Archive for August 5th, 2013


[84] Table 2.8. Geologic time scale.*

[85] Table 2.8 (continued)

Table 2-8 Geographic time scale (400dpi, 850 kb)geo time scale





Vaccination is the administration of antigenic material (a vaccine) to stimulate adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens. There is strong evidence for the efficacy of many vaccines, such as the influenza vaccine the HPV vaccine and the chicken pox vaccine among others. Vaccination is generally considered to be the most effective method of preventing infectious diseases. The material administered can either be live but weakened forms of pathogens (bacteria or viruses), killed or inactivated forms of these pathogens, or purified material such as proteins.


The word vaccination was first used by Edward Jenner in 1796. Louis Pasteur furthered the concept through his pioneering work in microbiology. Vaccination         is so named because the first vaccine was derived from a virus affecting cows—the relatively benign cowpox virus—which provides a degree of immunity to smallpox, a contagious and deadly disease. In common speech, ‘vaccination’ and ‘immunization’ generally have the same colloquial meaning. This distinguishes it from inoculation which uses unweakened live pathogens, although in common usage either is used to refer to an immunization. The word “vaccination” was originally used specifically to describe the injection of smallpox vaccine






All vaccinations work by presenting a foreign antigen to the immune system in order to evoke an immune response, but there are several ways to do this. The four main types that are currently in clinical use are as follows:

  1. An inactivated vaccine consists of virus particles which are grown in culture and then killed using a method such as heat or formaldehyde. The virus particles are destroyed and cannot replicate, but the virus capsid proteins are intact enough to be recognized and remembered by the immune system and evoke a response. When manufactured correctly, the vaccine is not infectious, but improper inactivation can result in intact and infectious particles. Since the properly produced vaccine does not reproduce, booster shots are required periodically to reinforce the immune response.


  1. Virus-like particle vaccines consist of viral protein(s) derived from the structural proteins of a virus. These proteins can self-assemble into particles that resemble the virus from which they were derived but lack viral nucleic acid, meaning that they are not infectious. Because of their highly repetitive, multivalent structure, virus-like particles are typically more immunogenic than subunit vaccines (described below). The human papillomavirus and Hepatitis B virus vaccines are two virus-like particle-based vaccines currently in clinical use.





Immunization Schedule for Babies




At Birth BCG, OPV (0 dose), HepatitisB (1st dose)
6 weeks DPT (1st dose), OPV (1st dose), HepatitisB (2nd dose)
10 weeks DPT (2nd dose), OPV (2nd dose), HepatitisB (2nd dose)
14 weeks DPT (3rd dose), OPV (3rd dose), HepatitisB (3rd dose)
9 – 12 months Measles vaccine
15 – 18 months DPT (4th dose), OPV (4th dose), MMR vaccine
5 years DT
10 years TT, HepatitisB
16 years TT




This list of vaccine ingredients indicates the culture media used in the production of common vaccines and the excipients they contain:


Culture media


Anthrax vaccine (BioThrax) Puziss-Wright medium 1095, synthetic or semisynthetic Aluminum Hydroxide, Amino Acids, Benzethonium Chloride, Formaldehyde

or Formalin, Inorganic Salts and Sugars, Vitamins

BCG (Bacillus Calmette-Guérin) (Tice) Synthetic or semisynthetic Asparagine, Citric Acid, Lactose, Glycerin, Iron Ammonium Citrate,

Magnesium Sulfate, Potassium Phosphate

DTaP (Daptacel) Cohen-Wheeler or Stainer-Scholte media, synthetic or semisynthetic Aluminum Phosphate, Ammonium Sulfate, Casamino Acid, Dimethyl-betacyclodextrin,

Formaldehyde or Formalin, Glutaraldehyde, 2-Phenoxyethanol







Immunity and herd immunity

Vaccination policies aim to produce immunity to preventable diseases. Besides individual protection from getting ill, with some vaccines policies aim also to provide herd immunity which is based on the idea that the pathogen will have trouble spreading when a significant part of the population has immunity against it.

