but also reduces the risk of lung and other cancers,
emphysema, and many other serious illnesses.

Losing weight is appropriate for most people at risk for atherosclerosis. The two key factors in
losing weight are to increase activity and to eat appropriately. A minimum of 30 minutes of
moderate activity, at least three times a week, is necessary for weight loss and for heart
health. If you have been inactive for a period of time, check in with your physician before
starting an exercise program. Appropriate eating habits for most people who are overweight
involve eating less of everything, especially high-fat foods and sweets.

The other crucial part of avoiding atherosclerosis involves your doctor‘s help. Having regular
preventive health checkups will allow a chance to diagnose problems such as diabetes, high
blood pressure, and high levels of cholesterol in your blood. Treatment of all of these problems,
with lifestyle changes and appropriate medication if necessary, is proven to reduce the risk of
serious consequences such as heart attack or stroke. In the prevention of atherosclerosis, the use
of cholesterol-lowering medication referred to as ―statins‖, for individuals with LDL- cholesterol
levels above target may reducie deaths or hospital admissions due to heart attack.

SIGNS AND SYMPTOMS

Sometimes the first symptom of atherosclerosis is a heart attack or stroke. Symptoms of

atherosclerosis depend on where the affected artery is located and whether it has gradually
become narrowed or suddenly blocked. Sudden blockage can cause a heart attack (if the arteries
supplying blood to the heart muscle are blocked), a stroke (if the arteries supplying blood to the
brain are blocked) or gangrene of a toe, foot or leg (if the arteries supplying blood to the leg are
blocked).

If the artery is narrowed rather than blocked, atherosclerosis usually doesn‘t cause symptoms
until the inside of the artery has been narrowed by more than 70%. In this case, the first symptom
is often pain or cramps whenever the blood flow can‘t keep up with the muscles‘ need for
oxygen. This can cause chest pain (angina) while exercising if the heart muscle is affected, or leg
pain while walking if the leg muscles are affected.

DIAGNOSIS

A person with symptoms that suggest a blocked artery may have tests done to discover the
location and severity of the artery blockage. For example:

• An angiogram is an x-ray study in which dye is used to detect a blockage or other problem in
the arteries supplying blood to the heart. It may be used in patients with chest pain or suspected
blockage of the arteries feeding the heart.

An exercise electrocardiogram (ECG) or ―stress test‖ measures your heart‘s electrical activity,
blood pressure and heart rate while you exercise, usually by walking on a treadmill. It is usually
done to determine the cause of unexplained chest pain, especially if atherosclerosis of the arteries
supplying the heart is suspected.

In anyone with symptoms possibly caused by atherosclerosis, doctors will also test blood
pressure, blood sugar and blood cholesterol levels to look for risk factors that may have
contributed to the problem. These tests are also usually done as part of an annual physical exam
in adults.

Treatment

If atherosclerosis becomes severe enough to cause complications (such as angina, heart attack,
heart failure, stroke, kidney failure, leg cramps or gangrene), these complications must be treated
directly. In addition, however, treatment is usually recommended for the risk factors that have
been making the atherosclerosis worse.

Lifestyle changes are a good idea both for those who have already had a complication of
atherosclerosis and for those at risk of such a complication. Stopping smoking, losing weight,
eating a better diet and exercising more can all slow down the development of atherosclerosis
and/or reduce the risk of a heart attack or stroke.

People with atherosclerosis also may benefit from taking certain drugs. Someone who has
already had a heart attack is often prescribed a beta-blocker, because these drugs reduce the risk
of death by about 25%. Low-dose aspirin (such as one baby aspirin or half of an adult aspirin
daily) can help prevent blood clots and reduces the risk of a heart attack or stroke in people at
particularly high risk. Cholesterol-lowering drugs such as statins may also reduce these risks,
even in people who have normal cholesterol levels.

You have come to the end of this lecture.you have discussed the role of infectious agents in the
etiology of non communicable diseases and also the atherosclerosis disease.
 Having had successfully completed this lecture, answer
the following questions:

i. Explain the epidemiology of atherosclerosis.

ii. Outline the signs and symptoms of atherosclerosis.

iii. Describe the control and preventive measure of atherosclerosis.

Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart dis- ease with pravastatin in
men with hypercholesterolemia. N Engl J Med 1995.

Breslow JL. Cardiovascular disease burden increases, NIH funding decreases. Nat Med 1997.

LECTURE 4

CARDIOVASCULAR DISEASES
 LECTURE REVIEW

CVDs include diseases of the heart, vascular diseases of the brain and diseases of blood vessels.
CVDs are responsible for over 17.3 million deaths per year and are the leading causes of death in
the world.

The majority of cardiovascular disease (CVD) is caused by risk factors that can be controlled,
treated or modified, such as high blood pressure, cholesterol, overweight/obesity, tobacco use,
lack of physical activity and diabetes. However, there are also some major CVD risk factors that
cannot be controlled.

• In terms of attributable deaths, the leading CVD risk factor is raised blood pressure (to which
13 per cent of global deaths is attributed), followed by tobacco use (9 per cent), raised blood
glucose (6 per cent), physical inactivity (6 per cent)

• and overweight and obesity (5 per cent) CVDs are the leading causes of death
and disability in the world.
By the end of this lecture, you should be able to:
Although a large proportion of CVDs is preventable they continue
to rise mainly eventive measures are inadequate.
i. Describe the determinants and risk factors of
Out of the 17.3 million cardiovascular
cerebrovascular diseases. deaths in 2008, heart attacks
were responsib 7.3 million

Types of cardiovascular
Stroke
Strokes are caused by disruption of the blood supply to the brain. This may result from either
blockage (ischaemic stroke) or rupture of a blood vessel (haemorrhagic stroke).
Risk factors High blood pressure, atrial fibrillation (a heart rhythm disorder), high blood
cholesterol, tobacco use.

Coronary heart disease

Disease of the blood vessels .
Rheumatic heart disease
Damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal
bacteria.
 Congenital heart disease
Malformations of heart structures existing at birth may be caused by genetic factors or by
adverse exposures during gestation. Examples are holes in the heart, abnormal valves, and
abnormal heart chambers.
Other cardiovascular diseases
Tumours of the heart; vascular tumours of the brain; disorders of heart muscle (cardiomyopathy);
heart valve diseases; disorders of the lining of the heart.

Modifiable risk factors:

Hypertension (high blood pressure)

• Globally, nearly one billion people have high blood pressure (hypertension); of these, two-
thirds are in developing countries.

• Hypertension is one of the most important causes of premature death worldwide and the
problem is growing; in 2025, an estimated 1.56 billion adults will be living with
hypertension.

• Hypertension is the leading cause of CVD worldwide.

• People with hypertension are more likely to develop complications of diabetes.

• High blood pressure is called the ―silent killer" because it often has no warning signs or
symptoms, and many people do not realize they have it; that is why it's important to get
blood pressure checked regularly.

Tobacco use

• Smoking is estimated to cause nearly 10 per cent of all CVD.

• The risk of developing CVD is higher in female smokers, young men, and heavy smokers.

• There are currently about 1 billion smokers in the world today.

• Within two years of quitting, the risk of coronary heart disease is substantially reduced, and
within 15 years the risk of CVD returns to that of a non-smoker.

Blood pressure is measured as two numbers, written one over the other and recorded in
millimetres of mercury – for example, 120/78 mm Hg. The top (higher) number is the systolic
pressure – the pressure in the arteries as the heart is contracting – and the bottom (lower) number
is the diastolic pressure – the pressure in the arteries when the heart is relaxed between beats.
High blood pressure is defined as a repeatedly elevated systolic pressure of 140 or higher OR a
diastolic pressure of 90 or higher.

Raised blood glucose (diabetes)

• Diabetes is defined as having a fasting plasma glucose value of 7.0 mmol/l (126 mg/dl) or
higher.

• In 2008, diabetes was responsible for 1.3 million deaths globally.

• In 2008, the global prevalence of diabetes was estimated to be 10 per cent.

• CVD accounts for about 60 per cent of all mortality in people with diabetes.

• The risk of cardiovascular events is from two to three times higher in people with type 1 or
type 2 diabetes and the risk is disproportionately higher in women.

• In some age groups, people with diabetes have a two-fold increase in the risk of stroke.

• Patients with diabetes also have a poorer prognosis after cardiovascular events compared to
people without diabetes.

• Cardiovascular risk increases with raised glucose values.

• Lack of early detection and care for diabetes results in severe complications, including heart
attacks, strokes, renal failure, amputations and blindness.

• Primary care access to measurement of blood glucose and cardiovascular risk assessment as
well as essential medicines including insulin can improve health outcomes of people with
diabetes.

Physical inactivity

• Insufficient physical activity can be defined as less than five times 30 minutes of moderate
activity per week, or less than three times 20 minutes of vigorous activity per week, or
equivalent.

• Insufficient physical activity is the fourth leading risk factor for mortality.

• Approximately 3.2 million deaths and 32.1 million DALYs† – representing about 2.1 per cent
of global DALYs – each year are attributable to insufficient physical activity.

• People who are insufficiently physically active have a 20 to 30 per cent increased risk of all-
cause mortality compared to those who engage in at least 30 minutes of moderate
intensity physical activity most days of the week.
• In 2008, 31.3 per cent of adults aged 15 or older (28.2 per cent men and 34.4 per cent women)
were insufficiently physically active.

• The prevalence of insufficient physical activity is higher in high-income countries compared to

low-income countries due to increased automation of work and use of vehicles for
transport in high-income countries.

• High-income countries have more than double the prevalence of insufficient physical activity
compared to low-income countries for both men and women, with 41 per cent of men and
48 per cent of women being insufficiently physically active in high-income countries
compared to 18 per cent of men and 21 per cent of women in low-income countries.

Unhealthy diet

• High dietary intakes of saturated fat, trans-fats and salt, and low intake of fruits, vegetables
and fish are linked to cardiovascular risk.

