Scope of Epidemiology-2

Types of Epidemiological Investigations:

There are four approaches to epidemiological investigation

• Descriptive epidemiology
• Analytical epidemiology
• Experimental epidemiology
• Theoretical epidemiology

Descriptive epidemiology

Descriptive epidemiology involves observing and recording diseases and possible causal factors. “First part of an investigation” Observations may generate hypotheses that can be tested more rigorously later.

Analytical epidemiology

Analytical epidemiology is the analysis of observations using suitable diagnostic and statistical procedures.

Experimental epidemiology

• Experimental epidemiologists observe and analyze data from groups of animals from which they can select, and in which they can alter, the factors associated with the groups
• An important component of the experimental approach is the control of the groups
• Use of laboratory animals whose short lifespan enable events to be observed more rapidly than in humans

Theoretical epidemiology

Theoretical epidemiology consists of the representation of disease using mathematical ‘models’ that attempt to simulate natural patterns of disease occurrence. 

Epidemiological subdisciplines:

There are various epidemiological subdisciplines

Clinical epidemiology

Clinical epidemiology is the use of epidemiological principles, methods and findings in the care of individuals, with particular reference to diagnosis and prognosis.

Computational epidemiology

• Application of computer science to epidemiological studies
• Representation of disease by mathematical models
• Use of expert systems (Formulating disease control strategies, predicting animals productivity Supporting management decisions)

Genetic epidemiology

• Genetic epidemiology is the study of the cause, distribution and control of disease in related individuals, and of inherited defects in populations. Also explore Interactions between genetic and non-genetic factors.

Field epidemiology

• Field epidemiology is a timely, judgmental process based on description, analysis, common sense and the need to design practical control policies
• When outbreaks of foot-and –mouth disease occur, field epidemiologists promptly trace potential sources of infection in an attempt to limit spread of the disease.

Participatory epidemiology

• 1980 with development of veterinary services, animals were economically and socially important, use of local knowledge to gain information, with the main goal of improving animal health
• Techniques that are employed evolved in the social science, and consist of simple visual methods and interviews to generate qualitative data
• “Participatory epidemiology” it is a tool for the field epidemiologist, which is increasingly used in developing counties. Is concerned with local knowledge of, and practices relating to, the health of animals

Molecular epidemiology

• Study of small genetic and antigenic differences between viruses and other microorganisms at a higher level of discrimination
• The methods include peptide mapping, nucleic acid ‘fingerprinting’ and hybridization, restriction enzyme analysis, monoclonal antibodies and the polymerase chain reaction
• Nucleotide sequencing of foot-and–mouth  that some outbreaks of the disease involved vicinal strains, suggesting that improper inactivation or escape of virus from vaccine production plants. Unrestricted animals movement is a major factor in dissemination of the disease in West Africa.

Environmental Epidemiology:

• Concerned with the relationship between disease and environmental factors such as industrial pollution and occupational hazards

Micro-Epidemiology:

• Study of disease in a small group of individuals with respect to factors that influence its occurrence in larger segments of the population

Macro-Epidemiology:

Study of national patterns of disease, and the social, economic and political factors that influence them

Chronic disease epidemiology

Nutritional epidemiology

Subclinical epidemiology

Social epidemiology

Psychosocial epidemiology

Components of epidemiology:

The first stage in any investigation is the collection of relevant data. Investigations can be either qualitative or quantitative or a combination of these two approaches.

• Qualitative investigations
• Quantitative investigations

Qualitative investigations

• The natural history of disease
• The ecology of diseases, including the distribution, mode of transmission and maintenance of infectious diseases, is investigated by field observation. Field observations also may reveal information about factors that may directly or indirectly cause disease.
• Causal hypothesis testing
• If filed observations suggest that certain factors may be causally associated with a disease, than the association must be assessed by formulation a causal hypothesis

Quantitative investigations

• Quantitative investigations involve measurement (e.g., the number of cases of disease), and therefore expression and analysis of numerical values. Quantitative investigations include surveys, monitoring and surveillance, studies, modeling, and the biological and economic evaluation of disease control. Walls of the research organization- ‘armchair epidemiology’

Surveys

• A survey is an examination of an aggregate of units.       
• Surveys can be undertaken on a sample of the population.
• A census, a cross-sectional survey records events occurring at a particular point in time.
• A longitudinal survey records events over a period of time. Prospectively form the present into the future; on may be a retrospective record of past events. 
• In epidemiological surveys, characteristics might include the presence of particular diseases, or production parameters such as milk yield.

Screening

• A particular type of diagnostic survey is screening. Identification of undiagnosed cases of disease using rapid tests or examination
• Screening tests are not intended to be diagnostic; individuals with positive test results (i.e., that are classified as diseased by the screening test) usually require further investigation for definite diagnosis. They therefore differ from diagnostic tests.
• Screening involves investigation of the total population (mass screening). Targeted at animals only in areas where there have been cases of disease (strategic screening). Prescriptive screening aims at early identification of diseases that can be controlled better if they are detected early in their pathogenesis.

