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Human Disease & Health Introduction These diseases kill more people than all others combined (except for dying “naturally” of organ failure due to old age) ~ 247 heart disease deaths / 100,000 people / year (USA - 2001)* ~ 195 cancer deaths / 100,000 / year (USA - 2001)* ~ 87 iatrogenic deaths / 100,000 / year (USA – 2004) ~ 60 stroke deaths / 100,000 / year (USA - 2001)* ~ 25 diabetes deaths / 100,000 / year (USA - 2001)* ~ 15 auto-accident deaths / 100,000 / year (USA – 2003) ~ 10 firearms deaths / 100,000 / year (USA – 2001)* *(statistics from Kaiser Family Foundation) Although these numbers are a little dated, they still represent the relative importance of each disease in terms of overall significance to USA mortality. NOTE that iatrogenic deaths are #3!!! & that cancer and cardiovascular deaths are by far the most common – and although diabetes is #5, it kills predominantly through cardiovascular disease. Thus cardiovascular disease and cancer are by far the most important killers in the USA. Some Random Statistics (from CDC – 2004) 1918-1919 Spanish Flu 20-40 million deaths world-wide 1957 (Asian) & 1968 (Hong-Kong) 1.5 million+ deaths ~ 35 – 50 million infected with influenza (USA) each year ~ 20,000 deaths/year ~ 64,000 deaths/year due to influenza + pneumonia Hantavirus ~ 50% mortality (USA- Four corners) HIV ~ 30 million infected worldwide ~ 100% mortality Ebola ~ 90% mortality West Nile (USA) 2002: 3,389 infected 2003: 9,862 infected 2004: 2,470 infected 201 deaths 264 deaths 88 deaths (as of 11-01-05) Measles ~ 30+ million cases world-wide 1 million deaths Hepatitis A (liver failure/liver cancer) ~ 1.4 million infections world-wide Hepatitis B ~ 2 BILLION people infected world-wide Hepatitis C ~ 3 – 4 million infections world-wide Rotavirus (stomach virus – massive diarrhea/vomiting & death) ~ 600,000 children die world-wide Malaria (a parasite) ~ 3 million die world wide S0… why all the stats… They illustrate that the greatest disease problems we have are from the chronic diseases… these are diseases that we are not “born with” and that develop over a period of many years… Most cancers, most cardiovascular and neurological diseases, and type II diabetes are all chronic diseases (not to diminish the importance of infectious diseases, although they do not necessarily kill vast numbers of people, they do cause a massive amount of suffering, hence, they also are discussed in detail… What Exactly Is A Disease? A disease is really a process which results in cellular dysfunction leading to a specific array of symptoms which are dependent of the specific type of cellular dysfunction and the organ in which the dysfunction exists … Another way of saying it: A relatively simple definition could be: “disease” is a process which results in some type of damage or over activation of a normal process that results in some type of abnormal cellular function (cellular dysfunction) that has an impact on the ability of a cell to perform its normal “job”. We can expand on this definition to include the concept that a specific array of cellular dysfunctions will lead to a specific array of symptoms. If only one cell is affected not much happens and there is no way to recognize that anything is (went?) wrong. If sufficient numbers of cells within a particular organ are affected, then the abnormal cellular function could lead to abnormal “organ” function; and an array of symptoms that are specific to the form of organ dysfunction and possibly even to symptoms of a local or systemic inflammatory response, ultimately leading to possible organ failure and maybe even to death. A disease process can be initiated by infectious agents such as bacteria, viruses, fungi, or parasites. It also can be initiated through nutritional deficiency (e.g. scurvy, pellagra …) or through an inherited gene defect (eg: some cancers, different cardiomyopathies, Phenylalanine-ketonuria, sickle cell anemia, type I diabetes, and so on). Another type of diseases are the chronic diseases that not caused by any single agent (toxic chemicals or infectious organisms aka: “pathogens”) but are rather a result of a complex interplay of sub-optimal (and very normal) cellular processes exacerbated by a poor quality lifestyle and a sub-optimal environment (i.e. diet sucks, not enough exercise, and way too many exposures to too many potentially toxic chemicals). Chronic diseases such as Alzheimer’s, many different cancers, atherosclerosis, metabolic syndrome, type II diabetes, obesity, and a host of others are simply the result of normal (suboptimal, but still normal) living processes which lead to the development of specific cellular dysfunctions; dysfunctions that then lead to clinical symptoms of organ dysfunction. These symptoms of “organ dysfunction” are the clinical manifestation of the disease - the point at which a physician will say you have “the disease”. For example: inability to remember recent events and constant childish and “bizarre” behavior in the elderly would indicate the possibility of Alzheimer’s; shortness of breath on any physical activity with pressure in the center of the chest and pain radiating down the left arm may indicate advanced atherosclerosis and so on… The logic of the mechanistic-based definition of disease that has a focus on cellular