• Approximately 16 million (1.0 per cent) DALYs and 1.7 million (2.8 per cent) of deaths
worldwide are attributable to low fruit and vegetable consumption.1

• The amount of dietary salt consumed is an important determinant of blood pressure levels and
overall cardiovascular risk and the WHO recommends a population salt intake of less
than 5 grams/person/day to help the prevention of CVD.

• Frequent consumption of high-energy foods, such as processed foods that are high in fats and
sugars, promotes obesity compared to low-energy foods.

• High consumption of saturated fats and trans-fatty acids is linked to heart disease; elimination
of trans-fat and replacement of saturated with polyunsaturated vegetable oils lowers
coronary heart disease risk.

• Adequate consumption of fruit and vegetables reduces the risk of CVD.

• A healthy diet can contribute to a healthy body weight, a desirable lipid profile and a
desirable blood pressure.

• It is estimated that decreasing dietary salt intake from the current global levels of 9–12
grams/day to the recommended level of 5 grams/day would have a major impact on blood
pressure and CVD.

Cholesterol/lipids

• Raised blood cholesterol increases the risk of heart disease and stroke.

• Globally, one third of ischaemic heart disease is attributable to high cholesterol.

 • Overall, raised cholesterol is estimated to cause 2.6 million deaths (4.5 per cent of total) and
29.7 million DALYS, or 2 per cent of total DALYS globally.

• In 2008, the prevalence of raised total cholesterol among adults – defined as total cholesterol
of 6.2 mmol/l (240 mg/dl) or higher – was 9.7 per cent (8.5 per cent for males and 10.7
per cent for females).

• Lowering raised blood cholesterol reduces the risk of heart disease.

• In 2008, the global prevalence of raised total cholesterol among adults was 39 per cent (37
per cent for males and 40 per cent for females).

• The prevalence of raised total cholesterol noticeably increases according to the income level of
the country. In low-income countries, around 25 per cent of adults have raised total
cholesterol, while in high-income countries, over 50 per cent of adults have raised total
cholesterol.

Overweight and obesity

• Obesity is strongly related to major cardiovascular risk factors such as raised blood
pressure, glucose intolerance, type 2 diabetes and dyslipidaemia.

• Worldwide, at least 2.8 million people die each year as a result of being overweight or
obese, and an estimated 35.8 million (2.3 per cent) of global DALYs are caused
by overweight or obesity.

• In 2008, 34 per cent of adults over the age of 20 were overweight with a body mass index
(BMI, a measure of weight relative to height).

• In 2008, 9.8 per cent of men and 13.8 per cent of women were obese (with a BMI greater than
or equal to 30 kg/m2), compared to 4.8 per cent for men and 7.9 per cent for women in 1980.

• To achieve optimal health, the median BMI for adult populations should be in the range of 21–
23 kg/m2, while the goal for individuals should be to maintain a BMI in the range 18.5– 24.9
kg/m2.

• The prevalence of raised BMI increases with income level of countries, up to upper-middle-
income levels. The prevalence of overweight in high-income and upper-middle-income
countries was more than double that of low- and lower-middle-income countries.

• For obesity, the difference more than triples from 7 per cent obesity for both males and
females in lower-middle-income countries to 24 per cent in upper-middle- income countries.

Non-modifiable risk factors:

• In addition to the modifiable risk factors, there are some risk factors that cannot be changed.
However, people in these high-risk categories should receive regular check-ups.

Age

• CVD becomes increasingly common with advancing age. As a person gets older, the
heart undergoes subtle physiologic changes, even in the absence of disease.

• The heart muscle of the aged heart may relax less completely between beats, and as a
result, the pumping chambers become stiffer and may work less efficiently.

• When a condition like CVD affects the heart, these age-related changes may compound
the problem or its treatment.

Gender

• A man is at greater risk of heart disease than a pre-menopausal woman. Once past the
menopause, a woman‘s risk is similar to a man‘s. Risk of stroke, however, is similar for men and
women.

Family history

• A family‘s history of CVD indicates a person‘s risk. If a first-degree blood relative has had
coronary heart disease or stroke before the age of 55 years (for a male relative) or 65 years (for a
female relative), the risk increase.

Behavioural risk factors:

1. tobacco use 2. physical inactivity 3. unhealthy diet (rich in salt, fat and calories) 4. harmful
use of alcohol.

Metabolic risk factors:

• raised blood pressure (hypertension)

• raised blood sugar (diabetes)

• raised blood lipids (e.g. cholesterol)

• overweight and obesity.

Other risk factors:

• poverty and low educational status

• advancing age
• gender

• inherited (genetic) disposition

• psychological factors (e.g. stress, depression)

• other risk factors (e.g. excess homocysteine).

Activity 4.1

1.Describe the clinical presentation cardiovascular diseases.

______________________________________________________________________________
______________________________________________________________________________
2.Explain the diagnosis and treatment of cardiovascular diseases.

______________________________________________________________________________
______________________________________________________________________________

Prevention and control of cardiovascular diseases

 Congratulations .You have come to the end of this lecture where you have
discussed the epidemiology ,determinants and risk factors of cardiovascular
diseases.

Now take a break and reflect on some of the issues we

have discussed today. After your break, answer the following questions:

i. Explain the epidemiology of cardiovascular diseases.

_________________________________________________________
_________________________________________________________

ii. Explain the modifiable risk factors of cardiovascular diseases.

_______________________________________________________________
____________________________________________________

References

1 Global Atlas on Cardiovascular Disease Prevention and Control. Mendis S, Puska P, Norrving
B editors. World Health Organization (in collaboration with the World Heart Federation and

2.Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease.
Hypertension. 2001;
LECTURE 5

CEREBROVASCULAR DISEASES

LECTURE OVERVIEW

Cerebrovascular diseases (CD) are a global health problem. They are the second cause of death
in the developed world, the first cause of adult disability and the second cause of dementia.
According to World Health Organization (WHO) data, 15 million people suffer a stroke every
year; of these, 5.5 million die (10% of total deaths) and another 5 million are left with some
permanent disability. It is estimated that the 38 million days of healthy life lost in 1990 from
stroke will become 61 million by 2020.

In the last 20 years, developed countries have experienced a 29% decrease in the incidence of all
types of stroke; and, with the exception of cerebral hemorrhage (CH), a 25% stroke mortality
reduction. Greater burdens of chronic disease are emerging in developing countries, and of
cerebrovascular diseases in particular. These are coupled with serious burdens of infectious
diseases, a pattern that is expected to continue until the year 2020.Today, cardiovascular and
cerebrovascular diseases cause twice the number of deaths as do HIV, malaria, and tuberculosis
combined.

Due to the aging of many populations in the world, projections for year 2020 seem to indicate
that stroke will continue to be the second cause of death both in developed and developing
countries. In terms of disability, it will be among the five major contributors to disease burden.
CD also imply huge economic burdens for health systems due to the resources needed to provide
care for acute phase patients and long-term care for survivors, with the concomitant social
implications.

At the same time, psychological and social changes associated with migration to urban or semi-
urban areas or rapid urbanization of human settlements prompt changes in living conditions and
lifestyles, including the adoption of harmful food consumption pat- terns and habits that facilitate
development of chronic diseases.

In Cuba, CD are the third cause of death. In 2006, there were 8,347 deaths by stroke, for a crude
rate of 74.0 and an age- adjusted rate of 42.2 per 100,000 in the healthy population. Moreover,
according to estimates based on year 2000 data, CD are the fifth cause of years of healthy life
lost (YPLL).Although the greatest impact was felt by persons aged ≥65 years, CD were a major
cause of premature mortality – 16.1 per 100,000 population in 2002 .
 CD are linked to habits, lifestyles, and risk factors that can be identified early and for which
prevention and control measures can be implemented.

By the end of this lecture, you should be able to:

i. Describe the epidemiology of cerebrovascular diseases

ii. identify the determinants and risk factors of cerebrovascular diseases.
iii.Describe the prevention and control of cerebrovascular diseases.

Determinants and risk factors of cerebrovascular

They are:
• high blood pressure (hypertension)
• atrial fibrillation (a form of irregular heartbeat)
• smoking
• poor diet
• high blood cholesterol
• lack of exercise
• being overweight or obese
• diabetes
• excessive alcohol consumption
• stress
Many of the risk factors for cerebrovascular disease are linked, which means if you have one, it's
likely you'll also have others. For example, someone who's overweight or obese is more likely to
have high blood pressure, high cholesterol and diabetes.

To significantly reduce the risk of cerebrovascular disease, you need to look at your lifestyle as a
whole. In particular, you need to consider:
• your weight
• your diet
• how active you are and the amount of regular exercise you do
• whether you need to stop smoking
• how much alcohol you drink
• your stress levels
As well as reducing your risk of developing cerebrovascular disease, making changes to your
lifestyle will also lower your risk of getting other serious health conditions, such as coronary
heart disease, heart attack and cancer.
High blood pressure
High blood pressure (hypertension) is a significant risk factor for cerebrovascular disease.
The increase in blood pressure damages the walls of the brain's blood vessels, increasing the
risk of a blood clot forming or an artery rupturing (splitting). Both of these can trigger a stroke.
If you have high blood pressure, you're four times more likely to have a stroke than someone
with healthy blood pressure.
You can prevent high blood pressure by excercising regularly, eating healthily, not smoking
and drinking alcohol in moderation.However, hypertension is still common, even in people who
have a healthy lifestyle, and treatment with medication is usually required. It's therefore
important to have your blood pressure checked from time to time.

Atrial fibrillation
Atrial fibrillation is a common disorder that causes the heart to beat irregularly. It can occur
without any symptoms, but clots can form in the heart, which can break off and travel to the
brain and cause a stroke.
Atrial fibrillation can be treated to prevent stroke, so if you have a pulse that beats irregularly or
you have undiagnosed palpitations, you should visit your GP to test for the condition.
High blood cholesterol
High blood cholesterol can cause your arteries to narrow, increasing your risk of developing a
blood clot.
Smoking
The toxins in tobacco can damage and narrow the blood vessels that supply the brain. Smoking
also causes high blood pressure.
It's estimated that a person who smokes 20 cigarettes a day is six times more likely to have a
stroke than someone who doesn't smoke.
Diet
A diet that contains a high amount of saturated fat and salt can lead to high blood pressure, high
cholesterol and narrowing of the arteries, which all increase your risk of cerebrovascular disease.
A low-fat, high-fibre diet that includes whole grains and at least five portions of fresh fruit and
vegetables a day is recommended for a healthy heart and brain.
Limit the amount of salt in your diet to no more than 6g (0.2oz or 1 teaspoon) a day. Too much
salt will increase your blood pressure.