Eradication of disease


Malaria Clinic in Tanzania helped by SMS for Life program which organizes malaria vaccine delivery

With some vaccines, a goal of vaccination policies is to eradicate the disease – make it disappear from Earth altogether. The World Health Organization coordinated the global effort to eradicate smallpox globally Victory is also claimed for getting rid of endemic measles, mumps and rubella in Finland The last naturally occurring case of smallpox occurred in Somalia in 1977. In 1988, the governing body of WHO targeted polio for eradication by the year 2000, but didn’t succeed. The next eradication target would most likely be measles, which has declined since the introduction of measles vaccination in 1963.

Individual versus group goals

Rational individuals will attempt to minimize the risk of illness, and will seek vaccination for themselves or their children if they perceive a high threat of disease and a low risk to vaccination











Vaccine court is the popular term which refers to the Office of Special Masters of the U.S. Court of Federal Claims, which administers a no-fault system for litigating vaccine injury claims. These claims against vaccine manufacturers cannot normally be filed in state or federal civil courts, but instead must be heard in the Court of Claims, sitting without a jury. The program was established by the 1986 National Childhood Vaccine Injury Act (NCVIA), passed by the United States Congress in response to a threat to the vaccine supply due to a 1980s scare over the DPT vaccine. Despite the belief of most public health officials that claims of side effects were unfounded, large jury awards had been given to some plaintiffs, most DPT vaccine makers had ceased production, and officials feared the loss of herd immunity.


Some parents of children with autism spectrum disorders have attributed the disorders’ onset to vaccines, often citing the mercury-based preservative thiomersal as the cause, and have demanded compensation from vaccine makers. However, the mainstream medical and scientific communities have consistently found no link between routine childhood vaccines and autism.


International AIDS Vaccine Initiative

The International AIDS Vaccine Initiative (known as IAVI) is a global not-for-profit, public-private partnership working to accelerate the development of vaccines to prevent HIV infection and AIDS. IAVI researches and develops vaccine candidates, conducts policy analyses, serves as an advocate for the field and engages communities in the trial process and AIDS vaccine education. The organization takes a comprehensive approach to HIV and AIDS that supports existing HIV prevention and treatment programs while emphasizing the need for new AIDS prevention tools. It also works to ensure that future vaccines will be accessible to all who need them. The organization has offices in Africa, Europe, India and the United States.



IAVI’s scientific team, drawn largely from private industry, researches and develops AIDS vaccine candidates and engages in clinical trials and research through partnerships with more than 50 academic, biotechnology, pharmaceutical and governmental institutions. A major portion of the organization’s activities occur in developing countries, where 95 percent of new HIV infections occur. IAVI sponsors AIDS vaccine trials in collaboration with local scientists primarily in Africa and India, where subtypes of HIV different from that common in North America circulate.The organization also has provided resources to translational research to fill roles traditionally played by the biotechnology or biopharmaceutical companies


The UK Vaccination Acts of 1840, 1853 and 1898 reflect the continuing argument over vaccination policy in the United Kingdom. Similar legislation was passed in the USA and other countries.Alfred Russel Wallace gave an account of smallpox and vaccination in 1895 in which he characterized the historical policies into encouragement, compulsion, and penal compulsion.

United Kingdom

–  The 1840 Act

  • Made variolation illegal.
  • Provided optional vaccination free of charge.

In general, the disadvantages of variolation are the same as those of vaccination, but added to them is the generally agreement that variolation was always more dangerous than vaccination.

Vaccination was first made compulsory in 1853, and the provisions were made more stringent in 1867, 1871, and 1874.

–  The 1853 Act

By the Act it was required:

  • That every child, whose health permits, shall be vaccinated within three, or in case of orphanage within four mouths of birth, by the public vaccinator of the district, or by some other medical practitioner.
  • That notice of this requirement, and information as to the local arrangements for public vaccination, shall, whenever a birth is registered, be given by the register of births to the parents or guardians of the child.



  • Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who get an excessive reaction to adsorbed tetanus toxoid may be given the simple vaccine when time for a booster occurs.
  • In the preparation for the 1990 Gulf campaign, Pertussis vaccine (not acellular) was used as an adjuvant for Anthrax vaccine. This produces a more rapid immune response than giving only the Anthrax, which is of some benefit if exposure might be imminent.
  • They may also contain preservatives, which are used to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal was used in many vaccines that did not contain live virus. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine which is currently recommended only for children with certain risk factors. Single-dose Influenza vaccines supplied in the UK do not list Thiomersal (its UK name) in the ingredients. Preservatives may be used at various stages of production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole.



