Essential Hypertension
In about 95% of cases of high blood pressure the cause is unknown, and this condition is
referred to as “essential hypertension” or “primary hypertension”. It is treatable but
not curable.8 It is more common in adolescents.5, 6

Essential hypertension is of two types.13
1. Benign hypertension11
2. Malignant hypertension11

Benign hypertension
In early stages of this condition, there is a moderate increase in blood pressure. E.g.
200/100 mmHg. The blood pressure, especially the systolic, fluctuates considerably.
During sleep or emotional and physical rest, the blood pressure returns to normal level. In
stages of stress, the pressure rises to higher levels. Later there is further increase in blood
pressure and it doesn’t come back to normal level in resting conditions, too.
Malignant hypertension
This is also called accelerated hypertension. During this, the blood pressure is rapidly
elevated to a large extent of about 250/150 mmHg, much higher than the benign form.
This is always developed due to combined effect of primary and secondary hypertension.
Patients with malignant hypertension need immediate hospitalization and treatment. If
not treated, they can die within 6 to 12 months; however, normal life expectancy can be
restored with medical treatment unless the kidney is already impaired.
Recognized Causes
1. Genetic factors3,9
2. Foetal factors9
3. Environmental factors9
Genetic factors
Blood pressure levels tend to correlate within a family partly due to genetic factors.
Foetal factors
Studies have consistently shown a relationship between lower birth weight and
subsequent higher blood pressures. This relationship may be due to foetal adaptation in
intrauterine undernutrition with long term changes in blood vessel structure or in the
function of crucial hormonal systems.
Environmental factors
Obesity 9
Blood pressure is associated with overall body mass and more closely with central
obesity.
Alcohol9
Heavy alcohol intake (greater than 6 units per day) is associated with an increase in blood
pressure. Moderate drinking (2-3 units daily) does not appear to exert a pressure effect.
Electrolyte intake9
There’s a positive association between sodium intake and blood pressure, but negative
association between potassium intake and blood pressure. By combining the two into a
sodium-potassium ratio, a closer correlation has been observed.
Stress9
An acute major rise in blood pressure can be produced by acute pain, tension, or mental
stress, but it is much more difficult to show the chronic stress produces sustained
elevation of blood pressure.
Vegetarian diet
Vegetarians have lower blood pressures at all ages than omnivores. Increased intake of
fruits and vegetables has been shown to lower blood pressure in omnivore hypertensives.
One possibility is that an unsaturated vegetable fat lowers the blood pressure.
Insulin resistance9,12
An association between diabetes and hypertension has long been recognized, but more
recently a syndrome has been described of hyperinsulinaemia, glucose intolerance,
reduced levels of HDL cholesterol, hypertriglyceridaemia and central obesity (all of
which are related to insulin resistance) in association with hypertension.

Secondary Hypertension
In the remaining 5% of cases, high blood pressure is a symptom of a recognizable
underlying problem such as a kidney abnormality, endocrine disorder or medication.
When the root cause is corrected, blood pressure usually returns to normal. This
type of high blood pressure is called “secondary hypertension” because it is
hypertension caused by another disorder.
Some causes for secondary hypertension
Renal disorders
Renal artery stenosis
Chronic renal disease
Endocrine disorders9
Primary hyperaldosteronism
Hyper- or hypothyroidism
Pheochromocytoma
Cushing syndrome
Growth hormone hypersecretion
Cardiovascular disorders9
Aortic coarctation
Atherosclerosis
Neurogenic disorders
Pregnancy
Renal artery stenosis (renovascular disease)
Renal artery disease can cause of narrowing of the vessel lumen (stenosis). The
reduced lumen diameter increases the pressure drop along the length of the diseased
artery, which reduces the pressure at the afferent arteriole in the kidney. Reduced
arteriolar pressure and reduced renal perfusion stimulate renin release by the kidney.
This increases circulating angiotensin II and aldosterone. These hormones increase
blood volume by enhancing renal reabsorption of sodium and water. Increased
angiotensin II causes systemic vasoconstriction and enhances sympathetic activity.
Chronic elevation of angiotensin II promotes cardiac and vascular hypertrophy. The
net effect of these renal mechanisms is an increase in blood volume that augments
cardiac output by the Frank-Starling mechanism. Therefore, hypertension caused by
renal artery stenosis results from both an increase in systemic vascular resistance and
an increase in cardiac output.
Chronic renal disease
Any number of pathologic processes (e.g., diabetic nephropathy, glomerulonephritis)
can damage nephrons in the kidney. When this occurs, the kidney cannot excrete
normal amounts of sodium which leads to sodium and water retention, increased
blood volume, and increased cardiac output by the Frank-Starling mechanism. Renal
disease may also result in increased release of renin leading to a renin-dependent
form of hypertension. The elevation in arterial pressure secondary to renal disease
can be viewed as an attempt by the kidney to increase renal perfusion and restore
glomerular filtration.

Primary hyperaldosteronism (Conn’s syndrome)
Increased secretion of aldosterone generally results from adrenal adenoma or adrenal
hyperplasia. Increased circulating aldosterone causes renal retention of sodium and
water, so blood volume and arterial pressure increase. Plasma renin levels are
generally decreased as the body attempts to suppress the renin-angiotensin system;
there is also hypokalemia associated with the high levels of aldosterone.
Hyper- or hypothyroidism
Excessive thyroid hormone induces systemic vasoconstriction, an increase in blood
volume, and increased cardiac activity, all of which can lead to hypertension. It is
less clear why some patients with hypothyroidism develop hypertension, but it may
be related to decreased tissue metabolism reducing the release of vasodilator
metabolites, thereby producing vasoconstriction and increased systemic vascular
resistance.
Pheochromocytoma
Catecholamine secreting tumors in the adrenal medulla can lead to very high levels
of circulating catecholamines (both epinephrine and norepinephrine). This leads to
alpha-adrenoceptor mediated systemic vasoconstriction and beta-adrenoceptor
mediated cardiac stimulation, both of which contribute to significant elevations in
arterial pressure. Despite the elevation in arterial pressure, tachycardia occurs
because of the direct effects of the catecholamines on the heart and vasculature.
Excessive beta-adrenoceptor stimulation in the heart often leads to arrhythmias. The
pheochromocytoma is diagnosed by measuring plasma or urine catecholamine levels
and their metabolites (vanillylmandelic acid and metanephrine).
Cushing’s syndrome

Both adrenal glands can overproduce the hormone cortisol or it can arise in a benign or

malignant tumor. Hypertension results from the interplay of several pathophysiological

mechanisms regulating plasma volume, peripheral vascular resistance and cardiac output,

all of which may be increased. More than 80 percent of patients with Cushing’s syndrome

have hypertension.
Growth Hormone excess
Growth hormone induces sodium retention, thus increasing fluid volume and blood
pressure.
Aortic coarctation
Coarctation, or narrowing of the aorta (typically just distal to the left subclavian
artery), is a congenital defect that obstructs aortic outflow leading to elevated
pressures proximal to the coarctation (i.e., elevated arterial pressures in the head and
arms). Distal pressures, however, are not necessarily reduced as would be expected
from the hemodynamics associated with a stenosis. The reason for this is that
reduced systemic blood flow, and in particular reduced renal blood flow, leads to an
increase in the release of renin and an activation of the renin-angitensin-aldosteron
system.This in turn elevates blood volume and arterial pressure. Although the
aortic arch and carotid sinus baroreceptors are exposed to higher than normal
pressures, the baroreceptor reflex is blunted due to structural changes in the walls of
vessels where the baroreceptors are located. Also, baroreceptors become
desensitized to chronic elevation in pressure and become “reset” to the higher
pressure.

Pregnancy
Although few women of childbearing age have high blood pressure, up to 10% develop
hypertension of pregnancy. While generally benign, it may herald three complications of
pregnancy: pre-eclampsia, HELLP syndrome and eclampsia. Follow-up and control with
medication is therefore often necessary. Hypertension is very dangerous to pregnant
women and causes miscarriages

Hypertension Risk Factors
There are two types of factors that may place a person at increased risk for high blood
pressure:
1. Risk factors that are beyond control (predetermined)
2. Lifestyle or modifiable risk factors.