Also, avoid eating foods high in saturated fat because they'll increase your cholesterol level.
Foods that contain high levels of saturated fat include:
• meat pies
• sausages and fatty cuts of meat
• butter
• ghee – a type of butter often used in Indian cooking
• hard cheese
• cakes and biscuits
Foods high in unsaturated fat can help decrease your cholesterol level. These foods include:
• oily fish
• avocados
• nuts and seeds
• olive oil

Exercise
Not exercising regularly puts you at risk of developing high blood pressure and high cholesterol.
Being physically inactive also increases your chances of becoming overweight.
To maintain a good level of health, the Department of Health recommends you do at least:
• 150 minutes (2 hours and 30 minutes) of moderate-intensity aerobic activity, such as cycling
or fast walking, every week,
and
• muscle-strengthening activities on two or more days a week that work all major muscle groups
(the legs, hips, back, abdomen, chest, shoulders and arms)
Weight
Being overweight or obese increases your risk of developing a number of serious health
conditions, such as diabetes and high blood pressure.
To lose weight, you need to combine regular exercise with a calorie-controlled diet. After you've
reached your ideal weight, you should aim to maintain it by eating healthily and exercising
regularly.
You can use the healthy weight calculator to calculate your body mass index (BMI) and get tips
about how to lose weight. You can also read more about losing weight.
Diabetes
The high blood sugar levels associated with diabetes can damage the body's organs and arteries.
If you have type 1 diabetes, regular insulin treatment should keep your blood sugar levels
normal.
If you have type 2 diabetes, it may be possible to control your symptoms by making simple
lifestyle changes, such as exercising regularly and eating healthily. However, you may need
medication (tablets or injections) to keep your blood glucose normal.

Alcohol
Drinking excessive amounts of alcohol can increase your cholesterol and blood pressure
levels, and increases the risk of bleeding into the brain.
You shouldn't exceed the recommended daily alcohol limits. These are:
• 3-4 units a day for men
 • 2-3 units a day for women
One pint of ordinary strength beer, lager or cider contains two units of alcohol, and a single pub
measure (25ml) of spirits contains one unit. A small glass of wine (125ml) contains 1.5 units of
alcohol.
Visit your GP if you're finding it difficult to moderate your drinking. Treatments such
as counselling and medication are available to help you reduce your alcohol intake..
Stress
Reducing the amount of stress in your life may help you control your blood pressure, as well
as keeping your blood sugar levels under control. Both of these will help reduce your risk of
getting cerebrovascular disease.
Regular exercise has been shown to reduce stress levels, as have relaxation techniques such as
deep breathing and yoga.
Medication
If your risk of getting cerebrovascular disease is thought to be particularly high, medication may
be prescribed to help reduce the risk.
For example, you may be prescribed:
• statins – to help lower blood cholesterol levels
• anticoagulants (blood-thinning medication) – such as warfarin to help prevent blood clots from
heart disease or atrial fibrillation
• antiplatelet agents – such as low-dose aspirin or clopidogrel to prevent blood clots from blood
vessel diseases
• angiotensin-converting enzyme (ACE) inhibitors or a calcium blocker – to treat high blood
pressure
Activity 5.1

1.Outline the signs and symptoms of cerebrovascular diseases

______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
 Well done. You have successfully completed lecture 5 where you have discussed the
epidemiology ,risk factors and control and prevention of cerebrovascular diseases.

Now take a break and reflect on some of the issues we

have discussed today. After your break, answer the following questions:

i.Describe the epidemiology of cerebrovascular diseases.

ii.Explain the control and prevention of cardiovascualar diseases.

• Bejot Y, Benatru I, Rouauda O, Fromont A, Be- sancenot JP, Moreau T. Epidemiology of

stroke in Europe: Geographic and environmental differ- ences. J Neurol Sci. 2007.
• Mackay J, Mensah GA. Deaths from stroke. In: The Atlas of Heart Disease and Stroke. World
Health Organization. WHOLIS[Internet data base]. [Accessed on February 11, 2008].
Available from: http://whqlibdoc.who.int/ publications/2004
• Mackay J, Mensah GA. Burden from stroke. In: The Atlas of Heart Disease and Stroke. World
Health Organization. WHOLIS [Inter- net data base]. [Accessed on February 11, 2008].
Available from: http://whqlibdoc.who.int/ publications/2004/
LECTURE 6
DIABETES MELLITUS
LECTURE REVIEW
Welcome to lecture 6.In the previous lecture you discussed about cerebrovascular diseases.This
lecture will discuss diabetes mellitus.

By the end of this lecture, you should be able to:

i.Describe the epidemiology of diabetes mellitus.

ii.Differentiate between types1 and type 2 diabetes mellitus.
iii.Outline the signs and symptoms of diabetes mellitus.
iv. Describe the control and prevention of dibetes mellitus.

Diabetes Mellitus is a disorder caused by the total (or relative) abscence of insulin, which
manifests clinically as an elevated blood glucose. The classification of diabetes mellitus has been
a major discussion point over the last few years. It has been increasingly recognised that the old
classification system based upon a patients‘ dependence on insulin was misleading; under the old
system patients were either classified as either Insulin Dependent Diabetes Mellitus (IDDM) or
Non Insulin Dependent Diabetes Mellitus (NIDDM). In 1998, a new classification system based
upon the aetiological factors at work in diabetes was proposed by the WHO and we have listed it
below: this has now become the accepted system for classifying diabetes mellitus.

Type 1 diabetes: immune mediated and idiopathic forms of b cell dysfunction, which lead to
absolute insulin deficiency. This is an autoimmune mediated disease process which gives rise to
absolute deficiency of insulin and therefore total dependancy upon insulin for survival.

Type 2 diabetes: disease of adult onset, which may originate from insulin resistance and relative
insulin deficiency or from a secretory defect. This is a disease, which appears to have a very
strong genetic predisposition and is caused by a combination of inadequate insulin secretion and
an insensitvity of the body tissues to insulin so leaving patients with this condition relatively
deficient in insulin.

Type 3 diabetes: this covers a wide range of specific types of diabetes including various genetic
defects in insulin action, and diseases of the exocrine pancreas.

Type 4 diabetes is gestational diabetes.

THE EPIDEMIOLOGY OF DIABETES.

Diabetes places a huge burden of illness on sufferers and society. People with diabetes in the age
group 45-64 years are 23 times more likely to be registered blind than the non diabetic
population of the same age. Diabetic retinopathy is the lead cause of blindness in this age group.
Diabetes often affects the kidneys and up to 40% of people who develop Type 1 diabetes before
the age of 30 years can expect to develop diabetes related nephropathy. A significant number of
these will progress to renal failure requiring long term renal dialysis treatment. 30% of people
with diabetes develop diabetic neuropathy leading to a range of problems including from foot
ulceration, sexual difficulties, cardiac arrhythmias and sudden death.

Mortality

It is thought that 20 000 people per year die prematurely because of diabetes associated disease.
Most of these deaths are from the macrovascular complications of diabetes such as myocardial
infarcts and cerebrovascular accidents. The number of people dying prematurely in the diabetic
population is double that of the non diabetic population.

Clinical Features and Aetiology

Type 1 diabetes typically presents in the teens with a short history of weight loss, incredible
thirst and polyuria (passing lots of urine). Such patients are often thin, there is very often no
family history of diabetes and although the cause of the illness is not known, it is thought to be
triggered by a viral infection.

Type 2 diabetes typically presents later in life. Such patients are often overweight at diagnosis
and there is often a strong family history of the disease. It is not known why the disease develops
but it may be related to over-eating. In contrast to type 1 diabetes, patients with type 2 diabetes
are often asymptomatic when it is diagnosed and the diagnosis is often made whilst a doctor is
investigating some other complaint.

CONTROL AND PREVENTION

The implementation of a national diabetes programme should address primary, secondary and
tertiary prevention. While there is not yet conclusive evidence to suggest that type 1 diabetes
mellitus can be prevented, primary prevention of type 2 is possible.

Primary prevention has an impact by reducing both the need for diabetes care and the
need to treat diabetic complications .Secondary and tertiary preventions are key to reducing the
risk of costly diabetic complications, as well as their associated disabilities. There is great
potential for tertiary prevention in diabetes, especially with regard to blindness, limb amputation
and adverse pregnancy outcomes. Rehabilitation and special assistance are required for those
who do develop disabling complications. Overall, action taken early in the course of diabetes is
more beneficial in terms of quality of life as well as being more cost-effective, especially
if this action can prevent hospital admission.

Many barriers exist at the prevention level, including:

• lack of knowledge and awareness by individuals and communities;
• inadequately trained personnel in the preventive health care field;
• inadequate use of media for creating awareness for health education;
• changing of deeply-rooted lifestyles is very difficult;
• social problems.
Primary prevention
Lifestyle changes aimed at weight control and increased physical activity are important
objectives in the prevention of type 2 diabetes mellitus. The benefits of reducing body weight
and increasing physical activity are not confined to type 2 diabetes, they also play a role in
reducing heart disease and high blood pressure. Lifestyle is the key to reversing these trends.
Ministries of health, other ministries and the private sector need to have a commitment to a
healthy lifestyle in order to reduce the risk of type 2 diabetes and its complications developing in
populations. The management of high blood pressure and raised blood lipids is equally important
physical inactivity and unhealthy diets as strong risk factors for diabetes mellitus. A reasonable
exercise programme and a modest amount of weight loss led to a marked decrease in diabetes
incidence by more than 50%.
Due to the importance of the prevention of type 2 diabetes and its complications, Eastern
Mediterranean countries should give priority to the development of community-based healthy
lifestyle programmes that focus on:
• maintaining a ‗healthy‘ weight
• an active lifestyle which includes regular physical activity
• early identification of subjects at risk of developing type 2 diabetes mellitus
• identifying subjects at high risk of noncommunicable diseases, such as hypertension,
diabetes and heart disease;
• optimal maternal nutrition and weight maintenance.