  • Inoculation was developed in ancient China. Scholar Ole Lund comments: “The earliest documented examples of vaccination are from India and China in the 17th century, where vaccination with powdered scabs from people infected with smallpox was used to protect against the disease. Smallpox used to be a common disease throughout the world and 20% to 30% of infected persons died from the disease. Smallpox was responsible for 8% to 20% of all deaths in several European countries in the 18th century. The tradition of inoculation may have originated in India in 1000 BCE The mention of inoculation in theSact’eya Grantham, an Ayurvedic text, was noted by the French scholar Henri Marie Husson in the journal Dictionaire des sciences me`dicales. Almroth Wright, the professor of pathology at Netley, further helped shape the future of vaccination by conducting limited experiments on the professional staff at Netly, including himself. The outcome of these experiments resulted in further development of vaccination in Europe. The Anatolian Ottoman Turks knew about methods of inoculation.This kind of inoculation and other forms of variolation were introduced into England by Lady Montagu, a famous English letter-writer and wife of the English ambassador at Istanbul between 1716 and 1718, who’d almost died from smallpox as a young adult and was physically scarred from it.








Some modern vaccines are administrated after the  patient  already has contracted a disease, as in the case of experimental AIDS ,cancerand alzheimer’ disease vaccines .



Vagina given after exposure to small pox , within the first hour days , is reported to attenuate the disease considerbaly and vaccination within the first week is known to be benificial to a degree .















Many times this words are used interchangeably , as if they were synonyms . infact they are different things .

As Doctor Byron plant explains: “ vaccination is the more commonly used term whish actually consists of a “safe” injection of a sample taken from a cow suffering from cow pox …… Inoculation ,a practice probably as old as the disease itself, is the injection of the variola virus taken from a pustule or scab of a small pox sufferer into the superficial layers of the skin , commonly on the upper arm of the subject .











SUBMITTED TO :-                   SUMITTED BY:-

Mr. Nishikant Agarwal                     Hansraj Rohlan











Blood, vital fluid found in humans and other animals that provides important nourishment to all body organs and tissues and carries away waste materials. Sometimes referred to as ”the river of life,” blood is pumped from the heart through a network of blood vessels collectively known as the circulatory system.

An adult human has about 5 to 6 liters (1 to 2 gal) of blood, which roughly 7 to 8 percent of total body weight. Infants and children have comparably lower volumes of blood, roughly proportionate t their smaller size. The volume of blood in an individual fluctuates. During dehydration, for example while running a marathon, blood volume decreases. Blood volume increases in circumstances such as pregnancy, when the mother’s blood needs to carry extra oxygen and nutrients to the body.                                                                                             2.  ROLE OF BLOOD

Blood carries oxygen from the lungs to all the other tissues in the body and, in turn, carries waste products, predominantly carbon dioxide, back to the lungs where they are released into the air. When oxygen transport fails, a person dies within a few minutes. Food that has been processed by the digestive system smaller into smaller components such as proteins, fats, and carbohydrates is also delivered to the tissues by the blood. These nutrients provide the materials and energy needed by individual for metabolism, or the performance of cellular function. Waste products during metabolism, such as urea and uric acid, are carried by the blood to the kidneys, where they are transferred from the blood into urine and eliminated from the body. In addition to oxygen and nutrients, blood also transports special chemicals, called hormones, that regulate certain body functions. The movement of these chemicals enables one organ to control the function of another even though the two organs may be located far apart. In this way, the blood acts not just as a means for transportation but also as a communication system.

The blood is more than a pipeline for the nutrients and information; it is also responsible for the activities of the immune system, helping fend off infection and fight disease. In addition, blood carries the means for stopping itself from leaking out of the body after an injury. The blood does this by carrying special cells and proteins, known as coagulation system, that start to form clots within a matter of seconds after injury. Blood is vital to maintaining a stable body temperature; in humans, body temperature normally fluctuates within a degree of 37.0′ C (98.6′ F). Heat production heat loss in various parts of the balanced out by heat transfer via the bloodstream. this is accomplished by varying the diameter of blood vessels in the skin. The increased flow of blood in the skin makes the skin appear pink or flushed. diverting blood from the skin and reducing heat loss.