Predetermined Risk Factors
Some risk factors are beyond control. These include:
Family history: A person is more likely to develop high blood pressure if his parents
also had it.
Sex: Men are more likely to develop high blood pressure at a younger age than
women. Women are at a higher risk after age 60.
Age: High blood pressure generally occurs in people over 30 years old.
Race: African-Americans are at higher risk for developing high blood pressure, heart
disease, stroke and kidney failure.
Lifestyle Risk Factors
High blood pressure is often related to lifestyle factors.
The most common lifestyle factors that affect blood pressure are:
• Obesity
• Excess sodium (salt) in diet.
• Habitual alcohol use
• Smoking
• Exercise
• Use of certain medications, drugs, or other chemicals
• Anxiety or stress
• Agitation
• Pain
• Diabetes mellitus type1 and 11
• Other modifiable disorders - e.g. arteriosclerosis

Symptoms and signs
Hypertension has been described as “the silent killer” because it often occurs without
symptoms - indeed most people with high blood pressure don’t know they have it until
their blood pressure is checked. One out of four people with high blood pressure is
unaware of their condition.
There are symptoms associated with hypertension but by and large these symptoms are
not specific to high blood pressure.

These may include:
• headache (occasionally)
• tiredness
• confusion, anxiety
• vision changes
• nausea, vomiting
• excessive perspiration
• pale skin, or redness of the face or other areas
• muscle tremors
• angina-like pain: crushing substernal chest pain
• spleenomegaly
• nosebleeds
• heartbeat sensations e.g. palpitations
• ear noise/buzzing
• stroke
• congestive cardiac failure

Investigations commonly performed in newly diagnosed hypertension
Tests are undertaken to identify possible causes of secondary hypertension, and seek
evidence for end-organ damage to the heart itself or the eyes (retina) and kidneys.
Diabetes and raised cholesterol levels being additional risk factors for the development
of cardiovascular disease are also tested for as they will also require management.

Blood tests commonly performed include:
• Creatinine (renal function) - to identify both underlying renal disease as a cause of hypertension and conversely hypertension causing onset of kidney damage. Also a baseline for later monitoring the possible side-effects of certain antihypertensive drugs.
• Electrolytes (sodium, potassium)
• Glucose - to identify diabetes mellitus
• Cholesterol
Additional tests often include:
• Testing of urine samples for proteinuria – It is to pick up underlying kidney disease or evidence of hypertensive renal damage.
• Electrocardiogram (EKG/ECG) – It is for evidence of the heart being under strain from working against a high blood pressure. Also it may show left ventricular hypertrophy or of the occurrence of previous silent cardiac disease (either subtle electrical conduction disruption or even a myocardial infarction).
• Chest X-ray – It is to check for signs of cardiac enlargement or evidence of cardiac failure.

COMPLICATIONS
There are many serious complications that can result from hypertension - both life
threatening as well as seriously debilitating, which serves to underline the importance of
prevention and treatment of hypertension.
Some of the main ones include:
Heart
• heart attacks
• congestive heart failure
Blood vessels
• blood vessel damage (arteriosclerosis)
• hyaline degeneration
• aortic dissection (tearing of the aorta)
• micro- angiopathic haemolytic anaemia
Brain
• stroke
• brain damage (encephalopathy) 4
• Berry aneurysms
• cerebral thrombosis
• cerebral embolization
Eye
• impaired vision
Kidney
• kidney damage

Stroke and coronary heart disease.

Hypertension causes hardening of arterial walls, clot formation, atheroma and obstruction

of blood vessels, such as the aorta and the arteries supplying blood to the brain, heart,

kidneys and legs. Obstruction of blood flow in these vessels causes transient ischemic

attacks (sometimes called mini-strokes) in parts of the brain, heart attack, myocardial

infaction or pain in the leg muscles (due to poor blood supply to the legs).

Hypertension is considered an important risk factor for a type of irregular heart beat,

called atrial fibrillation, in the upper chambers of the heart. This condition is associated

with a three- to five-fold increase in the risk of strokes.

Left ventricular hypertrophy

Due to increased peripheral resistance, the heart must work hard to have enough cardiac

output to pump blood to every part of the body. This increased workload causes the

muscles of the left ventricle of the heart to become thicker. The enlarged left ventricle

requires more blood supply, but the coronary arteries may not provide enough blood

because they are narrowed, so the myocardium becomes ischaemic as well. It leads to left

ventricular failure. Failure also reduces left ventricular compliance in diastole, and the

maintenance of cardiac output may require higher filling pressure produced by increased

capacitance vessel tone. Thus, patients with this condition have more frequent heart

attacks and congestive heart failure.

Congestive cardiac failure

This may occur with little evidence of either previous or concurrent left ventricular

failure. Nevertheless there is almost always elevation of left ventricular end -diastolic

pressure and the pulmonary hypertension. The right ventricle dilates and systemic venous

pressure is elevated without the development of pulmonary oedema.

Vascular hypertrophy

Arteries and arterioles show hypertrophy as a response to the increased work load.

Hypertrophy occurs due to fibrous thickening of the tunica intima, duplicating of the

internal elastic lamina and hypertrophy of smooth muscle.

Atheroma

Atheromatous plaques occur in the arterial intima and consist of swelling of ground

substance, disintegration of elastic fibers and deposition of lipoproteins. Associated with

these changes there is atrophy of the overlying media. Thrombosis may occur as a sequel

to atheromatous change.

Hyaline degeneration

There is a patchy, hyaline eosinophilic thickening of the whole vessel wall beginning in

the sub endothelial region and extending to media. In a hypertensive person, arteriolar

compliance is reduced. This affects the barorecepter function and thus may impair the

circulatory reflexes.
Micro- angiopathic haemolytic anaemia
Malignant hypertension is usually associated with some evidence of intravascular
coagulation although in some patients, the changes may be minimal. There is haemolytic
anaemia, with deformed red cells, thrombocytopenia, fibrin degradation product in
plasma and urine and accelerated fibrinogen catabolism.

Aneurysm.
High blood pressure weakens the wall of the blood vessels, resulting in an aneurysm

especially in the brain and the aorta. Aneurysm breaks easily, potentially leading to

dangerous bleeding in the brain and the abdomen.
Brain damage (encephalopathy)
Hypertensive encephalopathy can result from elevation of blood pressure above the
autoregulatory range (which may extend upto a mean pressure of 150-200 mmHg in
hypertensive individuals). The focal breakdown of autoregulation causes areas of
vasodilatation with associated oedema. Despite the increase in local cerebral blood flow,
localized ischaemia and actual infarction may result, as well as petechial haemorrhages.
Berry aneurysms
These occur at the junction of extra cerebral vessels, where there is a developmental

absence of tunica media. They are the source of subarachnoid haemorrhage and occur

with increased frequency in polycystic renal disease, coarctation and hypertension.

Kidney damage.
Hypertension damages the kidneys by narrowing the main arteries supplying the kidneys
and damaging the small arteries within the kidneys. These effects lead to progressive loss
of kidney function and renal failure, eventually.
Impaired Vision

High blood pressure can eventually cause blood vessels in the eye to burst or bleed.

Vision may become blurred or otherwise impaired and can result in blindness.