• introduction of healthy lifestyle programmes in the early school years. These should
focus on the prevention of risk factors, which will predispose to non communicable
diseases in later life;
• cessation of smoking

Secondary prevention
The primary purpose of secondary prevention activities such as screening is to identify
individuals without symptoms who already have the disease, are at high risk of developing
complications related to the primary disease, and where intervention could have a beneficial
effect. Secondary prevention is the key to reducing the risk of costly and disabling diabetic
complications. There is now conclusive evidence that good control of blood glucose levels can
substantially reduce these complications.
.
Tertiary prevention

Tertiary prevention of diabetes includes every action taken to prevent or delay

the consequences of diabetic complications, such as blindness, foot amputation and
adverse pregnancy outcomes. Strategies for tertiary prevention involve prevention of
the development of complications by strict metabolic control, education and effective
treatment. They also involve screening for early stages of complications, when
intervention and treatment are generally more effective. Such screening for complications
aimed at early intervention and treatment has proved successful and may be even more
effective than strategies aimed at preventing the development of complications. As an
example, the introduction of laser photocoagulation in the treatment of retinopathy has
led to a dramatic decrease in diabetes-related blindness. Rehabilitation of persons with

diabetic complications is essential since many individuals with diabetes may develop disabling
complications with high associated costs.

You have successfully completed lecture 6.In this lecture you have learnt the
types,epidemiology,determinants and risk factors and control and prevention of diabetes
mellitus.

Now take a break and reflect on some of the issues we

have discussed today. After your break, answer the following questions:
 i.Describe the different levels of prevention of diabetes mellitus.

ii.Outline the clinical presentation of diabete s mellitus type 2

1. Chapter 78: Insulin, Glucagon and Diabetes Mellitus. In TEXTBOOK OF MEDICAL

PHYSIOLOGY (9th Edition) Editors: A Guyton and J Hall.

LECTURE 7

CHRONIC RESPIRATORY DISEASES

LECTURE OVERVIEW

Welcome to lecture 7.In the previous lecture you discussed diabetes mellitus disease.This lecture
will discuss the chronic respiratory.

2. Preventable Chronic Respiratory Diseases: A Major Global Health Problem

KEY MESSAGES
Chronic respiratory diseases are chronic diseases of the airways and the other structures of the
lungs.
Major preventable chronic respiratory diseases include asthma and respiratory allergies, chronic
obstructive
pulmonary disease (COPD), occupational lung diseases, sleep apnea syndrome and pulmonary
hypertension.
Hundreds of millions of people of all ages (from infancy to old age) suffer from preventable
chronic
respiratory diseases and respiratory allergies in all countries of the world.
More than 500 million of these people live in low and middle income countries or deprived
populations.
Chronic respiratory diseases account for four million deaths annually.
Measured in DALYs, in 2005 the burden of chronic respiratory diseases was projected to
account for 4% of
the global burden and 8.3% of the burden of chronic diseases.
Preventable chronic respiratory diseases are increasing in prevalence, particularly among
children and
elderly people.
The burden of preventable chronic respiratory diseases has major adverse effects on the quality
of life and
disability of affected individuals.
Many risk factors for preventable chronic respiratory diseases have been identifi
ed and effi
cient preventive
measures established.
Effective management plans have been shown to reduce the morbidity and mortality caused by
chronic
respiratory diseases.
Prevention and management plans concerning chronic respiratory diseases are fragmented and
need to be
coordinated.
The health of the world is generally improving. Fewer people are dying from
infectious diseases and therefore in many cases are living long enough to
develop chronic diseases.

Chronic respiratory diseases, chronic diseases of the airways and the other
structures of the lungs, represent a wide array of serious diseases. Preventable chronic respiratory
diseases include asthma and respiratory allergies, chronic obstructive pulmonary disease
(COPD), occupational lung diseases, sleep apnea syndrome and pulmonary hypertension. They
constitute a serious public health problem in all countries throughout the world, in particular in
low and middle income countries and in deprived populations. Hundreds of millions of people of
all ages, in all countries of the world, are affected by preventable chronic respiratory diseases.
More than 50% of them live in low and middle income countries or deprived populations.
The prevalence of preventable chronic respiratory diseases is increasing
everywhere and in particular among children and elderly people.

The burden of preventable chronic respiratory diseases has major adverse

effects on the quality of life and disability of affected individuals. Preventable
chronic respiratory diseases cause premature deaths. They also have large
adverse and underappreciated economic effects on families, communities,societies in general.

Chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease, kill
more than four million people every year and affect hundreds of millions more. These diseases
erode the health and well-being of the patients and have a negative impact on families and
societies. Women and children are particularly vulnerable, especially those in low and middle
income countries, where they are exposed on a daily basis to indoor air pollution from solid fuels
for cooking and heating. In high income countries, tobacco is the most important risk factor for
chronic respiratory diseases, and in some of these countries, tobacco use among women and
young people is still increasing.

By the end of this lecture, you should be able to:

i.Describe the epidemiology of chronic respiratory diseases
ii.Outline the risk factors of chronic respiratory diseases
iii.Discuss the control and prevention of CHD
Determinants and Risk Factors of Chronic Respiratory Diseases

The causes of the chronic respiratory diseases are well known. The most important modifiable
risk factors are: tobacco use, other exposures to indoor and outdoor air pollutants, allergens,
occupational exposure, and to a lesser extent than for other chronic diseases, unhealthy diet,
obesity and overweight intake and physical inactivity.

Control and Prevention of Chronic Respiratory Diseases Activity 7.1

1.Describe the control and prevention of chronic respiratory diseases.

______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________

Bravo .You have successfully completed this lecture.You were able to learn the chronic
respiratory diseases in depth.
1.Desccribe the epidemiology of Asthma.

______________________________________________________________________________
______________________________________________________________________________
___________________________________________________________________________2W
hat is the control and prevention measures of lung cancer.

______________________________________________________________________________
______________________________________________________________________________
_______________________________________________________________________

Beaglehole R et al. Preventing chronic diseases: a vital investment.

Geneva, WorldHealth Organization, 2005.

Strong K et al. Preventing chronic diseases: how many lives can we save? The
Lancet,2005, 366:1578–1582.

Lee J. Global health improvement and WHO: shaping the future. The Lancet
, 2003
 LECTURE 8

COST EFFECTIVE INTERBENTIONS FOR CHRONIC ILLNESSES

LECTURE REVIEW

Welcome to lecture 8.This lecture discusses the cost effective interventions in both alcohol use
and tobacco.

By the end of the lecture you should be able to :

i.Discuss the cost effective interventions put in place in control of alcohol use.

ii.Discuss the cost effective inteventions on tobacco.

In relation to harmful use of alcohol, effective prevention strategies for certain cancers, liver
cirrhosis and CVD should target both the levels and patterns of alcohol consumption. Established
evidence for the effectiveness and cost-effectiveness of interventions to reduce the harmful use
of alcohol including examples from countries such as Brazil, China, Mexico, the Russian
Federation and Viet Nam, among other countries supports implementation of the following
effective measures:

• Increasing excise taxes on alcoholic beverages;

• Regulating availability of alcoholic beverages, including minimum legal purchase age,

restrictions on outlet density and on time of sale, and, where appropriate, governmental
monopoly of retail sales;

• Restricting exposure to marketing of alcoholic beverages through effective marketing

regulations or comprehensive advertising bans;

• Drink-driving countermeasures including random breath testing, sobriety check points and
blood alcohol concentration (BAC) limits for drivers at 0.5 g/l, with reduced limits or zero
tolerance for young drivers;

• Treatment of alcohol use disorders and brief interventions for hazardous and harmful drinking.
Available evidence does not support isolated classroom-based education, public education
 and mass media campaigns, or consumer warning labels and messages. However, educational
and information campaigns in support of the effective measures listed above can increase
their acceptance in populations. The cost-effectiveness of these policy measures may depend
on their degree of acceptance in the population and their level of enforcement, in addition to
the extent of harmful alcohol use in the society. In countries with low prevalence of drinking
or with high proportion of consumed alcohol produced informally or illegally and, therefore,
not covered by taxation, the cost-effectiveness of raising taxes on alcohol is far less
favourable. In May 2010, the Sixty-third World Health Assembly adopted resolution
WHA63.13, which endorsed the WHO Global Strategy to Reduce the Harmful Use of
Alcohol , and urged Member States to adopt and implement it. The strategy represents a
global policy framework for reducing harmful use of alcohol. It advances guiding principles
for development and implementation of alcohol policies and interventions at all levels, sets
priorities for global action and urges a set of policy options for implementation at the
national level. The strategy recommends 10 target areas for action in countries: leadership
awareness and commitment; health services participation through counselling and treatment;
community involvement in identifying needs and solutions; drink-driving control policies
and countermeasures; reducing the availability of alcohol; regulating the marketing of
alcoholic beverages; pricing policies; reducing the negative consequences of drinking and
alcohol intoxication; reducing the public health impact of illicit and informally produced
alcohol; and monitoring and surveillance.

Tobacco Control

Tobacco is the most widely available harmful product on the market. To reduce its harms, WHO
sponsored the negotiations of the WHO Framework Convention on Tobacco Control (WHO
FCTC), its first legallybinding international treaty. The treaty sets a framework for guidelines
and protocols to reduce tobacco consumption and tobacco supply through evidence-based
interventions .

The WHO FCTC includes measures on prices and taxes, exposure to tobacco smoke, the
contents of tobacco products, product disclosures, packaging and labelling, education,
communication, training and public awareness, tobacco advertising, promotion and sponsorship
and reducing tobacco dependence. It also includes sales to and by minors, measures to reduce
illicit trade, and support for economically viable alternative activities. It addresses liability,
protecting public health policies from the tobacco industry, protecting the environment, national
coordinating mechanisms, international cooperation, reporting and exchange of information and
institutional arrangements .