functions is revealed by considering the etiology of the chronic diseases. Chronic diseases such as cancer or atherosclerosis take many years to develop from the first cellular event through to the accumulation of sufficient dysfunctions and damage to actually produce the disease symptoms. Traditionally, medical practice demands the appearance of symptoms as a necessary event for the diagnosis of disease: “no symptoms” means “no disease”. The unfortunate by-product of such a requirement is the lay concept that you don’t have the disease until the symptoms appear and nothing needs to be done until you have the disease. If disease is recognized as a continual process that leads to the development of sufficient cellular damage and cellular dysfunction that ultimately results in organ dysfunction (and symptoms), then we can recognize that we already have the disease process going on and something can be done about it NOW (before symptoms appear). By slowing down the processes of a disease the ultimate accumulation of sufficient dysfunction and damage (such that symptoms actually appear) may be delayed for many years beyond a normal life-span. This would effectively prevent morbidity (loss of function) and mortality (loss of life) from the disease and give the appearance of preventing the disease itself. Each different disease will have its own specific etiology: etiology is simply a series of specific cellular events that lead to one (or more) specific organelle dysfunctions. These dysfunctions may ultimately lead to cellular failure and possibly to organ dysfunction or organ failure (this process is often referred to as: pathology). A different series of pathological events will lead to different cellular dysfunctions, and therefore to different diseases. By focusing on cellular dysfunction(s) as the major result (and cause) of disease it forces us to consider all the different “things” that can possibly go wrong. With many hundreds of different processes going on in a cell at the same time, that can be an awful lot of different “things”. This concept of looking at cell functions has changed how disease is understood. Heart disease provides a good example of this. Until the last 50 years or so, heart disease was a catch-all term that described the “disease” that caused someone to die from a “heart-attack”; heart attack meant heart disease. Today, there are many different forms of heart disease known and each has its own proper name. Atherosclerosis is a disease of arteries that ultimately results in occlusion of these blood vessels until no blood can get through - no blood flow leads to death of those cells on the other side of the blockage, death of enough heart cells means the heart can’t pump blood efficiently, and the heart “dies” of a heart attack; and we die soon after of brain-anoxia. Obviously, the blood vessels main function is to supply tissue cells with blood, oxygen, and essential compounds so the tissue cells can live and perform their appropriate functions. The heart cells main function is muscular contraction. With proper heart muscle contraction, blood is pumped through the entire body and all the cells in the body get what they need in order to do their job. If the “blood-flow function” of the blood vessels that supply the heart is compromised then heart cells can die . . . and then we die. Another form of “heart disease” is cardiac myopathy. This “disease” is actually a genetic disease that appears in several different forms. Each form is due to a specific gene defect in the gene (“gene” will be defined later) that codes for the contractile protein: myosin. Some variants of the gene produce a protein that works very poorly so the person who inherits such a gene polymorphism has a high risk of dying of a heart attack at any time. Other variants of this gene defect produce a protein that functions just a little bit less well than the “normal” myosin protein. Someone who inherits a “less bad” variant may only have a high risk of suffering a heart attack during very stressful physical activities such as shoveling snow or sports competition. Thus, by looking at specific cellular functions, and specific cellular dysfunctions, what used to be considered one disease is now known as a whole bunch of different diseases. Each different disease will have its own specific etiology: etiology is simply the series of specific cellular events that lead to one (or more) specific organelle dysfunctions. These dysfunctions may ultimately lead to cellular failure and possibly to organ dysfunction or organ failure (this process is often referred to as: pathology). A different series of pathological events will lead to different cellular dysfunctions, and therefore to different diseases. Another cell dysfunction concept relating to human disease is that the same dysfunction in different tissues can lead to different symptoms and therefore different diseases. Different tissues have different functions and therefore, even though the same disease process may occur, there will be different end results (different diseases). For example, it is now known that inflammation is the cause (or majority cause) of atherosclerosis, arthritis, the many forms of hepatitis, Alzheimer’s, many cancers, and many other chronic diseases. The location of the inflammation determines the tissue or organ dysfunction