MANAGING HYPERTENSION
Depending on the cause for the hypertension, treatment plan may include
lifestyle changes,
medication or a combination of both.
Lifestyle Changes
When high blood pressure is caused by lifestyle factors, the most effective way to control
it can be to change the behavior.
Achieve ideal body weight. Losing weight is the most effective non-clinical way
lowering the blood pressure. On average, a 10-pound weight loss will lower both
systolic and diastolic blood pressure measurement by about 5 mm Hg.
Restrict salt intake. It is recommended that healthy adults should have no more than
2400 mg of sodium or 1 1/4 teaspoons of salt per day.
• choose foods low in salt, such as fresh fruit and vegetables;
• avoid foods high in salt, such as processed meats, canned foods and snack foods;
• Avoid adding salt at the table, and minimize its use in cooking.
• Increase dietary potassium- Bananas, oranges, potatoes, tomatoes, milk, nuts, and cereals
Limit alcohol intake. Depending on the situation, fewer than three drinks or avoiding
alcohol completely is necessary.
Quit smoking. Smoking a cigarette can raise the blood pressure by 5 to 10 mm Hg
for about 30 minutes. It also greatly increases the risk of heart disease and stroke.
Exercise. Regular aerobic exercise and daily physical activity play a major role in the
prevention of high blood pressure, obesity, diabetes and heart disease. Aerobic
exercise involves continuous movement of the large muscle groups in the arms and
legs. These exercises benefit the heart by making it beat faster and more efficiently. If
performed daily, even moderate activities, such as gardening and housework, can
have long-term health benefits.
Relaxation therapy, such as meditation, that reduces environmental stress, high
sound levels and over-illumination can be an additional method of ameliorating
hypertension.

Blood Pressure Medication

There are five types of blood pressure medications, each made up of numerous

medicines. Each type acts in a different way to lower your blood pressure.
• Thiazides or Thiazide-like Diuretics10
• Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers 10
• Alpha blockers, beta blockers, or combined alpha and beta blockers 10
• Calcium channel blockers 10.
• Vasodilators
Homeopathy14
Homeopathy may be useful as a supportive therapy.
Acupuncture14
Acupuncture may help reduce blood pressure and alleviate stress.
Massage14
Therapeutic massage may be effective in reducing the effects of stress, helping relaxation, and lowering blood pressure.

2. Physiologic influence of sleep
Sleep is directly or indirectly effects in the human body. Lack of sleep causes functional changes in the central nervous system. Prolong wakefulness is caused to less functional of thinking process. If a person does not sleep for a long time it can be cause to abnormal behaviors also. And person can become insane after forced wakefulness.
All these mean that the sleep is an essential factor for keeping the brain activity in normal functioning state. The overusing of some brain area causes unbalance of whole brain stem and central nervous system. Therefore the principal importance of sleep maintains the natural balance among the neuronal centers.
Though sleep is directly affected to the central nervous system, it is not directly affect on somatic body functions. But prolonged sleep can indirectly involve with changes of body functions.
During wakefulness, the sympathetic activities are increased, and also nerve impulses to skeletal muscles tone. But during the sleep sympathetic activities are decreased and parasympathetic activities are increased.
So in sleep,
Arterial blood pressure falls
Skin resells dilate
Pulse rate decreases
Skeletal muscle becomes relaxed state etc…Because of all these activities whole basal metabolic rate of the body falls and body became rest state in sleep.

4. Stages of sleep . . .

Sleep can be roughly divided into two broad stages.
1. NREM sleep – (non –REM)
2. REM sleep –(Repaid eye movement sleep)
4.1. Non – REM sleep :-
This is also called as slow wave sleep. In this type of sleep the brain waves are very slow but very large. N-REM sleep is divided into four stages. The variations between those stages can be seen in an electroencephalogram.

Stage 1:-
The characteristic features of this stage are more similar in EEG waves of REM sleep. These waves are with low amplitude and high frequency. The waves are theta type. In this stage the person has very light sleep.
Stage 2:-
The characteristic features of this stage are the appearance of distinctive sleep spindles. Short spindles shaped bursts of alpha waves occur in EEG of this stage. This stage occupies about one-half of total sleep time.
Stage 3:-
Here frequency of waves become lower and amplitude get increased.
Stage 4:-
Person becomes deep sleep in this stage. So waves are very slow and can see large waves. These waves are rhythmic waves, which indicates the synchronization (operating at the same rate and simultaneously)
3rd and 4rt stage occupy about 15% of total sleep time.
The deeper stages (3rd&4th) of slow wave sleep occur primarily in the 1st half of the sleep period. The lighter stages of slow wave sleep (1st, 2nd) and long REM sleep occurs in second half of the sleep period. Thus the early morning is more like to be frequent awakenings.
After 60-90 minutes of NREM sleep, there is a gradual increase in the activity of cells in the pontine tegmentum which is responsible for triggering REM sleep 1,2.
4.2. REM sleep:-
The characteristic of REM sleep is, waves with low amplitude and high frequence, in EEG.
During REM sleep the threshold for arousal by environmental stimuli is increased. It has been known that the active dreaming occurs during this period. So body muscles can have movements in REM sleep 1
Heart rate and respiratory rate can be irregular in order to dream state. Increase in blood circulation and use of O2, as well as an increase in the uptake of amino acids by the brain tissue are some other features of REM sleep.
The REM sleep is also called as paradoxical sleep, because the brain activities are rapid, though the person is asleep. But brain activities are not focus in certain direction; so person have not an idea about his surrounding.12

REM sleep occupies 20-25% of daily sleep time in young adult.
The need of REM sleep shows since uterus. REM sleep fills approximately 80% of the total sleep of infants born 10 week prematurely.2
- 60-65% of sleep lime of those born 2-4 weeks prematurely.
- In full term neonate 50% of their 16 hrs sleep period of day is REM sleep.
- After 2 years it declines until 30-35% and stabilized at 25% by 10 years.

5. The Neurological influence of sleep
The generation of REM and NREM sleep types is under control of two nuclei in the brainstem, the locus ceruleus and the raphe nucleus.
The cells of the locus ceruleus secrete noradrinaline. If this is destroyed, the result is the abolition of REM sleep, but not slow-wave sleep.4 During REM sleep, noradrinaline supplies in a small pontine structure called the pedunculopontine segmental nucleus (PPN) get gradually exhausted and this may be the main regulatory factor that drives back towards NREM sleep.5 As the activity of the PPN decreased, the activity in the locus ceruleus increases. Locus ceruleus is considered to be the REM switch off. The cells of the nuclei of the raphe , reduce both types of sleep and results sleeplessness. Serotonin induces sleep and that destruction of 80% - 90% of raphe cells produced complete sleeplessness.
So a person in the less serotonin secretion becomes critical difficulty with sleep. Parachlorophenylalanine (PCPA) inhibits the synthesis of serotonin. When PCPA is administered, it leads initially to sleeplessness. But after only one week of daily injections, 70% of it becomes normal. However REM phase activity is no longer confined to REM sleep period, but emerges in all sleep stages and even in the waking state.
Now it has found that in normal individual serotonin secreting cells decrease their firing and become completely silent during REM sleep.4 So these cells inhibit phase REM sleep events. The reason to raphe lesions initially prevent sleep is waking stimuli can not be shut off. Other than those nuclei, nucleus of the solitary tract is a secondary medullary system. This also involved in inducing sleep. Since activation of this in sleeplessness (insomnia), it effects on sleep by modulating the arousal properties of the reticular formation. Electrical stimulation of the nucleus upon forebrain EEG activity that long outlasts the stimulation. This portion of medulla is involved in autonomic regulation and receives taste and visceral afferent input principally the vagus (x) nerve and glossopharyngeal (ix) nerve. Stimulation of afferent fibers in the vagus nerve also produces EEG synchrony, as do low-frequency (3 - 8 H2) stimulation of certain cutaneous nerves.

The suprachiasmatic nucleus serves as the biological clock for the sleep– wake cycle. This is located in the hypothalamus and adjacent basal forebrain which also essential for the induction of normal sleep.

5. Dimensions of consciousness
Consciousness is the awareness of experience. There may be awareness of objects or self –reflection
- Awareness of objects means the capacity to be aware of oneself as an objects.
- Self–reflection means the subjective experiencing of self.

