By K. Grimboll. Hood College.
The analysis shows that the phenotypic variation of some genomic disorders may be partially explained by the presence of additional large variants chloroquine 250 mg. Both types of variation are likely to have a major impact on humans generic 250 mg chloroquine with visa, including their health and susceptibility to disease purchase chloroquine 250mg with visa. The scientists expect to expand the map to between 1 and 2 million by continuing their efforts with additional human sequences. Transposon insertions have been identiﬁed in hemophilia, muscular dystrophy and cancer. The next phase of this work is to ﬁgure out which changes correspond to changes in human health and develop personalized health treatments. Currently, it incorporates a database – developed during the past year – of approxi- mately 200,000 novel predicted insertions, deletions and copy-number variations in the human genome. This previously unappreciated heterogeneity may underlie certain human phenotypic variation and susceptibility to disease and argues for a more dynamic human genome structure. Universal Free E-Book Store Molecular Biological Basis of Personalized Medicine 15 The size of genomes isolated from mouse liver tissues increases with age, peaking at 5 weeks and the copy number of several retro-element sub-families are up to twofold higher in liver tissue than in lung or spleen tissue (Lee et al. The ﬁndings that the genome structure of an individual is variable depending on age and organ type in association with the transposition of retroelements may have broad implications in understanding biologic phenomena. Data from this study indicate that there may be multiple variant isoforms of an individual. This ﬁnding indicates that a new protocol or system and more research will be needed to analyze and make sense of how the structural changes in the genome relate to an individual’s health. Further work is required to pinpoint which structural changes in the genome correlate to a particular disease process and this might eventually provide clinicians with new prognostic biomarkers. Structural Variations in the Human Genome Structural changes are extremely common in human populations. More bases are involved in structural changes in the genome than are involved in single-base-pair changes. Although the original human genome sequencing effort was comprehensive, it left regions that were poorly analyzed. A study offers a new view of what causes the greatest genetic variability among individuals − suggesting that it is due less to single point mutations than to the presence of structural changes that cause extended segments of the human genome to be missing, rearranged or present in extra copies (Korbel et al. This method of sequencing can generate hundreds of thousands of long read pairs, which are unique within the human genome, to quickly and accurately determine genomic variations. Even in healthy persons, Universal Free E-Book Store 16 1 Basic Aspects there are variants in which part of a gene is deleted or sequences from two genes are fused together without destroying the cellular activity with which they are asso- ciated. These ﬁndings show that the parts list of the human genome may be more variable and ﬂexible than previously considered. The researchers discovered 525 new insertion sequences, ranging in size from a few thousand to 130,000 base pairs, which are not present in the human reference genome, and many of these are variable in copy number between indi- viduals. Large genetic regions may be ﬂipped in one person compared with another and these differences can inﬂuence a person’s susceptibility to various diseases. These data provide a standard for genotyping platforms and a prelude to future individual genome sequencing projects. The results also indicate that the human genome sequence is still incomplete that sequencing of additional genomes will be required to ﬁll the remaining gaps. The eight people studied are part of a much larger group whose genomes will be sequenced as part of the 1,000 Genomes Project, an international effort to sequences the genomes of people from around the world. In order to understand structural variation, it is also essential to develop new technologies designed to detect genetic differences among people. Currently available biochips would miss an association for nearly half of these sites. Besides their potential applications, the new results provide a wealth of data to explore hypotheses and make discoveries as we now have eight new reference human genomes. Role of sequencing in synthetic biology for drug discovery and development is discussed later in this chapter. Personalized genome sequenc- ing would become an integral part of personalized medicine as the cost comes down. Sequencing will also lead to the development of many diagnostic assays that will contribute to personalized medicine. Simple-to-operate and affordable small sequencers can be integrated in point-of-care diagnostics for personalized medicine. Availability of low-cost genomic sequencing will expand the use of genomic information in the practice of medicine. Drugs will be targeted better to diseases in particular patients based on genotype information. By the end of the second decade of the twenty-ﬁrst century, it is anticipated that the general population will have the oppor- tunity to carry a chip card, like a credit card, with all the genetic information of the person coded on it. The picture emerging from analysis of whole-genome sequences, the 1,000 Genomes Project pilot studies, and targeted genomic sequencing derived from very large sample sizes reveals an abundance of rare and private variants (Lupski et al. One implication of this realization is that recent mutation may have a greater inﬂuence on disease susceptibil- ity or protection than is conferred by variations that arose in distant ancestors. Universal Free E-Book Store 18 1 Basic Aspects According to the authors, the most important thing is not to focus disproportionately on speciﬁc variants, but rather to integrate