About 55 percent of the blood is composed of the liquid known as plasma. The rest of the blood is made of three major types of cells: red blood cells (also known as erythrocytes), white blood cells (leucocytes), and platelets (thrombocytes).

A. Plasma 

Plasma consists predominantly of water and salts. the kidneys carefully maintain the salt concentration in plasma because small changes in its concentration will small cells in the body to function improperly. In extreme condition this can results in seizures, coma, or even death. The pH of plasma, the common measurement of the plasma’s acidity, is also carefully controlled by the kidneys within the neutral range of 6. to 7.7. Plasma also contains others small molecules, including vitamins, minerals, nutrients, and waste products. The concentrations of all of these molecules must be carefully regulated.

Plasma is usually  yellow in color due to proteins dissolved in it. However, after a person eats a fatty meal, that person’s plasma temporarily develops a milky color as the blood carries the ingested fats from the intestines to other organs of the body.


B. Red Blood Cells


Red blood cells make up almost 45 percent of the blood volume. their primary function is to carry oxygen from the lungs to cells in the body. Red blood cells are composed predominantly of a protein and iron compound, called hemoglobin, that captures oxygen molecules as the blood moves through the lungs, giving blood its red color. As blood passes through body tissues, hemoglobin then releases the oxygen to cells throughout the body. red blood cells so packed with hemoglobin that they lack many components, including a nucleus, found in other cells.


C. Blood Types

Blood typing is important for many medical reasons. If a person loses a lot of blood, that may person may need a blood transfusion to replace some of the lost red blood cells. Since everyone makes antibodies against substances that are foreign, or not of their own body, transfused must be matched so as not to contain these substances. For example, a person who is blood type A positive will not make antibodies against the A or Rh markers, but will make antibodies against the B marker, which is not on that person’s own red blood cells. If blood containing the B marker (from types B positive, B negative, AB positive, or AB negative) is transfused into this person, then the transfused red blood cells will be rapidly destroyed by the patient’s anti-B antibodies. In this case, the transfusion will do the patient no good and may even result in serious harm. For a successful blood transfusion into an A positive blood type individual, blood that is type O negative, O positive, A negative, or A positive is needed because these blood types will not be attacked by the patient’s anti-B antibodies.



D. White Blood Cells         


White blood cells only make up about 1 percent of blood, but their small number belies their immense importance. They play a vital role in the body’s immune system-the primary defense mechanism against invading bacteria, virus, fungi, and parasites. They often accomplish this goal through direct attack, which usually involves identifying the invading organism as foreign, attaching to it, and then destroying it. This process is referred to as phagocytosis.

White blood cells also produce antibodies, which are released into the circulating blood to target and attach to foreign organisms. After attachment, the antibody may neutralize the organism, or it may elicit help from other immune system cells to destroy the foreign substance. There are several varieties of white blood cells, including neutrophils, monocytes and lymphocytes, all of which interact with one another and with plasma proteins and other cell types to form the complex and highly effective immune system.









E.Platelets and Clotting


The smallest  cell in the blood are the platelets, which are designed for a single purpose-to begin the process of coagulation, or forming a dot, whenever a blood vessel is broken. As soon as an artery or vein is injured, the platelets in the area of the injury begin to clump together and stick to the edges of the cut, They also release messengers into the blood that perform a variety of functions; constricting the blood vessels to reduce bleeding, attracting more platelets to the area to enlarge the platelet plug, and initiating the work of plasma-based clotting factors, such as fibrinogen, Through a complex mecharism involving many steps and many clotting factors, the plasma protein fibrinogen is transformed into long, sticky threads of fibrin. Together, the platelets and the fibrin create an intertwined meshwork that forms a stable clot. This self-sealing aspect of the blood is crucial to survival.



Blood is produced in the bone marrow, a tissue in the central cavity inside almost all of the bones in the body. In infants, the marrow in most of the bones is actively involved in blood cell formation. By later adult life, active blood cell formation gradually ceases in the bones of the arms and legs and concentrates in the skull, spine, ribs, and pelvis.