There are three conditions that diminishing the consciousness.
1. Wakefulness and sleep
2. Clouding
3. consciousness of sleep
1. Wakefulness and sleep :-
Wakefulness and sleep is not uniform or unvarying but it is fluctuating.
Some factors promote the wakefulness.
E.g. - interest, anxiety, extreme fear, enjoyment
Some factors are promoted the sleep.
E.g.– Boredom.
The situation in the environment and the way of person perceives that situation also effect the sleep –wakefulness circle. Some abnormal states of health increase wakefulness and many diminish it.
A scanning a radar screen of a person in, wakeful state of mind is very different between an enemy interceptor and a music listening person Scanning of a person in sleep is more different than both above individuals.
Sleep is affected by some drugs.
REM and four stages of slow- wave sleep are differentially affected by these drugs.
Examples for the drugs that suppress the REM sleep is, psychoactive agents, alcohol, barbiturate, etc. But stage 4 of slow- wave sleep is not affected by these drugs.
Benzodiazepines reduces the stage 4

Stage of sleep Preconscious not readily available

Stages of sleep Preconscious readily available

Clouding

Drowsiness

Death

6. Dreams and sleep. . .

The discovery between REM sleep and visual dreaming in humans has found many notices about dream. In past scientists were believed that dreaming is rare, modern physiological studies have shown that everyone dreams. People think dreams are not remembered. The probability of them is not common because most of them are not remembered. The probability recalls in a dream become zero during slow-wave sleep, within 8 minutes after REM sleep. As a result of that usually remember only morning dreams.

There is a parallel increase through successive REM sleep, in the intensity of emotional tone and the activity of visual imagery in the content of the recalled them. Eventful dreams are more associated with more frequent REM than inactive dreams.
Form the ancient times dreams have been regarded as important factor which predict the future. Dreams are really experienced incidents during waking state. The congenitally blind have only auditory dreams, and they not seen visual dreams.

7. Why sleep is important?

Sleep is a basic human need. It is a natural part of every human life. But many of people know very few about how imports it is. Because of that they not get adequate sleep for a night. During sleep many of the babies’ major organs and regulatory systems continue to work actively.
Sleep like diet and exercise, is important to maintain our body and mind healthy. Children need at least 9 hours of sleep. And adults need approximately 8 hours of sleep each night.

When we get less sleep (one hour less) than we need to each night, it may cause to problem sleepiness, when we must be awake and active. It reduces our ability to function. Even not feel sleepy, lack of night sleep cause to less day time performance, thinking and mood.
Inadequate sleep can cause decrease in;
• Performance
• Concentration
• Reaction times
• Consolidation of information learning

Inadequate sleep can cause increase in;
• Memory lapses
• Accidents and injuries
• Behavior problems
• Mood problems

8. Physical changes during sleep

Many studies have been performed on the changes in physiology as organisms move between sleep and wakeful states. As sleep onsets occurs, basic metabolism slows down, resulting in a decrease in heart rate, blood pressure, respiration, core body temperature 12. A slower metabolism is maintained during all NREM stages of sleep throughout the duration of sleep until the organism wakes. Decreased activity in these physiological functions only applies to NREM sleep. During REM sleep there are shape rises in heart rate, blood pressure, respiration and core body temperature.

A large number of researches have done on the physiological changes of sleep in humans. In their studies they found that average heart rate fell down from 74/min to 52/min through the 1st 5 hours of sleep and then rise to 73/min just before awake. Some fluctuations in heart rate were present throughout sleep including shape rises up to 160/min during REM periods.

For respiration there is a general decline in tone through sleep. Before sleep there was an average breathing rate 18.3/min. This fell to a low of 16/min during stage four sleep, but would rise as high as 20/min during sleep seem obvious 7. The activity of the skeletal muscle greatly reduces during sleep and therefore requires lower amounts of ATP. Reduced need for ATP would results in a decreased rate for respiration and circulation. Reduction in body temperature results from a general decrease in the rate of metabolism.
The simple explanation becomes problematic when one addresses certain theories of sleep which claim that sleep provides a period of physiological systems. If there are increased in anabolic metabolism during sleep, these increases are slight and whatever decreased need of ATP in the skeletal muscles.
Why does though the decrease in activity of physiological system during sleep, the activity of these system increases during REM sleep?6 Skeletal muscle activity may increase slightly during REM periods, but not to the respiration and circulation, activity during REM is an arousal response to dreaming. Why dreaming occurs highly and why the body arouses itself is response to dream are questions that must answered for now.

9. Changes in systems of body during sleep
9.1. Respiratory system
In deep sleep, alveolar ventilation is decreased. Alveolar PCO2 rises from 40-60 mm Hg. Therefore, decreases the CO2 stimulus other than that anoxia increases pulmonary ventilation same in sleeping in an awake man; this occurs because the carotid and aortic bodies are so resistance to depression by anesthesia.
Other reflexes also change during sleep. One of these is the response to obstruction of the air way. But in this case person is not paralyzed or died, because he wakens instantly and, inspires forcefully even when he is in very deep sleep7.

9.2. Cardiovascular system
Control of cardiovascular parameters is a virtual function during wakefulness and sleep. Maintaining blood pressure within normal limits ensures sufficient O2 and energy supply as well as transport of metabolic products to the organs. There are several changes in cardiovascular system during sleep 8. In slow wave sleep blood pressure, cardiac output, heart rate, and peripheral vascular resistance are reduced. The bradycardia and hypotension accompanied with slow wave sleep. The hypotension is due to reduction of systemic vascular resistance and bradicardia is due to an increase in vagal activation.
During REM sleep sympathetic drive decreases in the splanchnic and renal circulation but increase in skeletal-muscle vessels. Initially pronounced decrease in blood pressure. It is interrupted by large, transient increase in blood pressure and in heart rate during increase in blood pressure and in heart rate during which sympathetic vasoconstriction in muscle further increases 9.
9.3. Renal system
Kidney filtration, plasma flow, and excretion of sodium, chloride, potassium, and calcium all are reduced sleep. These changes cause urine to be more concentrated during sleep.
There is also sleep related increase in plasma aldesterone levels, an increase in prolactin secretion. There is increased parathyroid hormone release during sleep, which may effect Ca excretion.
In general following are reduced during sleep.
*glomerular filtration rate
*Renal plasma flow
*Filtration fraction
Smaller quantities more concentrated urine is excreted during slow wave sleep than during wakefulness. During REM sleep urine excretion is decreased and concentrated to a greater extent than slow wave sleep.

9.4. Endocrine system
Most hormone secretions are controlled by the circadian clock or in response to physiological events. A number of hormones are secreted during sleep. Growth hormones related in part to repair processes that occur during sleep. Thyroid stimulating hormone released prior to sleep. Follicle stimulating hormone and luteinizing hormone which are involved in maturation and reproductive processes are released during sleep. Pulses of TCH and cortisol are released to superficial phases of the sleep.
As a result of the consolidation of the sleep period, the wake-sleep transition is associated with physiological changes with the endocrine system being part of the adaptive mechanism to reduce physical activity during sleep 13.

9.5. Gastrointestestinal system
In a person with normal digestive function, gastric acid secretion reduced during sleep. In those with an active ulcer, gastric acid secretion is actually increased and swallowing occurs less frequently.

10. Sleep related social and physical activities.
The Physiological function of sleep has not been clear. But it assumes sleep is associated with rest and time for mental regeneration. And also involve in memory formation and learning. Researches have been found the importance of the hippocampus, a small brain organ, for memory formation. The hippocampus acts as the central switchboard for the brain that can easily store short term memory patterns. These patterns have to be encoded in the neocortex to provide space for cording new short term memories. This complex process of rebuilding the neural network of the brain takes place during sleep.
Daily requirement of sleeping duration is vary according to the age

10.1 To children:-
More children need at least nine hours of sleep a night. Disturbed sleep in school children badly affect their day today school performances and neurocognitive abilities. The main disturbance to children’s sleep may be disordered breathing at night. Poor sleep cases to poor performance of students.