across all classes or risk-associated vari- ants. In some individuals, risk may be caused by an unusual combination of common variants, whereas in others it will be due to a smaller number of large effect rare vari- ants. Nevertheless, the extent to which private or rare genetic variation are turning up in large-scale genome sequencing studies, personal genome analyses, and targeted gene sequencing work hints that these mutations have a previously unappreciated inﬂuence over traits and diseases. There is considerable medically actionable infor- mation that can be gleaned from genetic and genomic studies of these recent muta- tions in the genome that are shared between family members. The authors state that this “clan genomics” model could help in interpreting personal genome and disease data. Another goal of the study was to encourage a move away from a preoccupation with accounting for all of the heritability for a given disease. It is not necessary to account for all of the herita- bility in order to better understand biology and improve human health. It is also important to consider the inﬂuence that rare and common variants can have on one another, because each personal genome has a collection of deleterious as well as protective variations, which in combination dictate the health of the individual. Considering common diseases involving many genes and Mendelian diseases associ- ated with high penetrance, rare genetic variants are not necessarily separate entities, since they sometimes involve different types of alterations to the same genes or path- ways. Common variations in the so-called Mendelian disease genes are also contrib- ute to more common chronic disease in the population. Basics Technologies for Developing Personalized Medicine D e ﬁ nitions of Technologies Relevant to Personalized Medicine Important basics of personalized medicine are derived from the following technolo- gies and approaches, which will be described in more detail in various chapters of the report: 1. It involves the study of mechanism of action of the drugs on the cells as revealed by gene expression patterns. Pharmacogenetics is a term recognized in pharmacology in the pre-genomic era and concerns the study of inﬂuence of genetic factors on response to drugs. With advances in genomics, role of gene polymorphisms on action of drugs has been added to this. Pharmacoproteomics is the application of proteomics to drug discovery and development. Discovery of protein biomarkers may serve as a common basis of diagnostics and therapeutics.
The most com- mon use of this reaction is to assess for infection with tuberculosis after injection of a pu- riﬁed protein derivative to Mycobacterium tuberculosis cheap chloroquine online. The Kveim reaction refers to the development of granulomatous inﬂammation 4–6 weeks after injection of a protein de- rived from the lesion of sarcoidosis 250mg chloroquine otc. An urticarial reaction demonstrates immediate hy- persensitivity reaction and is typical of allergy phenomena discount 250 mg chloroquine otc. It is important to assess for other potentially reversible causes of acute renal insufﬁciency, but this patient is not oth- erwise acutely ill and is taking no medications that would cause renal failure. The urinal- ysis shows evidence of active nephritis with hematuria and proteinuria. Cyclophosphamide in combination with steroid therapy has been demonstrated to prevent development of end-stage renal disease better than steroids alone. Likewise, mycophenolate also prevents development of end-stage renal disease in combination with glucocorticoids, and some studies suggest that African Americans have a greater response to mycophenolate than to cyclophospha- mide. Finally, this patient has no acute indication for hemodialysis and, with treat- ment, may recover renal function. The disease course can be variable between patients; some patients experience minimal joint damage, while others have a relentless and debilitating polyarthritis. Pa- tients who develop Felty’s syndrome most commonly have more active disease with high titers of rheumatoid factor, subcutaneous nodules, and other systemic manifestations of disease. The leukopenia is a selective neutropenia with polymorphonuclear leukocytes below 3 1500/mm. Hypersplenism has been proposed as a cause of Felty’s syndrome, but splenectomy does not consistently correct the abnormality. Excessive margination of granulocytes caused by antibodies to these cells, complement activation, or binding of immune com- plexes may contribute to neutropenia. Cardiac disease is present in only a few percent of these patients and most commonly presents as aortic regurgitation. Other cardiac manifestations include complete heart block and congestive heart failure. Rare complications are upper lobe pul- monary ﬁbrosis and retroperitoneal ﬁbrosis. Antiglomerular antibodies are found in patients with Goodpasture’s syndrome, antihistone antibodies in those with drug-induced lupus, and antimicrosomal antibodies in those with autoimmune hepatitis. As the primary driving force of the disease is mechanical, ﬁrst-line therapy should be nonpharmacologic. Each pound of weight increases loading across a weight-bearing joint three- to six-fold. This patient would beneﬁt from a daily minimal- weight-bearing exercise regimen combined with nutritional goals aimed at slow, consis- tent weight loss. Avoidance of walking is impractical; a cane or supportive device to lessen the joint load can be offered. While the pathogenesis is not clear, there are associations with disturbed sleep (disruption of stage 4 sleep) and abnormal pain perception. Fibromyalgia is diagnosed by the presence of widespread pain, a history of widespread musculoskeletal pain that has been present for >3 months, and pain on palpation at 11 of 18 tender point sites. Besides pain on palpation, the neurologic and musculoskeletal examinations are normal in pa- tients with ﬁbromyalgia. Psychiatric illnesses, particularly depression and anxiety disor- ders, are common comorbidities in these patients but