File Name: essentials of human diseases and conditions ch 6 .zip
Richard D. Hockett, Sandra C. Kirkwood, Bruce H. Mitlak, Willard H. The first draft of the human genome was published recently by two independent groups 1 , 2. This important advance has led to a host of editorials describing how knowledge derived from the human genome will revolutionize medicine and drug development.
The ability to predict the likely development of disease or appropriate response to therapy has been touted as a means to improve clinical outcome 3. The term pharmacogenomics has often been employed to describe the application of genetics to certain aspects of drug development. Its classic meaning has been to understand the genetic influences on drug response.
The most studied aspect has been the genetic variation in the drug metabolizing enzymes of the liver, which leads to altered enzyme kinetics for drugs metabolized by these enzymes 4 — 6.
However, the sequencing of the genome and the development of newer technologies for exploring genes and proteins on a large scale have led to a redefinition of the term. In the broadest sense, pharmacogenomics now refers to the application of genetic technologies and information across the entire drug discovery and development platform. The overt goal is to understand the relationship between genotype and drug response, drug efficacy, or drug toxicity.
This stated goal has relevance to the discovery, preclinical, and clinical development platforms. A pharmacogenomics, or applied genomics, strategy leverages the human genetic sequence, a collection of sophisticated analytical tools, and genetic expertise to identify and develop better drugs faster, and to improve patient care. Although the term pharmacogenomics has application to the entire drug discovery chain, this paper will focus exclusively on applications of genetics in clinical use.
In this context, the genetic applications are directed to the identification of biomarkers to diagnose disease, predict drug response, or predict toxicity. Such personalized therapy to improve the overall benefit-risk profile is as yet the unrecognized promise of genetics. This long pursuit to improve patient care by customizing therapy will require genetic biomarkers to identify groups or subsets of patients with the same molecular basis of disease rather than clinical or phenotypic categorization who will respond with increased clinical efficacy to a specific therapy.
As a consequence, subsets of patients who would be less responsive to a particular therapy should be provided alternatives. Moreover, because the goal of personalized therapy is to improve the overall benefit-risk profile, appropriate attention should be directed toward clinical safety. For example, patients who are predisposed toward particular toxicities hepatic, cardiac, or bone marrow should be identified and excluded. As this overview will show, we are only just beginning to use the power of genetics in drug development.
Unfortunately our ability to identify patients at risk for disease, stratify patients by clinical outcome and treatment response, or predict adverse event occurrences is, in reality, several years away.
In drug discovery, the use of genetics has been positioned to fall into two broad categories: disease susceptibility genetics and drug activity genetics Fig. Disease susceptibility genetics refers to the identification of genetic polymorphisms that contribute to the risk for development of disease. This includes the identification of a single gene resulting in a well defined inherited disorder, such as sickle cell anemia, and the association of a number of genes with a complex disease, such as diabetes mellitus.
On the other hand, drug activity genetics refers to the identification of genetic polymorphisms and the response to drugs, either efficacy, toxicity, or side effects. Schematic of drug activity genomics vs.
Each category is subdivided into discovery and clinical phases. For both drug activity and disease susceptibility genomics, genetic applications encompass the entire drug discovery and development value chain.
Individual tasks associated with these functions are specific to parts of the pipeline, as with target identification in discovery or sample banking in the clinical setting, whereas other tasks appear in all three categories, such as biomarker development shaded overlap region.
MOA, Mechanism of action. Predicting how a patient will respond to a medication is the goal of drug activity genomics. Genetic biomarkers may facilitate classification of individuals, allowing for individualized prescriptions.
Furthermore, predicting toxicity or adverse events to a specific drug would have enormous utility, decreasing a significant health care problem. Although the widespread clinical utility of such genetic biomarkers is yet to be proven, the recent literature has contained a few reports of the association of genetic variants with a clinical response.
Currently, as mentioned above, the most common genetic biomarkers used in drug development are the genetic polymorphisms present in the metabolic enzymes of the liver.