Red blood cells, white blood cells, and platelets grow from a single precursor cell, known as a hematopoietic stem cell. Remarkably, experiments have suggested that as few as 10 stem cells can, in four weeks, multiply into 30 trillion red blood cells, 30 billion white blood cells, and 1.2 trillion platelets- enough to replace every blood cell in the body.




One-celled organisms have no need for blood. They are able to absorb nutrients, expel wastes, and exchange gases with their environment directly. Simple multicelled marine animals, such as sponges, jellyfishes, and anemones, also do not have blood. They use the seawater that bathes their cells to perform the functions of blood. However, all more complex multicellular animals have some form of a circulatory system using blood, In some invertebrates, there are no cells analogous to red blood cells, Instead, hemoglobin, or the related copper compound heocyanin, circulates dissolved in the plasma.

The blood of complex multicellular animals tends to be similar to human blood, but there are also some significant differences, typically at the cellular level. For example, fish, amphibians, and reptiles possess red blood cells that have a nucleus, unlike the red blood cells of mammals. The immune system of invertebrates is more primitive than that of vertebrates, lacking the functionality associated with the white blood cell and antibody system found in mammals. Some arctic fish species produce proteins in their blood that act as a type of antifreeze, enabling them to survive in environments where the blood of other animals would freeze. Nonetheless, the essential transportation, communication, and protection functions that make blood essential to the continuations of life occur throughout much of the animal kingdom.












Many diseases are caused by abnormalities in the blood. These diseases are categorized by which component of the blood is affected



A. Red Blood Cells Diseases



One of the most common blood diseases worldwide is anemia, which is characterized by an abnormally low number of red blood cells or low levels of hemoglobin. One of the major symptoms of anemia is fatigue, due to the failure of the blood to carry enough oxygen to all of the tissues.


The most common type of anemia, iron-deficiency anemia, occurs because the marrow fails to produce sufficient red blood cells.              When insufficient iron is available to the bone marrow, it slows down its production of hemoglobin and red blood cells. In the United States, iron deficiency occurs most commonly due to poor nutrition. In other areas of the world, however, the most common causes of iron-deficiency anemia are certain infections that result in gastrointestinal blood loss and the consequent chronic loss of iron. Adding supplemental iron to the diet is often sufficient to cure iron-deficiency anemia.


Some anemias are the result of increased destruction of red blood cells, as in the case of sickle-cell anemia, a genetic disease most common in persons of African ancestry. The red blood cells of sickle-cell patients assume an unusual crescent shape, causing them to become trapped in some blood vessels, blocking the flow of other blood cells to tissues and depriving them of oxygen.


Sickled Blood Cell


Sickled Blood Cell The curved, crescent-shaped blood cell (bottom, left) signals the presence of sickle-cell anemia, a genetic disorder that affects 72,000 people in the United States, primarily African Americans. Caused by a defective gene, this anemia results from abnormal hemoglobin, the oxygen-carrying component of red blood cells, which distorts the shape of blood cells after they have released oxygen. The misshapen, or sickled, cells cannot pass smoothly through tiny blood vessels. The resulting blockages cause intense pain and serious deficiencies of oxygen and other blood nutrients throughout the body.







B. White Blood Cell Diseases


Some white blood cell diseases are characterized by an insufficient number of white blood cells. This can be caused by the failure of the bone marrow to produce adequate numbers of normal white blood cells, or by diseases that lead to the destruction of crucial white blood cells. These conditions result in severe immune deficiencies characterized by recurrent infections.


Any disease in which excess white blood cells are produced, particularly immature white blood cells, is called leukemia, or blood cancer. Many cases of leukemia are linked to gene abnormalities, resulting in unchecked growth of immature white blood cells. If this growth is not halted, it often results in the death of the patient. These genetic abnormalities are not inherited in the vast majority of cases, but rather occur after birth. Although some causes of these abnormalities are known, for example exposure to high doses of radiation or the chemical benzene, most remain poorly understood.