Monitoring and surveillance

• Monitoring is the making of routine observations on health, productivity and environmental factors and the recording and transmission of these observations.
• Recording of milk yields or routine recording of meat inspection findings at abattoirs
• Surveillance is a more intensive form of data recording than monitoring. Used to describe the tracing and observation of people who were in contact with cases of infectious disease Include all types of disease – infectious and non-infectious 
• It is normally part of control programmes for specific diseases.

Studies

There are four main types of epidemiological study:

• Experimental studies;
• Cross-sectional studies;
• Case-control studies;
• Cohort studies

Modelling

Using mathematical equations ‘Modelling’

Risk assessment

Evaluation of the risk of the occurrence of adverse, development of formal methods of quantitative and quantitative risk assessment e.g. Microbiological risk assessment with food safely risks, and estimation of the magnitude of microbial exposure at various stages in the production chain (rearing on the farm; transport and processing; retail and storage; preparation) to campylobacter spp and salmonella spp.

Disease control

The goal of epidemiology is to improve the veterinarian's knowledge so that diseases can be controlled effectively, and productivity thereby optimized. This can be fulfilled by treatment, prevention or eradication

Cholinergic Drugs

• Cholinergic drugs are those which release acetylcholine as neurotransmitter. These are of two types;
• Cholinergic drugs which act directly on postsynaptic membrane receptors are called as direct acting drugs.
• Cholinergic drugs which stop the activity of acetyl cholinesterase thus increasing the Ach in the synaptic cleft are known as indirect acting drugs.

Direct Acting Drugs

Direct acting cholinergic drugs include two types of drugs;

Natural Alkaloids… Which Include nicotine, muscarine, pilocarpine and arecoline

Synthetic Drugs… which include Acetylcholine, carbachol, methacholine and bethanicol

If an additional methyl group attaches on β carbon, methacholine is formed.

If an NH2 group is attached instead of methyl group in Acetyl choline (Acetyl co-a portion), carbachol is formed.

If a methyl group is attached on β carbon in structure of Carbachol, Bethanichol is formed.

• Nicotinic receptors are only stimulated by Ach and Carbachol.
• Muscarinic receptors are stimulated by all.

Prototype Drugs
Drugs which are representative of groups. These drugs are studied thoroughly and then compared with other members of the group. E.g. Ach

Effects on Different organ Systems

Therapeutic Uses

Acetylcholine

• It is of no therapeutic use because it is degraded rapidly because of presence of PsuedoCholinesterase or Buterylcholinesterase in the plasma.
• It Hydrolyzes Ach rapidly
• Acetylcholinesterase is present in RBCs, grey matter of brain and nerve endings.
• Pseudocholinesterase is also present in liver and intestine.
• So, effect of Ach will not be observed intravenously or there will be short lived effect.

Methacholine

• It is slowly hydrolyzed so duration of activity will be greater.
• The primary clinical use of methacholine is to diagnose bronchial hyper reactivity. Which is the hallmark of asthma and also occurs in chronic obstructive pulmonary disease
• This is accomplished through the bronchial challenge test, in which a subject inhales aerosolized methacholine, leading to bronchoconstriction.
• Other therapeutic uses are limited by its adverse cardiovascular effects, such as bradycardia and hypotension, which arise from its function as a cholinomimetic.

Carbachol

• It is not hydrolyzed by enzymes.
• It increases motility of intestine and uterus.
• Carbachol is a parasympathomimetic that stimulates both muscarinic and nicotinic receptors. In topical ocular and intraocular administration its principal effects are miosis and increased aqueous humour outflow. Aqueous humour is a thich watery substance filling the space b/w lens and cornea.
• In the cat and rat, carbachol is well-known for its ability to induce rapid eye movement (REM) sleep when microinjected into the pontine reticular formation.
• Carbachol elicits this REM sleep-like state via activation of postsynaptic muscarinic cholinergic receptors (mAChRs).

Bethanicol

• Bethanechol is used clinically to treat post-op paralytic ileus (GI), urinary retention (GU) and glaucoma.  (In glaucoma the choline ester, bethanechol, is used to reopen the channels while the soon to be seen adrenergics will help decrease aqueous humor production.)
• It can also be used for the treatment of the gastro esophageal reflux.

Indirect Acting Drugs

These drugs are reversible or irreversible inhibitors of Acetylcholinestrase.

Reversible Inhibitors

• These inhibitors block enzyme and detach from it after some time. 
• These include Edrophonium, Physostigmine, Neostigmine, Pyridostigmine and Carbaryl.

Irreversible Inhibitors

• These block enzymes permanently but do not detach from it. 
• These include organophosphates (Di isopropylflourophosphate..DFP), Echothiophate, Melathion, Parathion (both are insecticides), soman, tabnum, cumaphos, trichlorofen and dichlorofen ( last 3 are used against ectoparasites).