As children get less than nine hours of sleep at night sleeping patterns maybe changed and it can badly effect to the educates. It has been found number of experiments that REM sleep is important for learning. Some scientists believe that REM is needed to reinforce little used synaptic connections, other that REM optimizes the memory storage and reactivate infrequently used circuits and it is necessary to prevent forgetting. REM sleep helps the brain recover from slow wave sleep, and REM evolved just to fine-tune bifocal vision or to prevent corneal anoxia by nourishing the cornea 14.

10. 2. In adults:-
The amount of sleep a person gets affects his or her physical health emotional well-being mental abilities, productivity and performance. Lack of sleep causes serious health problems such as an increased risk of depression, obesity, cardiovascular diseases and diabetes.
Sleep is a trouble more than half of adults over the age of 55 years. They have very lighter sleep and more likely to awake frequently during

11. Homeostatic regulation of short and long sleep

Homeostatic sleep regulation in habitual short sleepers (≤6h) and long sleepers (>9h) was investigated by studying their sleep structure and sleep electroencephalogram during baseline conditions and after prolonging their habitual waking time by 24h. In each sleep episode, total sleep time was >3h longer in the enhancement of EEG slow-wave activity in non-REM sleep after sleep loss was larger in long sleepers than in short sleepers. This difference in slow wave activity response was predicted by the basic of the different sleep duration. These results indicate that short sleepers live under a higher “NREM sleep pressure” thane long sleepers. But the two groups do not differ with respect to the homeostatic sleep regulatory mechanisms.
Both long and short sleep may be associated with increased risk of coronary heart disease and diabetes.

1. Short sleep
Short sleep duration is associated with reduced leptin and elevated ghrelin. These differences in leptin and ghrelin are likely to increase appetite, possibly explaining the increased body mass index (BMI) observed with short sleep duration.
Sleep duration may be an important regulator of body weight and metabolism. A relation between short habitual sleep time and increased BMI has been found. But potential hormones that associated with this are still unknown.
BMI and sleep duration were examined using multiple various factors. A U shaped curvilinear association between sleep duration and BMI was observed. In persons sleeping less than 8h increased BMI was proportional to decreased sleep 10.

Hypertension with short sleep
Prolong short sleep durations lead to hypertension through extended exposure to raised 24hour blood pressure and heart rate, elevated sympathetic nervous system activity and increased salt retention. Such forces could leads to structural adaptation and the entrainment of the cardiovascular deceases, but there are no aware of link between short sleep duration and the incidence of hypertension in subjects without sleep disorders.
Sleep duration of ≤5 hours per night were associated with a significantly increased risk of hypertension. The risk of hypertension increases after controlling for obesity and diabetes, which was consistent with the hypothesis that those variables would act as partial mediators.
Therefore short sleep duration could be a significant risk factor for hypotension.(Howard Hughes Medical institute)

12. The role of day time nap
Most of people over the world take a nap during the day. People nap out of habit, because they are sleep- deprived as a result of a sleep disorder, or after a long work shift. Individuals of all age groups, from infants to the elderly, indulge in an afternoon nap. This review examines the benefits and drawbacks of daytime naps in healthy adults. A nap during the afternoon restores wakefulness and promotes performance and learning. Several investigators have shown that napping for as short as 10 min improves performance. Naps of lees than 30 min duration confer several benefits, whereas longer naps are associated with a loss of productivity and sleep inertia. Frequent and longer naps may lead to adverse long- them health effects. A nap of less than 30 min duration during the day promotes wakefulness and long enhances performance and learning ability. In contrast, the habit of taking frequent and long naps may be associated with higher morbidity, especially among the elderly. The benefits of napping could be best obtained by tracing the body and mind to awaken a short nap.
. We must not use the alarm clock to get up from the sleep. Nap should not last longer than 20-30 minutes. Coffee or other caffeine should drink after the nap but should not before the nap.

13. Physiology of sleep – summary

Sleep is an important factor to keep our body function in proper state. But most of people do not have awareness about how much sleep is necessary for us. Really sleep is physiologically essential for maintain our living mechanisms, such as regeneration of wasted tissues, refreshing both cognitive and emotional equilibrium, preserving recent memory, and etc.

There are two components of sleepiness that drive a person to bed.
• Circadian component-sleepiness comes back to us in cycles which are usually about one day long. We can observe this on our own without complex measurements.
• Homeostatic component- sleepiness increase with the length of time we stay awake. The homeostatic mechanism prepares us for sleep after a long day of intellectual work. At some time it prevents you from falling asleep in emergencies.

Even strong sleepiness resulting from the homeostatic component may not be sufficient to get good sleep if the timing goes against the sleep-high in the circadian component.
The most important, and most closely related to sleep are cycles in the level of hormones such as serotonin & melatonin, ACTH, cortisol, acetylcholine, adenosine, and GH.
Sleep has main two phases; slow wave sleep (NREM) and REM phases. Neurologically these phases have different mechanisms and they affect activity of the organ systems either together or separately. The metabolic processes taking place within the central nervous system during sleep. The general pattern of the energy requirement of the brain during sleep is varying. The brain energy metabolism dramatically decreases during slow wave sleep where as during
REM sleep the level of metabolism is similar or slightly less that of wakefulness.
REM and NREM sleep woke together to consolidate memories. Brain can easily store short term memory patterns. However these patterns have to be encoded in neocortex to provide space for coding new short- term memories. This complex process of rebuilding the neural network of the brain takes place during sleep. Due to physiological function of sleep, witch is the rewiring of neural network of the brain at the synapse level we can expect that the demand for sleep be associated with the amount of learning on the preceding days.
Most people use to get sleeping pill due to their less sleepiness. Those sleeping pills can help to sleep, but this sleep is of far less quality than naturally induced sleep. So we must try to avoid sleeping pills whenever possible.
Final advice of most of researches is go to sleep only when we are really tried. If we do not fell confident we will fall a sleep with 10-20 minutes latency, must not go to sleep. On some day we may fell sleepy before our expected time. Similarly if we do not fell sleepy at expected hour, we should stay up, even if this falls 2-4 hours after our expected time. But we must remember to have enough sleep during for a day.
Many aspects of sleep physiology are hotly debated and highly hypothetical. So those above investigations may soon appear outdated as new researches done.

1. Carbon.
2. Hydrogen.
3. Nitrogen.
4. Oxygen.
Structure of caffeine, (1,3,7-trimethylxanthine ,C8H10N4O2)
History of coffee
Coffee was first discovered around 850 A.D by a goat herder named khaldi in Abyssinia (Upper Egypt).legend has it that one night his usually reliable goats did not return home. the following morning he found the animals dancing around the shiny, dark- leaved shrub with red berries. He nibbled some of the berries and according to the legend, joined in the dance. Thus, coffee bush was discovered. Khaldi share his discovery with some local monks who experimented with berries, tossing them on a fires and then soaking them in boiling water. The liquid turn out to be tasty, and drinking it allowed to monks to stay up through marathon prayer sessions. Thus, the beverage coffee was born and spread, from monastery to monastery. Country to country, content to content. Caffeine was removed from coffee in the early 1900’s, and decaffeinated coffee became popular in 1930’s.
Sources of caffeine
Varying amounts of caffeine are present in over 200 foods, drinks and nonprescription medications. Adults take in more caffeine from coffee than from any other dietary source. Children tend to get most of their caffeine through soft drinks. By some estimates, up to 70 percent of soft drinks contain caffeine, including non-cola drinks such as root beer and orange soda Caffeine also can be found in chocolate milk, cocoa and milk chocolate candies. However, the amount of caffeine in these foods is often quite low and often does not impact a person’s mood or behavior. In contrast, some foods do contain significant amounts of caffeine. These include dark chocolate candies and some coffee ice creams and yogurts finally; some medicines contain significant amounts of caffeine. These include stimulant. Medications and some analgesics. Examples of caffeine sources are presented below (in milligrams [mg]):
Food Caffeine
Dark (semi-sweet) chocolate, 1 oz. 5 to 35
Unsweetened chocolate, 1 oz. 26
Milk chocolate, 1 oz. 1 to 15
Coffee flavored yogurt, 6 oz. 35
Coffee ice cream, 1/2 cup 20 to 30
Chocolate ice cream, 1/2 cup 2
Beverage Caffeine
Brewed coffee, 8 oz. 60 to 160
Instant coffee, 8 oz. 30 to 120
Espresso, 2 oz. 100
Brewed imported tea, 8 oz. 25 to 110
Brewed American tea, 8 oz. 20 to 90
Energy drinks, 8 oz. 35 to 90
Functional waters, 8 oz. 20
Iced tea, 8 oz. 6 to 60
Caffeinated water, 8 oz. 30 to 60
Soft drinks or soda, 8 oz 15 to 50
Instant tea, 8 oz. 24 to 31
Chocolate milk, 8 oz. 2 to 7
Decaffeinated coffee, 8 oz. 2 to 4
Medication Caffeine
Aspirin, 1 tablet 0
Appetite suppressant, 1 tablet
200
Medication to help people stay alert, 1 tablet 100 to 200
Phenylpraponolanine Hcl 30
acetominophen 32
Propoxyphene Hcl 32.4