There is robust evidence that tobacco control is cost-effective compared to other health
interventions. The evidence base on what works to reduce harm from tobacco provided the
foundation for the WHO FCTC. The 1998 book Curbing the Epidemic (4), a landmark World
Bank publication, addressed the economic costs of tobacco and estimated the overall impact of
tobacco control interventions.

Key cost-effective interventions include tobacco tax increases, timely dissemination of

information about the health risks of smoking, restrictions on smoking in public places and
workplaces, and comprehensive bans on advertising, promotion and sponsorship. These are each
considered best buys in reducing tobacco use and preventing NCDs. All of these interventions
reduce social acceptance of tobacco use, thereby increasing demand for cessation therapies. In
this context, it is a good buy to provide smokers in particular, and tobacco users in general, with
treatment for tobacco dependence.

Increases in taxes on and prices of tobacco products are by far the best buys in tobacco control
because they can significantly reduce tobacco use through lower initiation and increased
cessation, especially among young people and the poor. Increases in tobacco excise taxes
increase prices and reduce the prevalence of adult tobacco use.

Smoke-free work and public places reduce second-hand smoke and effectively help smokers cut
down or quit, while reducing smoking initiation. Smoke-free policies reduce the opportunities to
sustain nicotine addiction in individuals at early stages of dependence, youth in particular .
Furthermore, smoke-free laws enjoy popular support and high levels of compliance when
properly implemented, providing an additional message that smoking is not socially acceptable.
For all these reasons, protection from second-hand tobacco smoke is a best buy.

Providing information to adults about tobacco-dependence and health impacts of tobacco can
reduce consumption and is another best buy. Regular and creative mass media campaigns and
graphic health warnings on tobacco packages have been shown to reduce demand . Country-
based experience suggests that despite tobacco companies‘ opposition and the resource
constraints faced by health authorities, implementation of health warnings is generally powerful
and successful. A comprehensive set of tobacco advertising, promotion and sponsorship bans is a
best buy and can reduce tobacco consumption by up to 6.3%. However, limited advertising bans
have little or no effect.

Cost-effective tobacco cessation assistance is a good buy. Treatment should be available at

public health (including toll free ‗quitlines‘ and awareness-raising campaigns) and primary care
services. The most effective treatment modality is a combination of behavioural and
pharmacological therapies.

Evidence shows that tobacco control interventions are affordable in all countries. One study
modelled price increases, workplace bans, health warnings and bans on advertising for 23
countries. This showed that 5.5 million deaths could be averted at a cost of less than US$ 0.40
per person per year in low- and lower-middle-income countries, and US$ 0.5–1.00 in upper-
middle-income countries. Yet, less than 10% of the world‘s population in 2008 was fully covered
by any of the tobacco control demand reduction measures in the WHO FCTC .

Bravo! You have come to the end of lecture 8.You were able to learn the cost effective
interventions put in place to control both alcohol and tobacco abuse.
 Now take a break and reflect on some of the issues we
have discussed today. After your break, answer the following questions:

i. Discuss the cost effective interventions put in place in your country to control
alcohol and tobacco use.

1) Guidelines for implementation of the WHO Framework Convention on Tobacco

Control. Geneva, World Health Organization, 2011.

2. History of the WHO Framework Convention on Tobacco Control. Geneva, World

Health Organization, 2009.

3. Anderson P, Chisholm D, Fuhr D. Effectiveness and cost-effectiveness of policies and

programmes to reduce the harm caused by alcohol. The Lancet, 2009, 373:2234–2246.

4. Evidence for the effectiveness and cost-effectiveness of interventions to reduce alcohol-

related harm. Copenhagen, World Health Organization Regional Office for Europe,
2009.

LECTURE 9

INJURIES

LECTURE REVIEW

This is lecture 9.In the previous lecture you learnt about cost effective interventions for
chronic illnesses .This lecture will discuss injuries.
 By the end of this lecture, you should be able to:
i.Describe the epidemiology of injuries.
ii.

Epidemiology of injuries

Worldwide, injury ranks fifth among the leading causes of death, accounting for 5.2 percent of
the total mortality and 10 to 30 percent of all hospital admissions. Nearly 3 million deaths of
injury and poisoning are reported annually; two- thirds of these occur in the developing countries
(WHO, 198The annual medical and social costs of injury are estimated to exceed $500 billion
world wide.

Observation of trends in the epidemiology of injury in developing countries raises the question of
the relationship between development and injury. Developing countries move through an
―epidemiological transition,‖ from a disease profile dominated by infectious diseases to one
characterised by the ―post-transition‖ non-communicable health problems, including injuries.
The global health burden of injuries in the year 2020 is projected to be equal to that of
communicable diseases, and even greater in some developing countries.

Demographic changes (such as the shift in age structure and urbanisation) have had effects on
the epidemiology of injury primarily through an increase in the incidence of injuries, which are
more prevalent among the elderly (such as falls) and in urban environments (such as motor
vehicle accident).

The incidence of moderate to severe burn injury is probably at least 600 per 100,000 people in
developing countries. The occurrence of new injuries from falls in developing countries is
probably at least 2,000 per 100,000. The average age of 30 years at the time of injury reflects the
higher incidence among the elderly and the occupational nature of many of these injuries.

The incidence of all injuries due to motor vehicle accident in developing countries is likely to be
at least 665 per 100,000. The average age of thirty years at the time of injury reflects the fact that
persons injured in motor vehicle accident in developing countries are older than their
counterparts in the industrial world . The estimated mortality rate from injury and poisoning in
Sub – Saharan Africa is much higher for males than females. For example, the mortality rates for
males for the years 1985, 2000 and 2015 were estimated to be 138, 129 and 123 per 100,000
persons respectively. For the years given above, the estimated mortality rates for females were
32, 32 and 31 per 100,000 persons respectively.

Although the impact is less well understood, injury is one of the leading causes of adult mortality
and a major contributor to disability in most age groups in many low- income countries such as
those in Africa. This is especially true in countries that experienced recent increases in
industrialization and motorization. Despite this, limited attention has been paid to injury as a
health problem. Comprehensive epidemiological information on injury incidence, severity, risk
groups and risk factors is essential for setting intervention priorities and preventive policies.
Development of these effective efforts depends on reliable, detailed information on the incidence
and outcome of specific mechanisms of injury. However, in developing countries, such sources
of data are limited. Many injury related deaths are not reported, while most injured persons do
not receive formal medical care, making health care records an incomplete source of data.

Predisposing Factors

Accidents happen in conditions and on individuals prone to injuries. The Presence of

predisposing factors promotes injuries to happen. The health center team thus is expected to
know some of these conditions.

a) Excessive alcohol intake and addictions of any kind:- reduces the concentration and motor
control of individuals. It is particularly associated with road traffic injuries, homicidal and
criminal acts. These predispositions are avoidable.

b) Mental illness:- mentally ill people can have self-inflected injuries or cause injuries to others.
For example seizure patients may suffer fits in a site close to fire and sustain fall or burn injuries.
Also they may be eating food and choke get.

c) Lack of knowledge or information:- Information regarding safety measures about use of

sharp instruments, irritants and electric systems, firearms and explosives are necessary. Failure to
have adequate knowledge and information about all these measures predisposes to injuries.

Good knowledge of traffic rules and regulations save lives that could be lost due to road traffic
injuries. d) Negligence and Carelessness: - there are some jobs which demand absolute
concentration and attention, otherwise leading to injuries.

For example: Machine operating, driving Electrical system or line maintenance Cooking

e) Lack of precautionary measures: - appropriate use of precautionary measures such as eye

goggles and fire-protecting jackets prevent injuries.

f) Defective Appliances:- such as leaking gas valves, inefficient maintenance of machines,

inappropriate storage of poisons, flammables, etc. cause injuries.

g) At careless approach to animals results in animal bites, stings, horn injuries, etc.

h) Age and sex: younger age individuals and adolescents are at risk of injuries caused by alcohol
 induced violence and road traffic injuries by virtue of their behavior. Females are more exposed
to burn injuries, rapes and assaults from male counter parts.

i) Socio-economic status: poor socio-economic conditions are associated with pedestrian

injuries, assaults and burns.

j) Occupation:- - Workers who work in:

- Areas with Heavy metals: (e.g. Mercury, lead, etc) recurrent stomach pain in a worker involved
in deleading. - Grinders and operators of chain saws, hammer and other tools are exposed to
segmental vibration, which affect the upper

limbs - Health professionals- in advertent infection during working times.

Common Causes

The mechanism by which accidents happen is long-listed. However, based on epidemiological

data on injury in our country and data from other African countries of similar settings, the
following causes are identified:

Physical causes

• Personal assault/ homicidal injuries These types of injuries are commonly intentional in the
event of producing an injury to another person. Many things can be used to cause injury:
throwing objects such as sticks or stones; using parts of the body and knives.

• Road traffic injuries: - play a major role as a cause of death in towns and cities. Studies have
shown that proper application of driving rules reduces injuries. Mixed traffic systems where
by vehicles, animals, and pedestrians share the roads, is one of the major causes of road
traffic injuries. Unsafe roads, old vehicles, lack of safety knowledge, and lack of driving
skills all contribute to road traffic injuries.

• Falls may occur in daily activities of individuals. All age groups may be affected. However,
most falls result in injury when they occur in either the young or old ages. Falls from trees
while trying to harvest fruits is an example. Walking on uneven roads may cause falls in the
young or old who may not have a steady and strong gait.

• Bullet injuries: - occurs both in war and peace. It can be homicidal, unintentional, suicidal, or
genocidal in origin. It is one of the leading causes of injuries in our country. Sexual assaults
(Rapes) :- produces both physical and psychological trauma; the psychological trauma may
be more disabling than the physical trauma and may be harder to detect.

• Mishandling of sharp objects, machineries, weapons, explosives etc.

• Drowning:-canoccurduringflooding,whentryingtocrossafloodedriver, swimming, infants may

drown in small tubes of water if left unattended.
• Choking/aspirations: - this may happen to occur while eating food. Children playing with
coins may aspirate or swallow the coin, which may result in choking.