Treatment for leukemia typically involves the use of chemotherapy, in which strong drugs are used to target and kill leukemic cells, permitting normal cells to regenerate. In some cases, bone marrow transplants are effective. Much progress has been made over the last 30 years in the treatment of this disease. In one type of childhood leukemia, more than 80 percent of patients can now be cured of their disease.







C. Coagulation Diseases


One disease of the coagulation system is hemophilia, a genetic bleeding disorder in which one of the plasma clotting factors, usually factor VIII, is produced in abnormally low quantities, resulting in uncontrolled bleeding from minor injuries. Although individuals with hemophilia are able to form a good initial platelet plug when blood vessels are damaged, they are not easily able to form the meshwork that holds the clot firmly intact. As a result, bleeding may occur some time after the initial traumatic event. Treatment for hemophilia relies on giving transfusions of factor VIII. Factor VIII can be isolated from the blood of normal blood donors but it also can be manufactured in a laboratory through a process known as gene cloning.





The Red Cross and a number of other organizations run programs, known as blood banks, to collect, store, and distribute blood and blood products for transfusions. When blood is donated, its blood type is determined so that only appropriately matched blood is given to patients needing a transfusion. Before using the blood, the blood bank also tests it for the presence of disease-causing organisms, such as hepatitis viruses and human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). This blood screening dramatically reduces, but does not fully eliminate, the risk to the recipient of acquiring a disease through a blood transfusion. Blood donation, which is extremely safe, generally involves giving about 400 to 500 ml (about 1 pt) of blood, which is only about 7 percent of a person’s total blood.

Blood Pressure

Blood Pressure, pressure of circulating blood against the walls of the arteries. Blood pressure is an important diagnostic index, especially of circulatory function. Because the heart can pump into the large arteries a greater volume of blood than can be absorbed by the tiny arterioles and capillaries, the resulting back pressure is exerted against the arteries. Any condition that dilates or contracts the blood vessels or affects their elasticity, or any disease of the heart that interferes with its pumping power, affects the blood pressure. In a healthy animal, the blood pressure normal for its species is maintained within a certain average range with great constancy. Controlled by both cerebrospinal and sympathetic nerve centers, the complex nervous system mechanisms that balance and coordinate the activity of the heart and arterial muscles permit great local variation in the rate of blood flow without disturbing the general blood pressure.


In 1996 scientists discovered that hemoglobin, the iron-protein compound that gives blood its red color, also plays a role in regulating local variation in blood pressure. Hemoglobin was found to carry nitric oxide, a gas that relaxes the blood vessel walls, thus increasing blood flow. Hemoglobin controls the expansion and contraction of blood vessels, and thus blood pressure, by regulating the amount of nitric oxide to which the vessels are exposed.


Blood pressure is measured at two points: the high point at which the heart contracts to empty its blood into the circulation, called systole; and the low point at which the heart relaxes to fill with blood returned by the circulation, called diastole. Pressure is measured in millimeters (mm) of mercury by an instrument called a sphygmomanometer, consisting of an inflatable rubber cuff connected to a pressure-detecting device with a dial. The cuff is wrapped around the upper arm and inflated by squeezing a rubber bulb connected to it by a tube. Meanwhile, the health professional making the examination listens to a stethoscope applied to an artery in the lower arm. As the cuff expands, it gradually compresses the artery. The point at which the cuff stops the circulation and at which no pulsations can be heard is read as the systolic pressure. As the cuff is slowly deflated, a spurting sound can be heard when the heart contraction forces blood through the compressed artery. The cuff is then allowed gradually to deflate further until the blood is flowing smoothly again and no further spurting sound is heard. A reading at this point shows the diastolic pressure that occurs during relaxation of the heart. During a single cardiac cycle, or heartbeat, the blood pressure reaches maximum during systole and minimum during diastole. Usually, both measurements are given as a ratio expression of maximum over minimum—for example, 140/80. When a single figure is given, it is usually the higher, or systolic, pressure.


In healthy persons, blood pressure increases from about 80/45 in infants, to about 120/80 at age 30, to about 140/85 at age 40 and over. This increase occurs when the arteries lose the elasticity that, in younger people, absorbs the force of heart contractions. Blood pressure is influenced by a wide range of factors and varies between individuals and in the same individual at different times. It is generally higher in men than in women and children and is lowest during sleep.