The U.S. Food and Drug Administration (FDA) does not require food labels to disclose how much caffeine a product contains. In fact, caffeine must be listed as an ingredient in only if it is added to a food or beverage. If caffeine naturally occurs in the product (e.g., tea, coffee, chocolate), it does not have to be listed as an ingredient.
Health impact of caffeine
The U.S. Food and Drug Administration has classified caffeine as generally recognized as safe (GRAS) since 1958, and the American Medical Association also has stated that caffeine is safe when used in moderation. according to most of the experiments regarding to caffeine revealed that there are disadvantages and some of advantages of caffeine intake.
Caffeine molecule chemically closely resembles other metabolically compound such as the purins (adenine, guanine), adenosine, xanthine and uric acids. when consume 99% of caffeine is reabsorbed quickly from beverages and reach peak concentrations in the serum in 30 to 60 minutes(1) .then it enters the bloodstream through the stomach and small intestine. As it is liphophilic, penetrates all biological membranes and distributes to all body tissues. But caffeine is not accumulated in any organs or tissues. caffeine readily crosses blood-brain barrier and the placenta. it also present in breast milk in central nerves system it stimulates certain chemicals in the brain that produce an energizing effect on the body. This effect can be felt approximately 15 to 45 minutes after consumption, and reaches a peak within 30 to 60 min.
Caffeine is extensively metabolized in the liver through the microsomal cytochrome 450 system. From 2% to 3% excreted unchanged in the urine. The rate of caffeine metabolism varies, with half lives ranging from 2 to 12 hours, and average half life 4 to 6 hours (about 15% metabolized per hour). Longer half lives are seen in patients with chronic liver disease and in pregnancy. Shorter half lives seen in smokers (2) .smoking accelerate caffeine metabolism and patients who stop smoking can have doubling of caffeine concentration in blood,which may contribute to smoking withdrawal symptoms. Major health consequences of caffeine are described below,

Effect on nerves system.
.
Caffeine is thought to inhibit phosphodiesterase, an enzyme which is responsible for degrading cAMP. This inhibition leads to an increase of intracellular cAMP level(3), which is known to have the effects on excitatory neurotransmitters such as norepinephrine and dopamine. Therefore, caffeine would lead to higher activity of the excitatory neurotransmitter causing the stimulatory effects psychomotor. However, substantial inhibition of phosphodiesterases requires mill molar concentrations of caffeine, roughly 100 times the caffeine levels in the brain after ingestion of typical doses in man. Furthermore, some inhibitors of phosphodiesterase are 100-1000 times more potent than caffeine lack behavior effects.
eg:
Two cups of coffee increases vigilance and arousal in young boys.
Caffeine also has substantial effects on sleep. There are large variations in sensitivity to sleep disturbances. Effects are greater in persons who do not drink caffeine beverage regularly (4).
Also caffeine act as an antagonist on adenosine receptors as follows, adenosine is a locally released purine hormone that acts on two different receptors, A1 and A2.receptors mediate either increase or decrease in cellular concentration of cyclic adenosine monophosphate.
1. High affinity A1 receptors-inhibit adenyl cyclase.
2. Low affinity A2 receptors-stimulate adenyl cyclase
these receptors are found throughout body, including the brain, heart and blood vessels, respiratory tract, kidneys, adipose tissues and gastrointestinal tract.adinosine act as a vasodilator, it also reduces platelet aggregation invitro, inhibit catecholamine and rennin
release, inhibit lipolysis.caffein nonselectively inhibit both adenosine receptors and competitively inhibits the action of adenosine.
Caffeine leads to reduce the cerebral blood flow. it is done by caffeine - induce cerebrovascular vasoconstriction as mention above(5).

Cardiovascular effects.
There is evidence for that caffeine involves in heart rate, blood pressure, coronary blood flow, serum cholesterol level and plasma catecholamine levels(6).
Heart rate –
With caffeine heart rate decrease for about an hour then increase two to three hours thereafter. However long-term ingestion has no or little effect on heart rate.
Blood pressure –
Blood pressure= systolic blood pressure + 1/3 diastolic blood pressure
Long-term studies indicated no relationship between caffeine consumption and blood pressure. Results of short-term studies confirmed caffeine sensitivity in some people. Those who consumed caffeine regularly did not show elevated blood pressure levels, whereas those who did not consume caffeine regularly experienced a short and temporary increase in blood pressure after consumption Systolic blood pressure is increased about 10mm of mercury (normal 120mmHg) with caffeine.
Coronary blood flow
As adenosine is inhibited by caffeine, caffeine leads to reduce coronary blood flow. so myocardial infraction can be occurred(7).
Serum cholesterol level
Affect of caffeine on cholesterol level is described below.
Arrhythmia
there is a correlation between caffeine and arythias.studies using animals have shown that in massive doses can reduces ventricular fibrillation threshold and alter electrical excitation in cultured cardiac cells(8).

Respiratory effects
Primary respiratory effect is an increase in the respiratory rate.caffein has been use as a stimulant in neonates to prevent recurrent apneic episodes because caffeine induces the sensitivity of the medullary respiratory center to carbon monoxide (2). It is also used frequently in infant facilitate weaning from mechanical ventilation.
In patient with asthma caffeine functions as a bronchodilator.

Endocrine and metabolic effects
Caffeine increase catecholamine levels (9). Through this mechanism, it increases the basic metabolic rate. So lipolysis is increased and serum free fatty acids concentration is increased to 50% 100% above normal level. so cholesterol level is increased. It has discovered that consuming two to three cups per day coffee leads to elevation of aporotein B which is a component of lipoproteins, leads to elevation of cholesterol.
it is found that strong coffee dose-response relationship between long-term coffee consumption and serum cholesterol level (10).there is a linear relationship for both men and women, with serum cholesterol levels(mg/dl) increasing about 30mg per dl as coffee intake
Increased from 0 to more than 9 cups per day.

Elevation of low-density lipoprotein (LDL) leads to athelosclerosis, which leads to reduce the blood flow to the important organ such as heart.

Gastrointestinal effects
In the gastrointerstinaltract caffeine stimulates small intestine to secrete water and sodium. It has a direct affect on gastric acid secretion. Also caffeine decreases the lower sphincter tone and hence promotes the esophageal reflux.

Irritable bowel syndrome.
The irritable bowel syndrome is defined on the basis of the recently modified Rome criteria as the presence for at least 12 weeks (not necessarily consecutive) in the preceding 12 months of abdominal discomfort or pain that cannot be explained by structural or biochemical abnormalities and that has at least two of the following three features: pain is relieved with defecation, its onset is associated with a change in the frequency of bowel movements (diarrhea or constipation), or its onset is associated with a change in the form of the stool (loose, watery, or pellet-like). The syndrome can be divided into four subcategories according to whether the predominant symptom is abdominal pain, diarrhea, constipation, or constipation alternating with diarrhea.
It is discovered that caffeine activates pituiery adenyl cyclase which involves increase bowel contractility. So caffeine increase risk of irritable bowel syndrome.