Burn and electrical injuries

Burns are accidental injuries known to mankind since ancient times. It is caused by exposure to
extreme heat from open fire, hot liquids, very hot surfaces or steam. Electrical injuries also
produce burns. When a high voltage current passing across the tissue, it encounters resistance
and heat will be generated resulting in tissue injury.

Chemical injuries: - exposure to harmful chemicals such as strong acids or alkaline damages
tissue. Chemicals used by the traditional healers may also cause tissue injury. The magnitude of
local industry and agricultural practices determines the prevalence of chemical injuries.

Prevention of common injuries

Prevention of injuries is an essential part of primary health care. Treatment is relatively

expensive, often lingering and not always successful in preventing permanent disability. It is
therefore, essential to strengthen the efforts of injury prevention.

In making plans for the prevention of injuries, it is useful to consider the following activities.

Primary Prevention

• Information, education and communication on injury prevention and control

• rums, which are considered

to be less toxic to humans, than some other pesticides.

• face shield, gloves, helmet,

dust masks, protective suits and safety shoes.

• ich proper electric wiring is essential, such as

proper installation of sockets, insulation of electric wires using conduits

• the room to
dilute the indoor air.

• and other mechanical injuries in the house through proper home

 management. (Such as eliminating tripping hazards)

•
measures, seat belts for all passengers, avoiding alcohol and overloading of vehicles when
driving.

• and
transportation safety.

• level and referral resources at

secondary and tertiary levels.

• Secondary prevention: prevention of further damage after a trauma has occurred.

• Tertiary prevention: prevention of serious complications of trauma and disability.

Congratulations for successfully completing lecture 9.You have discussed epidemiology,

types and control and prevention of injuries.

i.Discuss different types , control and prevention of injuries .

________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
 ii.Outline the causes of injuries.

________________________________________________________________________
________________________________________________________________________
________________________________________________________________________

• Dacie A. John V., and Lewis S.M. practical Haematology. Churchhil living stone 8th edition
1999.

• Cheesbrough M. Medical Laboratory Manual for Tropical Countries. Cambridge: Butter

worth – Heinemann Ltd 1987.

• Ethiopian Red Cross society national blood transfusion service. The blood bank manual June
1992.

LECTURE 10

MENTAL HEALTH

LECTURE REVIEW

Mental health is more than the mere lack of mental disorders. The positive dimension of mental
health is stressed in WHO‘s definition of health as contained in its constitution: ―Health is a state
of complete physical, mental and social well-being and not merely the absence of disease or
infirmity.‖ Concepts of mental health include subjective well-being, perceived self-efficacy,
autonomy, competence, intergenerational dependence and recognition of the ability to realize
one‘s intellectual and emotional potential. It has also been defined as a state of well-being
whereby individuals recognize their abilities, are able to cope with the normal stresses of life,
work productively and fruitfully, and make a contribution to their communities. Mental health is
about enhancing competencies of individuals and communities and enabling them to achieve
their self-determined goals. Mental health should be a concern for all of us, rather than only for
those who suffer from a mental disorder.

Mental health problems affect society as a whole, and not just a small, isolated segment. They
are therefore a major challenge to global development. No group is immune to mental disorders,
but the risk is higher among the poor, homeless, the unemployed, persons with low education,
victims of violence, migrants and refugees, indigenous populations, children and adolescents,
abused women and the neglected elderly.

For all individuals, mental, physical and social health are closely interwoven, vital strands of life.
As our understanding of this interdependent relationship grows, it becomes ever more apparent
that mental health is crucial to the overall well-being of individuals, societies and countries.
Unfortunately, in most parts of the world, mental health and mental disorders are not accorded
anywhere the same importance as physical health. Rather, they have been largely ignored or
neglected.

By the end of the lecture you should be able to:

i. Explain the epidemiology of mental health.

ii. Outline the determinants and risk factors of mental halth

iii. Describe the control and prevention of mental health

Today, about 450 million people suffer from a mental or behavioural disorder. According to
WHO‘s Global Burden of Disease 2001, 33% of the years lived with disability (YLD) are due to
neuropsychiatric disorders, a further 2.1% to intentional injuries . Unipolar depressive disorders
alone lead to 12.15% of years lived with disability, and rank as the third leading contributor to
the global burden of diseases. Four of the six leading causes of years lived with disability are due
to neuropsychiatric disorders (depression, alcohol-use disorders, schizophrenia and bipolar
disorder).

Neuropsychiatric conditions account for 13% of disability adjusted life years (DALYs),
intentional injuries for 3.3% and HIV/AIDS for another 6% (Figure 2). These latter two have a
behavioural component linked to mental health. Moreover, behind these oft-repeated figures lies
enor- mous human suffering.
• More than 150 million persons suf- fer from depression at any point in time; Nearly 1 million
commit suicide every year;

• About 25 million suffer from schizophrenia;

• 38 million suffer from epilepsy; and

• More than 90 million suffer from an alcohol- or drug-use disorder.

The number of individuals with disorders is likely to increase further in view of the ageing of the
population, worsening social problems and civil unrest.

RISK Factors for mental Health

It is becoming increasingly clear that mental functioning is fundamentally interconnected with

physical and social functioning and health outcomes. For example, depression is a risk factor for
cancer and heart diseases. And mental disorders such as depression, anxiety and substance- use
disorders in patients who also suffer from physical disorders may result in poor compliance and
failure to adhere to their treatment schedules. Furthermore, a number of behaviours such as
smoking and sexual activities have been linked to the development of physical disorders such as
carcinoma and HIV/AIDS.

Among the 10 leading risk factors for the global burden of disease measured in DALYs, as
identified in the World Health Report 2002, three were mental/behavioural (unsafe sex, tobacco
use, alcohol use) and three others were significantly affected by mental/behavioural factors
(overweight, blood pressure and cholesterol).

Control and Prevention of Mental Health

Health promotion is the process of enabling people to gain increasing control over their health
and improve it (WHO, 1986). It is therefore related to improving the quality of life and the
potential for good health, rather than only an amelioration of symptoms. Psychosocial factors
influence a number of health behaviours (e.g. proper diet, adequate exercise, and avoiding
cigarettes, drugs, excessive alcohol and risky sexual practices) that have a wide ranging impact
in the domain of health.

A growing body of cross-cultural evidence indicates that various psycho- logical, social and
behavioural factors can protect health and support positive mental health. Such protection
facilitates resistance (resilience) to disease, minimizes and delays the emergence of disabilities
and promotes more rapid recovery from illness . The following studies are illustrative. Breast-
feeding improves bonding and attachment between infants and mothers, and significantly
improves child development. Promotive interventions in schools improve self- esteem, life skills,
pro-social behaviour, scholastic performance and the overall climate.

Among various psychosocial factors linked to protection and promotion in adults are secure
attachment; an optimistic outlook on life, with a sense of purpose and direction; effective strate-
gies for coping with challenge; perceived control over life outcomes; emotionally rewarding
social relation- ships; expression of positive emotion; and social integration.
You have successfully completed lecture 10.You have discussed the epidemiology, determinants
and risk factors , and control and prevention of mental health.

1.Outline the risk factors of mental health.

______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________

2.Discuss different types of mental health.

______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________

Albertyn C, McCann M (1993). Alcohol, Employ- ment and Fair Labour Practice. Cape Town,
Juta.

Babor TF, Grant M (1992). Project on identification and management of alcohol-related

problems. Report on Phase II: A randomized clinical trial of brief interventions in primary
health care. Geneva, World Health Organization.

Berto P et al. (2000). Depression: Cost-of-illness studies in the international literature: A review.
The Journal of Mental Health Policy and Eco- nomics, 3: 3-10.

Birnbaum HD, Greenberg PE, Barton M (1999). Workplace burden of depression: A case study
in social functioning using employer claims data. Drug Benefits Trends, 11: 6BH-12BH.
 LECTURE 11

GENETIC VARIANT ASSOCIATION

REPRODUCTIVE OUTCOME

LECTURE REVIEW
By the end of th lecture you should be able to:

i.Explain how functional genetic variant associations with common chroninc diseases can
provide robust estimates of the effects of environmental exposure on diseases.

Research on reproductive outcomes in the 21st century will use epidemiologic methods in
conjunction with biologic measurement, and will increasingly focus on couples and sexual
networks as the units of observation. Traditionally, epidemiologists have used interview
information, which is subject to recall errors and bias. Moreover, many conditions, such as early
subclinical pregnancy loss or asymptomatic sexually transmitted infections, may not be
recognized by respondents, and interviews provide limited insight into mechanisms underlying
reproductive outcomes. There is therefore a need for biologic measurement. However, biologic
measurement in the past has required clinical examinations or specialized investigations, which
are invasive and often costly, and generalization of such findings is limited by the self- selection
of clinic populations. Reproductive research in the next century will involve improved biologic
measurement of reproduction and its determinants in representative populations.

In the past, most reproductive research has used women as the unit of observation, partly because
women bear children and better recall reproductive events. In addition, research on reproductive
decisions or on sexually transmitted diseases has generally been based on information derived
from individuals, rather than from couples or sexual networks. The next century will witness a
change in focus toward utilization of data on both members of a couple or on the wider
membership of a sexual network.

IMPROVED BIOMEDICAL MEASUREMENT OF REPRODUCTIVE HEALTH

Advances in research methods have involved improved measurement of hormonal processes an

Detection of sexually transmitted infections, using accessible body fluids. These advances now
allow studies in representative populations.

Hormonal assays

Hormonal assays performed on daily, early morning urine samples can detect ovulation,
implantation, early pregnancy loss, and hormonal disturbances of the menstrual cycle . This
allows integration of data from interview-based studies with those of prospective endocrinologic
studies. Urine provides a readily accessible body fluid, and small (10-ml) samples collected after
sleep reflect a pooled, 6- to 8-hour average of serum hormone levels. These samples can be
readily collected by women in their homes over protracted periods of time .