A variety of mutations are found in the metabolizing enzymes, with single nucleotide polymorphisms the most common 7. Unlike disease susceptibility polymorphisms, the genetic variants in these enzymes do not predict disease. Nor do these enzyme variants predict response to therapy, but lead to the marked alteration in clearance of drugs, sometimes leading to marked drug toxicity 8 , 9. As such, these enzymes are not targets for new therapeutics. The list of drugs metabolized by each enzyme system is large and is reviewed elsewhere 4 — 6.
A patient with two copies of a defective gene e. The importance of reduced drug clearance is heightened when the therapeutic margin of safety is relatively low. Therefore, in individuals with decreased clearance of the drug due to certain polymorphisms in a metabolic enzyme, a reduced dose may be warranted. Even though these tests are not widely used outside of clinical trials, there is growing acceptance for their use in determining proper dosing regimens.
Two recent examples in the literature pertaining to the drug activity arena are in the field of asthma, and they associate drug response to genetic polymorphisms. Individuals homozygous for rare alleles demonstrated significantly decreased response as measured by FEV1 when compared with individuals heterozygous and homozygous for the wild-type allele. This study provides evidence for the importance of the regulatory region of genes, rather than in the coding regions of the genes themselves, in predicting response.
Another example is the relationship between polymorphisms in the B 2 adrenergic receptor gene and response to B agonists aimed at reversing acute bronchospasm in asthma While predicting who will respond, both studies highlight problems inherent in this kind of analysis. Although the identified variants in the B 2 adrenergic receptor gene have demonstrated functional consequences in vitro and in vivo , their relationship with bronchodilatory response to B agonists remains uncertain.
Thus, there may be other genetic defects in the pathway yet to be identified. Although these examples illustrate the potential applicability of genetic biomarkers for response, these markers clearly are in the early stages of development. Genetic markers for disease susceptibility can have large impact in medicine, with many rare disorders explained by single gene mutations. The vast majority of these mutations are germline and inherited in a Mendelian fashion dominant or recessive with high penetrance, often resulting in a definitive disease phenotype.
The identification of these rare variants has led to improved understanding of the pathophysiology of disease but has had relatively little impact on drug development.
Conversely, the genetic markers with the greatest potential to impact medicine and drug development are those associated with complex diseases.
Complex human disorders, caused by multiple genetic and environmental factors, are characterized by high population prevalence, lack of clear Mendelian patterns of transmission, etiological and phenotypic heterogeneity, and a continuum between disease and nondisease states 17 , Complex diseases cause significant morbidity and mortality, adding billions of dollars to the health care budget each year. In the field of endocrinology, diabetes mellitus, osteoporosis, and obesity are a few examples.
Most of the genetic research in these fields has centered on the identification of disease susceptibility genes. However, as with single disease genetics above, to date no targeted therapeutics have been developed by first identifying a genetic association and then developing a drug to treat the associated disease. Although investigation of the susceptibility to complex diseases is an important area of research, the immediate impact on the development of new therapeutics is uncertain.
Both disease susceptibility and drug activity genetics will play key roles in shaping clinical practice in the future. We will start with an in-depth review of osteoporosis, showing current status in both drug activity genomics and disease susceptibility genomics, and end with brief descriptions of the other disorders. Osteoporosis is a global medical problem for older men and women, resulting in a huge economic burden.
It is hoped that understanding the pathophysiology and underlying genetics for this disease will lead to additional therapeutic options. Evidence for the importance of genetic factors contributing to the development of osteoporosis has been obtained from heritability studies in twins and families.
These studies have demonstrated that genetics plays an important role in achievement of peak bone mineral density BMD as well as other factors that also contribute to the risk of fracture such as bone size and geometry, bone turnover, and muscle strength Further insights into the importance of genetic differences underlying variations in BMD have been gained by linkage studies in both humans and animals.