Other situations which are involved by caffeine
Diuretic Drinking coffee or other caffeinated beverages also has a diuretic effect, meaning that it causes water loss through increased urination. However, the water that is lost is usually balanced by the amount of fluid obtained from the beverage

Osteoporosis
Consuming caffeine slightly increases the loss of calcium through urine and feces. The amount of calcium lost with each cup of coffee is equal to the amount of calcium contained in 1 teaspoon of milk. Thus, adding milk to coffee easily restores the calcium lost through caffeine use. People who consume caffeine in moderation do not raise their risk of osteoporosis.

Cancers
Caffeine or coffee intake have implicated in many solid tumors such as pancreatic cancer, urinary tract cancer (mostly bladder cancer), renal cell carcinoma, ovarian cancers and breast cancers.
Breast cancers
. An investigation of 100,000 deaths due to breast cancer reported no relationship between .

Pancreatic cancer
According to many experiments it is discovered that there is a link between caffeine and pancreatic cancers. But process is not clearly identified yet.
Pregnancy
Use of caffeine in pregnancy has long been debated. Even among the heaviest caffeine beverage drinkers, research results of three major studies involving 15,000 women indicate that birth defects are not associated with caffeine consumption. Also indicates that moderate in caffeine consumption does not delay a woman’s time to conception. Although studies have shown a link between caffeine consumption and spontaneous abortions. It has discovered that there is an association with spontaneous abortions and serum paraxanthine which is a caffeine metabolite. Also it is found that abortion in second trimester is greater than first trimester as exposure of the fetus can be assumed to be greater in that period than later in the pregnancy. Some studies have indicated that consuming high levels of caffeine while breastfeeding may be associated with lower sleep levels and poor feeding in the baby. At present many obstetrician recommended that caffeine intake be limited to less than 400mg per day during pregnancies. Also according to experiments it is not discovered yet association between total caffeine consumption and reduced fertility.

Protective function of caffeine against UV irradiation
UV irradiation–induced apoptosis through apoptosis signal-regulating kinase 1 (ASK1) and MAKK4 (SEK1) upstream from JNK(c-Jun N-terminal kinase) is caffeine sensitive.
Caffeine (1, 3, 7-trimethylxanthine) is one of a potential enhancer of chemotherapy, it effectively protected corneal epithelial cells against apoptosis by its specific effect on the JNK cascade. Theophylline (1, 3-dimethylxanthine) exhibited an effect similar to that of caffeine on prevention of UV irradiation–induced apoptosis. However, alterations of either intracellular cAMP or Ca2+ levels did not alter the effect of caffeine on the JNK signaling pathway. In addition, the blockade of PI3K-like kinases by wortmannin had no impact on the protective effect of caffeine against UV irradiation–induced apoptosis, suggesting that the protective effect of caffeine acts through a specific mechanism involving UV irradiation–induced activation of ASK1 and SEK1. In contrast, caffeine had no effects on melphalan-, hyperosmotic stress–, or IL-1 β-induced activation of the JNK signaling pathway (11) in these cells.

Protective function of caffeine in Parkinson disease.
Parkinson disease is occurred due to progressive degeneration of neuron cells in a part of the brain called the substantia nigra, occurring generally after age 50. Here, patients have difficulty in coordinate movement. Also they have symptoms of trembling arms and legs, trouble speaking. Many of these neurons that degenerate contain the neurotransmitter called dopamine. As these neurons degenerate, dopamine levels fall, and the balance between dopamine and other neurotransmitters, such as acetylcholine, is thrown off. This neurotransmitter imbalance affects the way muscles work and leads to movement problems. As mention Caffeine belongs to the xanthine chemical group. A naturally occurring xanthine in the brain called adenosine is used as a neurotransmitter at some synapses. When adenosine receptors are blocked, levels of the neurotransmitter dopamine increase. Caffeine may protect against Parkinson’s disease by blocking adenosine receptors, thus increasing the amount of dopamine in the brain.

caffeine therapy for apnea of prematurity.
Apnea of prematurity defined as cessation of breathing that lasts for more than 15 seconds and is accompanied by hypoxia or bradycardia — occurs in at least 85 percent of infants who are born at less than 34 weeks of gestation. It recognized that, methylxanthines, aminophylline, theophylline and caffeine reduce the frequency of apnea.
Caffeine sensitivity
Caffeine’s impact varies from person to person. Some people are not greatly affected, while others may be especially susceptible to the effects of caffeine use. Several factors may be involved in increased sensitivity to caffeine. They include:
• Body mass People with smaller body mass feel the effects of caffeine more quickly.
• History of caffeine use.
People who do not regularly use caffeine may be more susceptible to its effects. Regular use of caffeine helps an individual to build up a tolerance to the substance.
• Stress. All forms of stress increase a person’s susceptibility to caffeine.
Other factors that may contribute to caffeine sensitivity include age, smoking habits, medication or hormone use, and health conditions such as anxiety disorders. In addition, if a beverage contains certain additional ingredients (e.g., guarana, ginseng), the stimulating effect of caffeine is increased. Although age may play some role in a person’s sensitivity to caffeine, most studies have shown that caffeine affects children and adults in a similar manner.

Research has also shown that as little as 100 mg of caffeine per day can cause some people to become tolerant to caffeine. This can also result in withdrawal symptoms such as headaches, drowsiness and difficulty concentrating when the usual amount of caffeine is not consumed. These withdrawal symptoms usually disappear within a day or two after restricting or eliminating caffeine use.
For most people, caffeine does not pose serious health risks when moderate amounts are consumed, such as between 250 and 350 mg per day. Even when a person experiences effect of caffeine consumption, such as increased heart rate, anxiety, the jitters or insomnia, these effects only last for a few hours since caffeine does not accumulate in the body.
People who do not use caffeine regularly are likely to experience positive mood effects when they consume low amounts of the substance. They may feel happy, alert, energetic and more sociable. People who regularly consume caffeine also feel a boost when the substance enters their body, but this is more likely to be a response to the caffeine’s effect of suppressing withdrawal symptoms.
People who consume large amounts of caffeine at once often experience temporary negative effects, such as anxiety, nervousness and an upset stomach. Some studies also indicate that high levels of caffeine may cause an increase in anxiety levels and panic attacks.

Affect of caffeine to children
Children also should limit their intake of beverages that contain caffeine, including sodas and sports drinks. High levels of caffeine affect children in ways that are similar to the effects on adults.
Extraordinarily high caffeine intake (150 mg per kilogram of body weight) can lead to serious health consequences. Even moderate caffeine intake can create symptoms of caffeine overdose in certain people who are highly sensitive to caffeine.
People who drink high levels of caffeine often have trouble sleeping at night. They wake in the morning feeling fatigued and drink coffee or another caffeinated beverage throughout the day to help them stay awake. This in turn causes them to again have trouble falling asleep, creating a cycle that leaves a person increasingly tired as the cumulative effects of
Caffeine “addiction”
Many would say that caffeine or even coffee this case and generally means a habit of practice. The World Health Organization states, “There is no evidence whatsoever that caffeine use has even remotely comparable physical and social consequences which are associated with serious drugs of abuse.” Moderate caffeine consumption is considered to be about 300 mg of caffeine, which is about two to three 8-oz cups of coffee or five to six cups of tea a day

Symptoms of caffeine overdose
• Flushed face
• Frequent need to urinate (diuresis)
• Rapid heart rate (tachycardia)
• Restlessness or feeling jittery
• Shakiness
• Throwing up (vomiting)
• Trouble sleeping (insomnia)
• Upset stomach (nausea)
More severe cases of caffeine overdose can also include symptoms such as delirium (acute mental confusion) and visual disturbances. In rare cases, caffeine overdose can also result in death.