that occurs and the subsequent symptoms that will appear, and therefore what disease you have. One common factor to the many different inflammatory diseases (different because of the different tissues affected) is some sort of localized damage to a particular tissue that leads to an inflammatory response at that site. Inflammation is normally a good thing. It turns on processes that lead to formation of blood clots to stop bleeding, scar formation to permanently close wounds, jump-start an adaptive immune response, and increase rates of protein synthesis for repair processes and so on. Unfortunately, with prolonged uncontrolled inflammation a variety of cell functions can be compromised and some sort of disease will result. As already implied, inflammation just happens to be the major (and in some cases, the only) etiological factor for many of our chronic diseases. Therefore, it is important to understand the inflammatory process and how physical damage to cell structures can lead to inflammation. Chemical radicals and oxygen radicals created during normal cellular metabolism processes are very important damaging agents that may be responsible for many inflammation-related chronic diseases. In addition, lifestyle issues such as food choices and activity habits can greatly alter the impact of these damaging molecules on your cells and therefore alter the disease process. For example: there are many more men who smoke (much more carcinogen-laden cigarettes, too) in China compared to the USA yet, incidence of lung cancer per capita is almost half that of the USA. Obviously there is much more to smoking and cancer than just the smoking - other lifestyle variables count! As mentioned “a couple slides ago”, atherosclerosis is a disease of arteries - predominantly the coronary arteries that supply blood to the heart. Our current understanding of the etiology of the atherosclerotic process is that mechanisms of inflammation are the predominant driving forces behind the development of the atherosclerotic placque. Essentially, normal signaling processes associated with producing adaptive changes in blood-vessel structure result from the physical characteristics of blood flow at very specific locations in the blood vessels; signaling processes that are characteristic of inflammatory responses. These signaling processes initiate a series of cellular responses that result in remodeling of the physical structure of the blood vessel, with the unfortunate side effect of ultimately leading to a build-up of placque over many decades. If the placque is thick enough it can occlude the coronary blood vessel and cause a heart-attack. When the heart dies, we “go” along with it - in other words, we die of “coronary artery disease”. Alcoholic cirrhosis is another disease caused by the same inflammatory signaling processes, with the exception that the signaling processes are initiated by chemical-induced damage. Molecules produced as a result of metabolism of large amounts of ethanol can cause damage to the membranes of hepatocytes (liver cells). This damage leads to an inflammatory response which ultimately leads to the build-up of fibrous tissue in the liver. If the fibrosis is extensive enough, liver function will be severely compromised and the heavydrinking individual’s liver will fail, they will then die of “alcoholic liver disease”. Interestingly enough, the mechanisms that lead to both coronary artery disease and alcoholic liver disease are almost identical; they are both caused by an inflammatory response to localized membrane damage - only the damaging agents and the (tissue) location of the damage are different. Of course, none of this information has always been “common knowledge”. In fact, there are still many clinicians and a large majority of educators that still believe that cholesterol, or high fat diets, or saturated fats cause heart disease in spite of the fact that the bulk of the biological evidence learned in the last 20 years points to a very different conclusion (see above) and that cholesterol is not only essential for normal function of all cellular cell membranes but it also does not cause the disease (although oxygen-radical damaged cholesterol does play a relatively minor role in the etiology). This leads to some basic questions about understanding disease: How do we learn about disease? How do we know that a new disease has appeared? How do we know how to treat/prevent the disease? It boils down to research… in many cases; EPIDEMIOLOGY research: Epidemiology of symptoms & lifestyle variables (- correlate variables vs. variables vs. presence vs. absence of disease) - calculate relative risk profiles of variables Experimental research on probable causes identified by epidemiology research - control vs. treatment(s) group(s) Experimental and basic research on etiology of disease progression - disease models, compare diseased vs. non diseased Experimental research on treatment/prevention in humans - calculate relative risk profiles of experimental variables Epidemiology, by definition, is a type of research within the health-research field that tries to analyze the incidence and distribution of determinants and deterrents of morbidity and mortality in both manipulated and non-manipulated populations of people. The overall concept of health-research in general is to provide an