Focusing on disease susceptibility genetics, linkage studies have identified illuminating examples in which low or high BMD is inherited in simple Mendelian fashion. Examples of these include osteogenesis imperfecta 20 , osteopetrosis 21 , and osteoporosis due to inactivating mutations in the aromatase gene 22 or the estrogen receptor gene An extended family has been described in which there is linkage between a genetic locus on chromosome 11 11q12—13 and very high spinal BMD A gene that appears to be responsible for these effects has recently been identified as LRP5 As with most single gene mutations leading to disease, these are rare and account for only a small portion of individuals with osteoporosis.
As a complex disease, osteoporosis is a result of interactions between environmental and genetic factors 26 , which may differ by skeletal site.
One of the more promising genetic associations was reviewed recently by Mann et al. Furthermore, results from a cultured osteoblast system provide evidence for a molecular basis for the association of allelic variation at this site and skeletal fragility.
It is not yet clear what proportion of osteoporosis can be attributed to the COL1A1 polymorphism. To highlight further the phenotypic and genotypic complexities in osteoporosis, this disease can also be part of a syndrome.
The osteoporosis-pseudoglioma syndrome 28 and autosomal recessive osteopetrosis 29 are two examples. Subsequent work by Koller et al. It is interesting to note that osteoporosis-pseudoglioma syndrome has been mapped to the same gene on chromosome 11, 11q12—13 as noted above It is unclear whether additional genes affecting BMD are also present in this region.
The aforementioned examples in osteoporosis are focused on disease susceptibility genetics. To date, none of the identified genes have resulted in novel treatments for this disease or changes in prescribing practices.
Approaching drug activity genomics and getting closer to targeted therapeutics at defined genetic polymorphisms, one could hypothesize a plausible scenario using the vitamin D receptor. Studies from several groups have examined the relationship between allelic variations in the vitamin D receptor, BMD, bone turnover, and calcium metabolism. The initial report 32 suggested that a significant proportion of the gene effect on BMD could be explained by a polymorphism in the untranslated region of the vitamin D receptor gene.
Although this finding continues to be controversial, with different groups providing both confirmatory and conflicting data, a meta-analysis 33 supports an association of vitamin D receptor polymorphisms and BMD. Although the clinical utility of determining polymorphisms in the vitamin D receptor remains uncertain, one could envision targeted therapy to increase the activity of this signaling system, if the specific genetic defect is present.
In the future, knowledge about relevant genetic polymorphisms may allow risk stratification as well as selection of specific dietary or pharmacologic therapies. Ultimately, a better understanding of the process by which specific genes and environmental factors affect skeletal health will serve as the basis for advances in clinical management of osteoporosis and other skeletal diseases.
This will enable development of new biological markers for determining the risk of osteoporosis and fracture and may aid in optimal selection and use of a growing number of pharmacological treatments. In hypertension, identifying simple genetic disorders, although uncommon, can lead to targeted therapy. Further work must be done to confirm that prospective identification of such subsets and providing specific therapy, e. Maturity onset diabetes in the young MODY provides excellent examples in which specific genetic mutations are associated with clinical disorders that may not be phenotypically differentiated at the time of disease onset but have a very different course of disease progression.