Reducing caffeine intake
Generally, people are encouraged to gradually cut down on caffeine. Abruptly quitting caffeine altogether produces a rebound effect in which the body becomes overly sensitive to adenosine (the natural sleep-enhancer). Consequently, adenosine has a more powerful sleep-enhancing effect, causing blood pressure to plunge and leading to a variety of other withdrawal symptoms such as:
• Depressed mood
• Headache, often severe
• Irritability
• Nervousness
• Restlessness
• Sleepiness(12)
• Throwing up (vomiting)
• Trouble concentrating
• Upset stomach (nausea)
Withdrawal symptoms can begin as soon as 12 hours after the last dose of caffeine. They usually peak within 20 to 48 hours and can last up to one week, although they generally go away after a day or two of eliminating caffeine use.
Some people choose to quit caffeine abruptly and then wait out the withdrawal symptoms. Others choose to avoid the withdrawal symptoms altogether by slowly weaning themselves from caffeine over a period of two to four weeks. For example, people may drink beverages that are half-caffeinated and half-decaffeinated, or drink decaffeinated beverages every other day.

Pathology
4 different types depend on appearance.
Some with minimal changes, some with grater changes.
80% cases are minimal change – response to treatment.

Clinical features
Preschool chid
Oedema – swelling in face, leg and abdomen.
Ascites
Protein urea – heavy.
Hypertension might develop later.

Biochemical features
Reduction of total serum protein
Main reduction is albumin.
Reduction of gamma globulin.
High serum cholesterol.

Progress
Most recover completely.
Some might get relapses.
Might develop to renal failure.
Infection - due to low gamma globulin.

Treatment
Steroids – prednisolone for long duration.
At the beginning fluid intake can be reduced with low sodium intake.
Increase protein intake.
Relapses are common.
Careful about side effect of steroids.
Immunosuppressive drugs.

Symptom and signs
Mainly with lower UTI (bladder & urethral infection)
Increase frequency of micturition.
Painful voiding – dysuria
Suprapubic pain and tenderness.
Haematuria
Smelly urine.
Loin pain and tenderness, fever, systemic symptom – suggest upper UTI.
Symptom and signs
Childers – possibility of UTI with all fever, fails to thrive.
Urethral syndrome –
Frequency, dysuria,
50% symptomatic woman with no bacteriuria.
Can be – postcoital bladder trauma, vaginitis, atrophic vaginitis, interstitial cystitis (Inflammatory ulcer in the bladder), irritable bladder.
Diagnosis
Culture of clean catch, mid stream urine. How to collect sample ??
Need refrigerated to prevent organism growth.
Excretion urography – Female if two or more attack, but male and child in first attack.

Treatment
Single isolated attack
If symptoms are sever - antibiotic before culture report.
Increase fluid intake.
If severely ill and suspect acute pyelonephritis – IV antibiotics.
Repeat culture after treatment – exclude relapse and reinfection.
Chronic pyelonephritis
Chronic nfection in kidney.
Results of vesicoureteric reflux, infection in infancy or early childhood.
Normally urine in the bladder don’t go up – value mechanism.
If value not work – reflux urine with bladder empting.
Infection damage – papillary damage, interstitial nephritis, cortical scarring.

Chronic pyelonephritis
If started in childhood – can be progressive renal fibrosis even no further infection.
Doesn’t begin with adult life.
Doesn’t occur if there is not reflux.
Diagnosis – excretion urography – clubbed calyces, irregular renal outline.
Can lead to hypertension and renal failure in later life.
How to collect urine sample
Female
Bladder should full
Labia separate using left hand
Vulva clean front to back with sterile swab (not antiseptics, no soap)
Start urination, when half done, without stopping container hold to stream.
How to collect urine sample
Male
Bladder should full
Foreskin retract
Gland penis clean front to back with sterile swab (not antiseptics, no soap)
Start urination, when half done, without stopping container hold to stream.

Acute Pancreatitis
Acute abdominal pain with raised pancreatic enzyme.
Pathogenesis
Pancreatic necrosis
Associate with gall stone.
Autodigestion of pancreas.
Can be haemorrhage.
Oedema and exudates.
Acute Pancreatitis –clinical features
Abdominal pain – epigastrium or upper abdomen.
Severe pain with abdominal rigidity.
Nausea and vomiting.
Severe case – multisystem failure.

Acute Pancreatitis –Investigation
Increase serum amylase – 5 times than normal.
Abdominal xray.
Ultrasound.
Exploratory laparotomy might need.
Acute Pancreatitis – Treatment
Nasogastric suction might need
No feeding, only IV nutrition.
Analgesia.
No special treatment.
Acute Pancreatitis – Complication
Pancreatic abscesses – secondary infection.
Pseudocysts – usually not required treatment.

Chronic pancreatitis
Continuing inflammatory disease, irreversible morphological changes, permanent impairment of function.
Cause – alcohol >85% cases.
Fibrosis and calcification of pancreatic acinar.
Not reversible but will arrest.
Risk factors – smoking, low protein and high fat diet.
Chronic pancreatitis - clinical features
Pain – continuing episodes
Episodes might precipitated by heavy alcohol drink.
Steatorrhoea – reduced lipase.

Chronic pancreatitis - Investigation
Ultrasound
CT
Xray – calcification can be seen

Chronic pancreatitis - Treatment
Stop drinking
Analgesics
Surgery – case with severe pain.
Diabetes might need to treat.
Steatorrhoea – low fat diet.
Acute cholecystits
Inflammation of gallbladder.
Associated with gallstone.
Inflammation is sterile, but soon gut organisms cultured.
Can be mild
Can be severe with localized peritonitis.

Clinical features
Other features help to diagnosis
Hepatomegaly –hepatitis, malignancy,
Splenomegaly – portal hypertension
Ascites – cirrhosis, carcinoma.
Palpable gallbladder – carcinoma obstructing bile duct.

Investigation
Jaundice is not a diagnosis, but sign so need investigation.
Viral markers -
Ultrasound – extrahepatic obstructions.
Liver biochemistry – AST (aspartate amino transferase, AP (alkaline phosphatase)
Haematological test – Haemolytic jaundice.
Other test – alpha fetoprotein in hepatocellular carcinoma.

What is haemolysis?
Haemoglobin splits and globin and heme release.
Heme consists of four pyrrole rings.
Heme ring open and release pyrrole rings.
Pyrrole will under go several reaction and bilirubin form.
Conjugated bilirubin turn to urobilinogen by bacteria in the intestine.
Excrete via stool.
Urobilinogen can be reabsorbed to blood.
5% excrete via urine.

Urobilinogen turn to urobilin by oxidization when expose to air.
Stercobilinogen turn to stercobilin by oxidization when expose to air.
Jaundice
Excess bilirubin in the extracellular fluid.
Detectable when the serum bilirubin >30-60 µmol/letter.

Haemolysis
increase unconjugated bilirubin in plasma.
Urobilinogen increase

Intrahepatic cholestasis
acute and chronic liver diseases including cirrhosis, hepatitis, drugs,
increase in both type bilirubins

Congenital hyperbilirubinaemias
Glibert’s syndrome
common type
2-5% of population with mild increase unconjugated bilirubin.
Asymptomatic
Crigler-Najjar syndrome
rare
Problem of conjugation
Increase unconjugated bilirubin.
Dubin-johnson syndrome
Defect in bilirubin handling.
Increase conjugated bilirubin.

Intestinal Obstruction - clinical features.
Abdominal pain – colicky pain, around umbilical (s. intestinal), below umbilical (l. intestinal).
Vomiting – early in high obstruction, can be brown.
Constipation
Abdominal distension.
Increase bowel sound.
Might be features of dehydration.
Intestinal Obstruction- investigation
Xray – might see distended bowel loops.

Intestinal Obstruction- Treatment
Primary
Nasogastric aspiration
IV fluid
Surgical
Depend on cause.
Conservative treatment
Simple obstruction with adhesions will response.