Early subclinical pregnancy following implantation and early subclinical pregnancy loss are
detected by sensitive and specific immunoradiometric human chorionic gonadotropin assays
which do not cross react with luteinizing hormone . Studies of women attempting to conceive
and of occupational cohorts show that the rate of early pregnancy loss detected by human
chorionic gonadotropin assay is approximately 21 percent in healthy women . However, women
with a history of subfertility (defined as an inability to achieve a recognized conception for more
than 1 year, despite efforts to become pregnant) have higher rates of recurrent early pregnancy
loss (68 percent) compared with women with a normal fertility history . Therefore, it is possible
that repeat early subclinical losses which do not cause delayed menses may be misinterpreted by
women or their physicians as subfertility.

Monitoring of hormonal parameters during the menstrual cycle via assay of urine specimens
from representative samples of women has allowed detection and timing of ovulation, as well as
measurement of hormone levels, the length of the follicular and luteal phases of the cycle, and
factors affecting the cycle . The assays measure passively excreted gonadotropin peptide
hormones of pituitary origin (follicle-stimulating hormone or luteinizing hormone), as well as
urinary glucuronide metabolites of ovarian steroids (estradiol or estrone glucuronides and preg-
nanediol glucuronide). Algorithms based on changes in the ratio of estrogen/progesterone
metabolite excretion or luteinizing hormone peak excretion can accurately time ovulation. These
methods have been applied to normal populations to postpartum lactating and non lactating
women , and to the examination of toxic exposures . In addition, using steroid assays in
conjunction with human chorionic gonadotropin assays, it has been shown that delayed
implantation (longer than 10 days following ovulation) is associated with a marked increase in
the rates of early, subclinical pregnancy loss .

INTERDEPENDENCE OF REPRODUCTIVE PROCESSES

Much research has examined risk factors for impaired fertility and adverse pregnancy outcomes
as separate dependent variables. Research on subfertility has focused on women attempting to
conceive, whereas research on spontaneous abortion has focused on women with recognized
pregnancies. However, these are related phenomena, and they need to be investigated in the same
individuals. For example, women who experience a prolonged delay prior to achieving a
recognized conception also have increased rates of clinical spontaneous abortion and women
with a history of subfertility have excess rates of sub- clinical early pregnancy loss . This
suggests that subfertility and pregnancy loss may reflect a common underlying etiology, possibly
due to adverse effects of reproductive hazards prior to or during implantation and in later
embryonic/fetal life. Several toxic exposures are associated with disturbances of the menstrual
cycle and with in utero growth retardation and structural developmental defects in the newborn,
which again suggests a continuum of adverse effects. The biologic mechanisms are likely to
differ between toxic exposures, but they could involve hormonal or immunologic disruptors,
effects on DNA synthesis or adduct formation, or alteration in cellular replication and apoptosis .
Defining the biochemical or cellular mechanisms will be a priority for reproductive toxicology in
the next century. Thus, future studies of reproductive hazards should attempt to measure a broad
range of adverse effects by collecting information on menstrual cycle characteristics, subfertility,
and pregnancy loss, as well as newborn outcomes, including intrauterine growth retardation,
structural deformities, and infant survival.

The outcomes of repeated pregnancies and births in women are not independent events (e.g., the
risks of pregnancy loss, preterm delivery, low birth weight, and child death are higher among
women who have experienced a prior adverse outcome). In the past, most analyses relied on
standard statistical procedures which assume independence between events . If an association
between a woman's characteristics and type of birth outcome is of interest, and there are multiple
births for some women, then the matter is easily treated as clustering within women using
random-effects models or generalized estimating equations methods .

GENE-ENVIRONMENT INTERACTIONS

The rapid advance of genetic science, the anticipated availability of the fully sequenced human
genome, and increased knowledge of the molecular basis of disease promise rapid evolution of
epidemiologic studies on reproductive epidemiology and birth outcomes. Single gene mutations
have been implicated in reproductive dysfunction and understanding of the genetic mechanisms
of embryonic development and dysmorphogenesis has also advanced rapidly .

Perhaps the best paradigm for the new era of research on genetic and environmental interactions
is research on the etiology and prevention of neural tube defects . Epidemiologic evidence of
geographic and temporal variation in the incidence of neural tube defects suggested an
environmental component, and descriptive studies in conjunction with clinical trials showed that
folate micronutrient deficiency was a critical factor. Subsequent genetic studies identified genes
encoding folate receptors, and homozygosity for allelic variants was shown to increase
susceptibility to dietary folate deficiency, accounting for the excess risk of neural tube defects in
specific ethnic groups . More recent research has implicated other genotypes. The identification
of folate as the primary etiologic agent has led to major prevention programs.

Increased understanding of the molecular lesions caused by chemical teratogens has also
advanced knowledge and prevention. For example, epidemiologic studies implicated ethylene
glycol ethers as causes of subfertility and pregnancy loss in occupationally exposed women and
impaired sperm production in occupationally exposed men . Metabolites of these compounds
were shown to impair single carbon moiety incorporation into DNA and RNA synthesis,
resulting in disrupted embryo development and genotoxicity.

MALE REPRODUCTION

Biologic measurement of semen parameters in population-based studies has been constrained by

the need to use masturbation as a method of sample collection. As a consequence, most
investigations have used samples from men identified via artificial insemination programs or
from men undergoing vasectomy or infertility investigation, but these subjects are self-selected
Population-based studies have demonstrated effects of season and temperature on sperm
production . Several investigators have used clinic-based data from ostensibly normal men to
examine changes in sperm production and semen quality over time, but results have been
contradictory . Clinic-based studies are problematic because of the self-selection of donor
populations and definitions of "normal" donors which differ between clinics and over time, and
most of these studies have not controlled for interobserver variation in the evaluation of semen or
for the duration of sexual abstinence prior to sample collection. Despite the contradictory
evidence, these studies have raised concerns about possible deterioration of semen quality, and it
has been hypothesized that this may be due to environmental factors acting as "endocrine
disruptors," which may affect testicular development in utero or postnatally . The evidence for
adverse effects of such endocrine disruptors in humans is equivocal, and this hypothesis will
have to be tested in the 21st century. Assays that measure suspect chemicals or their metabo-
lites provide possible biomarkers for exposures. Urine samples can be used to measure
testosterone and gonadotropin hormone levels for detection of endocrine abnormalities, and urine
collection is more acceptable than semen collection, which improves compliance, coverage, and
representativeness . These approaches hold promise for future studies of male reproductive
health.

There is also concern over environmental factors affecting other aspects of male reproductive
dysfunc- tion, such as cryptorchidism, hypospadias, and testicular cancers among men aged 15—
45 years, all of which have increased in incidence in several countries over recent decades.
Cryptorchidism, delayed puberty, and subfertility are risk factors for testicular cancer, and it is
postulated that exposures to endocrine disruptors in utero may affect testicular development or
descent, leading to reduced testosterone production, which by feedback stimulation induces the
release of pituitary follicle-stimulating hormone and induction or promotion of testicular
neoplasia. There is therefore a role for endocrinology in future studies of testicular cancer and
disruption of male urogenital development.

COUPLES AND SEXUAL NETWORKS

Until recently, most epidemiologic studies of reproductive outcomes considered the individual as
the unit of study, although in many cases the most appropriate unit for analysis and intervention
is the couple. For example, studies of infertility and its treatment require the investigation of both
partners . The concept of unintended pregnancy should include the male partner's desires, since
outcomes such as induced abortion are likely to depend on the intentions of both partners .
Similarly, the concept of unmet need for contraception has traditionally been defined with
respect to women, but this concept should incorporate the male partner in order to improve
acceptance and continuation of use of contraception . In developing countries, maternal mortality
can be prevented by emergency obstetric care, but utilization of such services depends on
recognizing a problem and seeking care without delay, which often requires the involvement of
the husband .

The epidemiology of sexually transmitted diseases requires consideration of the couple and the
broader network of sexual contacts, including the degree of assortative and nonassortative
partner selectivity . Networks can be studied by identification of named sexual contacts or by
anonymous information on the partner's characteristics.

Well done! You have completed lecture 11.You have covered the genetic variant association in
men and female.
i.Describe the epidemiology of reproductive outcome.

______________________________________________________________________________
______________________________________________________________________________
__________________________________________________________________________

. Lasley BL, Troedsson M, Bravo W, et al. Estrogen conjugate measurements to monitor ovarian
activity. Theriogenology 1989;31:127-39.

2. Gray RH, Campbell OM, Zacur HA, et al. Postpartum return of ovarian activity in
nonbreastfeeding women monitored by urinary assays. J Clin Endocrinol Metab 1987;64:645-50.

3. Wilcox AJ, Weinberg CR, O'Connor JF, et al. Incidence of early loss of pregnancy. N Engl J
Med 1988;319:189-94.

LECTURE 12

MEASURING INEQUALITIES IN HEALTH

Health inequities are defined as inequalities in which the outcome is unnecessary and avoidable
as well as unjust and unfair. Most measurement of health inequality involves the use of
indicators or indexes to measure health, but it also involves decisions on what groups or areas to
compare and what is the most appropriate form of analysis for the question being investigated.
In all known societies health risks, health-related behaviours, physical and mental health, and life
expectancy tend to vary between social groups. Key axes of variation include socio-economic
status, gender, ethnicity, and place of residence. This briefing focuses on socio-economic status
(SES for short) inequalities but many of the same principles apply to other inequalities.

The most immediate causes of SES inequalities in health are specific exposures (e.g. damp
housing, hazardous work or neighbourhood settings, infectious agents, adverse life events),
behaviours (e.g. smoking, diet, exercise), and personal strengths or vulnerabilities (e.g. coping
styles, resilience, ability to plan for the future). Mechanisms can be physical (e.g. exposure to air
pollution), psychosocial (e.g. adverse life events), behavioural (e.g. smoking) or combinations of
these (e.g. smoking to deal with stress caused by living in a physically threatening environment).
Such influences are often referred to as ‗downstream‘ causes.