Back to Home. Home Back to Home. Health A to Z. F Fabricated or induced illness Face blindness, see Prosopagnosia face blindness Fainting Falls Farting flatulence Febrile seizures Feeling sick nausea Female genital mutilation FGM Femoral hernia repair Fibroids Fibromyalgia First aid Fits children with fever , see Febrile seizures Fits seizures , see What to do if someone has a seizure fit Flat feet Flat head syndrome, see Plagiocephaly and brachycephaly flat head syndrome Floaters and flashes in the eyes Flu Fluoride Foetal alcohol syndrome Food allergy Food colours and hyperactivity Food intolerance Food poisoning Foot drop Foot pain Foreskin problems, see Tight foreskin phimosis and paraphimosis Frontotemporal dementia Frostbite Frozen shoulder Functional neurological disorder, see Medically unexplained symptoms Fungal nail infection Back to top. Q Q fever Quinsy, see Tonsillitis Back to top. V Vaccinations Vaginal cancer Vaginal discharge Vaginal dryness Vaginal pain, see Vulvodynia vulval pain Vaginismus Vaginitis Varicose eczema Varicose veins Vascular dementia Vasculitis Vegetative state, see Disorders of consciousness Venous leg ulcer Vertigo Vestibular neuritis, see Labyrinthitis and vestibular neuritis Vestibular schwannoma, see Acoustic neuroma vestibular schwannoma Vitamin B12 or folate deficiency anaemia Vitamins and minerals Vitiligo Vomiting, see Diarrhoea and vomiting Vomiting blood haematemesis Vomiting bug, see Norovirus vomiting bug Von Willebrand disease Vulval cancer Vulvodynia vulval pain Back to top. W Warts and verrucas Watering eyes Wegener's granulomatosis, see Granulomatosis with polyangiitis Wegener's granulomatosis Weight loss unexpected , see Unintentional weight loss Weight loss surgery Weil's disease, see Leptospirosis Weil's disease West Nile virus Whiplash White blood cell count low , see Low white blood cell count Whitlow finger, see Herpetic whitlow whitlow finger Whooping cough Wind, see Farting flatulence Winter vomiting bug, see Norovirus vomiting bug Wisdom tooth removal Wolff-Parkinson-White syndrome Womb uterus cancer Worms in humans Back to top.
This hormone can cause the prostate gland to grow abnormally. Also known as a tummy tuck. Often occurs on the surface of the skin. ACE: Abbreviation for angiotensin-converting enzyme, an enzyme that converts the inactive form of the protein angiotensin angiotensin I to its active form—angiotensin II. ACE inhibitor: Abbreviation of angiotensin-converting enzyme inhibitor, a drug used to treat high blood pressure and congestive heart failure.
Human Diseases, 5th Edition, Marianne Neighbors; Ruth. Tannehill‐ Summarize effects of disease conditions on specific body ocr/docs/qarnasystemsbiology.org). Ch 6: Essentials of Pharmacology for Health Occupations: Safe. Dosage.
Reducing greenhouse gas GHG emissions will reduce the occurrence of extreme events and the likelihood of abrupt changes. Abrupt changes can be irreversible on human time scales and, as tipping points, bring natural systems to novel conditions. To reduce risks that emerge from these impacts of climate change, communities can protect themselves or accommodate to the new environment. In the last resort, they may retreat from exposed areas.
Blood is arguably the most important bodily fluid and its analysis provides crucial health status information. A first routine measure to narrow down diagnosis in clinical practice is the differential blood count, determining the frequency of all major blood cells. What is lacking to advance initial blood diagnostics is an unbiased and quick functional assessment of blood that can narrow down the diagnosis and generate specific hypotheses. In a drop of blood we can identify all major blood cells and characterize their pathological changes in several disease conditions in vitro and in patient samples. This approach takes previous results of mechanical studies on specifically isolated blood cells to the level of application directly in blood and adds a functional dimension to conventional blood analysis.
Although the nail is a structure produced by the skin and is a skin appendage, nail diseases have a distinct classification as they have their own signs and symptoms which may relate to other medical conditions. What causes smell and taste disorders? Some people are born with these disorders, but most are caused by.
Respiratory disease , any of the diseases and disorders of the airways and the lungs that affect human respiration. Diseases of the respiratory system may affect any of the structures and organs that have to do with breathing , including the nasal cavities, the pharynx or throat , the larynx , the trachea or windpipe , the bronchi and bronchioles, the tissues of the lungs , and the respiratory muscles of the chest cage. This article discusses the signs and symptoms of respiratory disease , the natural defenses of the human respiratory system, the methods of detecting respiratory disease, and the different diseases of the respiratory system.
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