unbiased inquiry into cause, etiology, and control of disease. Because some diseases may take decades from the start of the disease process until the appearance of actual symptoms, there may be serious difficulties in analyzing how separate variables may contribute to either enhancing or decreasing risk for disease. Some diseases are so complex it may take decades of study to figure out what variables to even ask about in the first place! Political realities, economic constraints, and a host of other factors actually limit our ability to produce truly unbiased and comprehensive research about any individual disease. The hoped-for end result of health-research, in spite of a non-perfect system, is the development of effective treatments, effective prevention paradigms, and the development of sound public policy. (And we actually do pretty well in spite of the inherent limitations!) By determining how incidence of a particular disease is distributed throughout different geographical regions within a population, and how this incidence changes over time, epidemiologists can then get some idea about whether the disease is “spreading” across the country, where the initial “outbreak” occurred, or the speed at which the disease is increasing (or decreasing) in incidence at any location. This happens to be one of the many jobs of the US Center for Disease Control and the World Health Organization. Monitoring incidence data is very important in determining if some form of public action needs to be taken; such as enforcing a quarantine in a specific location where deadly infections appear to originate (the SARS outbreak a couple years ago is a good example). The discovery of the form of AIDS which is caused by HIV (virus) is a good example of how epidemiology research was integrated with other forms of health-related research in order to understand the disease and to develop effective treatments. Initially, there was observed a sudden increase in death due to (formerly) obscure forms of cancer in New York City and San Francisco (among others). Following this observation, additional epidemiology research relating to AIDS was conducted in order to determine possible causes so the new form of AIDS could be understood Additional research studies on the new epidemic then focused on many different variables obtained from the medical histories and from the reported lifestyles of both AIDS patients and non-AIDS patients. By analyzing how different variables were associated with the probability of getting AIDS (some variables were strongly associated with AIDS and many variables were weakly associated with AIDS); epidemiologists were able to determine that there were at least three determinants, or variables, associated with increased risk for acquiring AIDS which occurred frequently: the two different lifestyle variables of frequent anal intercourse and that of sharing needles during illicit drug use, and the one medical variable of receiving blood transfusions. (Because of the dominant American political climate at the time, guess which one of the three got ALL the press - to the near-complete exclusion of the others!). This illustrates that by developing new knowledge about a specific (new) disease by analyzing many variables which are directly related to those people who get the disease and these same variables in those who do not, we can obtain clues relating to the probable source of cause. Obviously, the common variable among those who got AIDS was ‘sharing” blood. And the suspected pathogen, because of the long latency between infection and symptoms, was hypothesized to be some type of a (very slow?) virus. The very first hypothesis that a virus was responsible was an educated guess and many series of experiments were performed which ultimately provided sufficient evidence to support the viral hypothesis. Because we now know a lot more about AIDS and how it works (more than simply knowing that a virus causes the disease), the above example illustrates that epidemiology research is only one form of research among several types of research which are necessary to learn about all aspects of disease, including how to treat or prevent it. Once a virus was suspected as being the cause of AIDS then a huge amount of basic research was performed in order to find out which specific virus was the cause and exactly how it worked. As a result of a massive research effort involving testing tens of thousands of individual hypotheses in specific research studies, we now know that a specific form of retro-virus is the cause of HIV-associated AIDS as well as a lot of the details relating to how the virus invades specific “immune” cells and how it replicates; supporting the current theory that AIDS is caused by the HIV. Human Disease & Health If you really really really want to be an expert in human disease, then these are just a few important areas of study: chemistry micro-anatomy biochemistry enzymology physiology cell physiology epidemiology statistics molecular biology toxicology cell biology pathophysiology molecular biology signal transduction oncology immunology endocrinology To deal with all this stuff we need a cellular view of the world; and an understanding of how cellular function affects all health-related processes Hence… the Introductory PPt… A - Introduction to Cell Function and Inflammation