Intermediate causes are the pathways by which members of different SES groups get to be at
lower or higher risk of such exposures and vulnerabilities (e.g. the education, taxation, and health
care systems, the labour and housing markets, planning regulations, crime and policing etc).The
most fundamental causes are international political and economic forces, and the forms of social
stratification in a given society. For example, in the USA health tends to be strongly associated
with the distribution of income and with race, while in the UK it tends to be more strongly
associated with social class.

Some SES inequalities are generated at or before birth. For example, data from the West of
Scotland show that stomach cancer and stroke risk are associated more with one‘s parents‘ SES
than with one‘s own position in adult life Low birth weight is a good marker of the environment
in the womb, and thus of the mother‘s health. It is

strongly associated with socio-economic deprivation, and low birth weight babies have
continuing health and social disadvantages, not only in childhood but into adultlife, as expressed
for example in raised risks of coronary heart disease in middle age.

Exposure to socially patterned risks (e.g. to hazardous working environments, smoky

environments, poverty) also occurs in adult life. Earlier and later life risks can be cumulative;
exposure to damaging environments in both childhood and adulthood is worse than exposure in
only one period Experiences and behaviours in later life can help to reduce risks generated
earlier.

Social gradients in health and health risks

Health usually displays a gradient by socio-economic status, so that each successively more
advantaged group has longer life expectancy and better health. There is a gradient all the way up
the social scale, rather than a threshold between the poor and the rest of society above which
there are no social differences.

Although SES gradients are manifest in many biological measures (e.g. birth weight, height,
respiratory functioning) they are, somewhat surprisingly, not found in others (e.g. blood pressure
and cholesterol, even though these are risk factors for major illnesses, such as cardiovascular
disease, which are strongly socially patterned)
Social gradients differ by age, tending to be steep in infancy, flatter in youth, then steeper in
adulthood and flatter in old age. There are also gender differences in socio-economic gradients;
for example, overweight rises with decreasing SES among women, but the pattern is more mixed
or reversed among men.

SES patterning varies by levels of economic development and by culture, and can change over
time as patterns of exposure, and the relative influence of different determinants, change. For
example, rates of heart disease and smoking used to be higher in higher social classes whereas in
most developed countries they are now consistently higher in lower SES groups Smoking rates
are still higher in higher social classes in Southern countries in Europe. In developed countries
smoking has become a more important cause of health inequalities as its prevalence has declined,
because the decline has been greater among more affluent people.

Lecture 11 entailed measuring the inequalities in health.

i.Discuss different measures used measuring inequalities in health.

______________________________________________________________________________
______________________________________________________________________________
___________________________________________________________________________

ii.Explain what reduces inequalities in health.

______________________________________________________________________________
______________________________________________________________________________
____________

Bromley C, Sprosten K, Shelton N, editors. The Scottish Health Survey 2003. Volume 2: Adults.
Edinburgh: Scottish Executive, 2005.

Whitehead M, Dahlgren G. Levelling up (part 1): a discussion paper on concepts and principles
for tackling social inequalities in health. Studies on social and economic determinants of
population health, No. 2. Geneva: World Health Organisation (Regional Office for Europe),
2006.

LECTURE 13

HIGH RISK INDIVIDUAL VS POPULATION STRATEGIES FOR PREVENTION

LECTURE REVIEW

Welcome to lecture 13.This lecture will discuss high risk individuals vs population strategies for
prevention.

By the end of the lecture you should be able to:

i.Describe the four levels of diseases prevention.

ii. critique high risk individual and population strategies.

Prevention can be considered on a number of levels:

Primordial prevention - seeks to prevent at a very early stage, often before the risk factor is
present in the particular context, the activities which encourage the emergence of lifestyles,
behaviours and exposure patterns that contribute to increased risk of disease. For example, a
child seeing their parents smoke cigarettes may wrongly consider this a good lifestyle choice for
later in life: advising parents to quit smoking in such circumstances can be considered primordial
prevention.

Primary prevention - prevention of disease through the control of exposure to risk factors.
Strategies for primary prevention include population-wide strategies and targeted, high-risk
strategies focusing on population sub-groups. For example, careful weight control prevents
obesity which in itself is a risk factor for many conditions including heart disease and diabetes.

Secondary prevention - the application of available measures to detect early departures from
health and to introduce appropriate treatment and interventions. Screening is a major component
of secondary prevention for example, cervical screening for women to detect early changes
which may go on to lead to cancer of the cervix.
Tertiary prevention - the application of measures to reduce or eliminate long-term impairments
and disabilities, minimising suffering caused by existing departures from good health and to
promote the patient‘s adjustments to his/her condition. For example, a person identified as
having type 2 diabetes will have regular blood glucose checks to monitor control of their
diabetes and prevent complications of the disease.

Targeting populations versus high-risk only groups

There are two approaches to prevention- targeting a whole population whether they are exposed
to risk factors or not, or tackling only those identified as being high risk. There are pros and cons
to each approach.

Since diseases are rare, most individuals who adopt a behaviour designed to lower their risk of
disease will not benefit directly, although a few individuals may benefit enormously for example,
any one person‘s decision to lose weight may only have a small impact on that person‘s risk of
disease in the near future, but if many people each lose a little weight, this may have a substantial
impact on the community‘s obesity-related disorders.

Although individuals with high risk factors may benefit from interventions specifically targeted
at them, the effect on the overall incidence of the disease will be limited in the absence of a
population-oriented intervention.

High risk approach Population approach

Advantages  May be more cost-effective  Recognises that society

than population wide influences individual behaviour
approaches  Risk reduction can be achieved
 Those who are identified as at population rather than
being high risk may be more individual level
motivated to change their  In situations where there is a
behaviour than the whole of dose-response relationship in
society terms of risk and exposure,
 Easier for health shifting the entire population
professionals to promote distribution towards lower
change on an individual levels of exposure is effective.
basis
 Individuals are usually aware
of their exposure to adverse
risk, whereas in society not
everyone will have been
exposed
 Society prefers focusing on
 individuals to change rather
than a whole population

Disadvantages  Can be expensive to identify  Is less effective in situations

and treat those at increased where there is not a dose-
risk response relationship in terms
 Fails to address public health of risk and exposure.
problems arising from small
but widespread risks that
may be substantial
 Ignores the point that a large
number of people exposed to
a small risk may generate
more cases than a small
number of people exposed to
a large risk
 Tends to medicalise
prevention
 Strategies for the individual
tend to be either palliative or
temporary
 Does not focus on what
influences behaviour
 Does not tend to predict an
individual‘s change in risk
 May have little overall
impact on control of disease

Whilst the high-risk approach seemingly has many more disadvantages compared to the
population approach, the prevention paradox reduces the effectiveness of the population
approach, therefore a combination of population and high-risk approaches is usually most
effective.

High risk groups can be identified through screening, genetic testing, analytical studies linking
risk factors and disease and ecological studies to identify groups.
You have successfully completed this lecture. You were able to learn about the individual high
risk and population based prevention strategies.

1‘‘.Prevention is better then cure‖.Discuss

______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
_____________________________________________

Rose G (1992). The strategy of preventive medicine. Oxford University Press, Oxford.

Lewis et al. Mastering Public Health. A postgraduate guide to examinations and revalidation.
Royal Society of Medicine press. 2008

LECTURE 14

POPULATION BASED SCREENING

LECTURE REVIEW

Screening

The World Health Organization (WHO) defines screening as the presumptive

identification of unrecognised disease or defects by means of tests, examinations or other
procedures that can be applied rapidly.
 Screening is intended for all people, in an identified target population, who do not have
symptoms of the disease or condition being screened for. The process can identify: a pre-disease
abnormality; early disease; or disease risk markers.

By the end of the lecture you should be able to:

I .Distinquish between screening and population based screening
ii.Expalin the aims of screening
ii.Descibe the process of screening.

The aim of screening for a disease or a risk marker for a disease is to reduce the burden of the
disease in the community including incidence of disease, morbidity from the disease or
mortality. This is achieved by intervening to reduce individual risk of the disease or detecting the
disease earlier on average than is usually the case in the absence of screening and thereby
improving disease outcome.

Screening can reduce the risk of developing or dying from a disease, but it does not guarantee
that disease will not occur, or if it occurs, that it can be cured. A ‗positive‘ screening test
identifies people who are at increased likelihood of having the condition and who require further
investigation to determine whether or not they have the disease or condition.

As screening has benefits, costs, and harms, there is an ethical obligation to maximise benefits
and minimise harm; and the overall benefits should outweigh any harms that result from
screening. In addition, when community resources are used to fund screening there should be
community consensus that the benefits of screening justify the expense of screening. there should
be community consensus that the benefits of screening justify the expense
of screening.
In 1968 Wilson and Jungner developed the WHO principles of screening.

- Condition
The condition should be an important health problem.
There should be a recognisable latent or early symptomatic stage.

The natural history of the condition, including development from latent to

declared disease should be adequately understood.

-Test
There should be a suitable test or examination.

The test should be acceptable to the population.

-Treatment
There should be an accepted treatment for patients with recognised disease.

-Screening Program
There should be an agreed policy on whom to treat as patients.

-Facilities for diagnosis and treatment should be available.

-The cost of case-findings (including diagnosis and treatment of patients diagnosed) should be
economically balanced in relation to possible expenditure on medical care as a whole.

-Case-findings should be a continuing process and not a ‗once and for all‘ project

1.Describe the factors considered in screening.

______________________________________________________________________________
______________________________________________________________________________
_____________________________

Population-based screening

is where a test is offered systematically to all individuals in the defined target group within a
framework of agreed policy, protocols, quality management, monitoring and evaluation.

The screening process

The screening process has the following steps;

1 .RECRUITMENT- Targted population encouraged to participate in screening

2. SCREENING-Targeted population who participate in screening
3.ASSESSMENT-Screened population who require further assessment
4.DIAGNOSIS-Assessed participants diagnosed with the disease or condition
5.OUTCOME-Reduced morbidity and mortality from the disease
Well done.You have suceesfully completed lecture 14 where you discussed about population
based screening as one of the major preventivs strategies.

Beaglehole R, Bonita R and Kjellstrom T, 1993 Basic Epidemiology Geneva WHO.

Elwood JM, 1990 Screening programmes in disease control In McNeil JJ, King RWF,