Acetylcholinesterase

• This enzyme has two reactive sites which are used for hydrolysis of compounds like Ach.
• These sites are anionic and esteratic sites. Anionic site attaches to N portion of Ach and Esteratic site attaches to Carbon of Ach. So, complex is formed.
• After this, addition of water occurs and acetylated Enzyme and choline detaches.
• In the last step, choline detaches from esteratic site.

 

Edrophonium

Edrophonium first occupies anionic site and then OH covers the esteratic site and complex forms.

Its activity is short lived and again cholinesterase starts working after some time.

• Because its duration of action is only about 20 minutes, edrophonium (by the so-called Tensilon test) is used to differentiate myasthenia gravis from cholinergic crisis.
• In myasthenia gravis, where a person is not able to produce enough neuromuscular stimulation, edrophonium will reduce the muscle weakness by effectively supplying more acetylcholine.
• In a cholinergic crisis, where a person has too much neuromuscular stimulation, edrophonium will make the muscle weakness worse by inducing a depolarizing block.

Neostigmine

• When complex is formed, addition of water occurs.
• Anionic site become free but esteratic site remained occupied and carbamylated enzyme is formed.
• After some time, both sites become free.
• Neostigmine is converted into 3-HPTA (Hydroxy phenyl trimethyl acetate) and DMCA (dimethyl carbamic Acid) during the reaction.
• It is used to improve muscle tone in people with myasthenia gravis and routinely, in anesthesia at the end of an operation, to reverse the effects of non-depolarizing muscle relaxants such as rocuronium and vecuronium.
• It can also be used for urinary retention resulting from general anesthesia and to treat curariform drug toxicity.
• Another indication for use is the Ogilvie syndrome which is a pseudoobstruction of the colon in critically ill patients.
• Historically, it has been used as a test for early pregnancy. In a non-pregnant female whose menstrual period is delayed, administration of neostigmine can provoke menstrual bleeding. Modern tests which rely on detecting hCG in urine have rendered this application obsolete.
• Though one of only two treatments available for myasthenia gravis this drug is no longer available to anyone using the Medicare Part D program.

How Irreversible Inhibitors Act?

Organophosphates

• DFP interacts with esteratic site and occupies it. Enzyme becomes inactive.
• After some time, covalent bond if formed and it cannot be separated.
• Enzyme substrate complex in this reaction is phosphorylated enzyme.
• This enzyme is also called as aged enzyme and the process is called as aging of enzyme. This enzyme is long lived.
• Substances which reactivate the enzyme are called reactivators of enzyme. E.g. class Oximes which include paraladoxine and obidoxine.
• Paraladoxine first attaches itself to anionic site with N portion and then attaches to phosphate of DFP and separates it from Esteratic site. Then, 2-PAM itself detaches from anionic site and enzyme is free.
• Reactivation can only occur before the formation of covalent bond.

 

Signs of organophosphate poisoning

Signs of organophosphate poisoning include:

• Salivation
• Lacrimation
• Urinary incontinence
• Defecation
• GI upset/diarrhea
• Emesis
• miosis

Therapeutic uses of Organophosphates

• Several organophosphate agents are being tried therapeutically. Cholinesterase inhibition, which in large doses makes these agents effective pesticides, also may be useful in other doses for treating dementia. Metrifonate has been used to treat schistosomiasis and is undergoing trials for the treatment of primary degenerative dementia.
• The organophosphates pyridostigmine and physostigmine are carbamate anticholinesterases that have been used for many years for the treatment of myasthenia gravis. Although the short-duration anticholinesterases are generally safe, reports of their abuse are associated with a picture similar to pesticide intoxication.
• One of the author's patients had been diagnosed erroneously as a myasthenic. Long-term "therapeutic" doses of physostigmine chemically altered her neuromuscular junctions to the point where she had to be slowly weaned from the drug.
• Sung and others have reported on the ability of these substances to induce nicotinic receptor modulation. This explains the action of these drugs and may result in development of more effective agents.

Cholinergic Transmission

Cholinergic transmission occurs in many steps;

Synthesis

• It takes place in neurons.
• Choline is taken up by active transport from outside.
• Choline combines with acetyl-coA with the help of enzyme choline acetyl transferase (CAT) also called as choline acetylase. This enzyme is present inside the nerve fibers.
• In this way, acetylecholine is synthesized. Hemicholinine can stop the uptake of choline.

Storage

Acetylcholine molecules are stored inside vesicles in the nerve endings.

Release

• Storage vesicles empty Ach into synaptic cleft. Opening of ca channels occur and there is influx of calcium ions which help in release of Ach from the vesicles.
• Drugs also work in the same way. E.g. carbachol
• Some factors decrease this release. E.g. calcium deficiency

Binding

Ach binds with receptors on post-synaptic membrane and stimulates these receptors.

Removal

Ach is removed with the help of enzyme acetylcholinesterase (AchE).
Ach----------------------------------------choline + acetate.
This reaction occurs in the presence of Acetylcholinesterase.