do not help satisfy any diagnostic criteria. This patient is typical in that most persons af- fected by this disorder are middle-aged females with a female-to-male ratio of 9:1. Oc- ular involvement resulting in symptoms of a sandy or gritty feeling under the eyelids, burning, redness, itching, decreased tearing, and photosensitivity is due to destruction of corneal and bulbar conjunctival epithelium, deﬁned as keratoconjunctivitis sicca. Slit-lamp ex- amination of the cornea after rose Bengal staining may show punctate corneal ulcerations and attached ﬁlaments of corneal epithelium. The most common extranodal manifesta- tion of Sjögren’s syndrome is arthralgias or arthritis (up to 60% of patients). Rheumatoid arthritis may be considered; however, the examination did not demonstrate inﬂammation, and the diffuse joint complaints without persistent morning stiffness make this less likely. Vitamin A deﬁciency may lead to dry eye but does not explain the patient’s other symptoms. In the general population, rheumatoid factors become more prevalent with age, and 10–20% of patients older than 65 will have them. False-positive results can occur in patients with systemic lupus erythematosus, Sjögren’s syndrome, chronic liver disease, sarcoido- sis, hepatitis B, mononucleosis, tuberculosis, malaria, and a host of other conditions. In the pa- tient above, radiographs would not add anything to the diagnostic evaluation. In early disease they are no more revealing of active synovitis than a careful physical examination. Morning stiffness: Stiffness in and around the joints lasting 1 h before maximal improve- ment. Arthritis of three or more joint areas: At least three joint areas, observed by a physician si- multaneously, have soft tissue swelling or joint effusions, not just bony overgrowth. The 14 possible joint areas involved are right or left proximal interphalangeal, metacarpophalan- geal, wrist, elbow, knee, ankle, and metatarsophalangeal joints. Arthritis of hand joints: Arthritis of wrist, metacarpophalangeal joint, or proximal inter- phalangeal joint. Symmetric arthritis: Simultaneous involvement of the same joint areas on both sides of the body. Rheumatoid nodules: Subcutaneous nodules over bony prominences, extensor surfaces, or juxtaarticular regions observed by a physician. Serum rheumatoid factor: Demonstration of abnormal amounts of serum rheumatoid fac- tor by any method for which the result has been positive in less than 5% of normal control subjects. Her skin testing shows multiple sensitivities including ragweed, grass, pet dander, and dust mites. The ini- tial step in the treatment of chronic perennial rhinitis is avoidance of the offending aller- gens. This should include removal of the pet from the home, which is often difﬁcult given the emotional attachment to the pet. In this instance, the ﬁrst approach to the patient’s sensitivity to cat dander is to discuss potentially removing the pet from the home. In ad- dition, multiple other interventions are available that might decrease her symptoms. Other avoidance strategies that would decrease her exposure to offending allergens in- clude removal of carpet and drapes from the bedroom, weekly laundering of the bedding and clothes at high temperatures, use of a ﬁlter-equipped vacuum, and plastic-lined cov- ers for the mattress, pillows, and comforters.
Factors that affect likelihood of developing tuberculosis infection include the probability of contact with an infectious person discount chloroquine 250 mg overnight delivery, the intimacy and duration of contact 250mg chloroquine with mastercard, the degree of infectiousness of the contact generic chloroquine 250mg amex, and the environment in which the contact takes place. All of the individuals listed as choices have risk factors for developing active tuberculosis. While the risk of developing active tuberculosis is greatest in the ﬁrst year after exposure, the risk also increases in the elderly. In this man from an endemic area for tuberculosis, this ﬁnding should be treated as active pulmonary tuberculosis until proven otherwise. In addition, this patient’s symptoms suggest a chronic illness with low-grade fevers, weight loss, and temporal wasting that would be consistent with active pulmonary tuberculosis. If a pa- tient is suspected of having active pulmonary tuberculosis, the initial management should include documentation of disease while protecting health care workers and the population in general. This patient should be hospitalized in a negative-pressure room on airborne isolation until three expectorated sputum samples have been demonstrated to be negative. The samples should preferably be collected in the early morning as the burden of organisms is expected to be higher on a more concentrated sputum. The sensi- tivity of a single sputum for the detection of tuberculosis in conﬁrmed cases is only 40– 60%. Thus, a single sputum sample is inadequate to determine infectivity and the pres- ence of active pulmonary tuberculosis. These drugs are given for a total of 2 months in combination with pyridoxine (vitamin B6) to prevent neurotoxicity from isoniazid. Fol- lowing the initial 2 months, patients continue on isoniazid and rifampin to complete a to- tal of 6 months of therapy. If the sputum culture remains positive for tuberculosis after 2 months, the total course of antimycobacterial therapy is increased from 6 to 9 months. It can be difﬁcult for a clinician to decide which medication is the cause of the side effects and may lead unnecessarily to alterations in the antituberculosis regimen. Three-drug regimens are associated with a higher relapse rate if used as a standard 6-month course of therapy and, if used, re- quire a total of 9 months of therapy. Situations in which three-drug therapy may be used are pregnancy, intolerance to a speciﬁc drug, and in the setting of resistance. Streptomycin and pyrazinamide are discontinued after 2 months if susceptibility testing is unavailable. If susceptibility testing is available, the treatment should be based upon the susceptibility pattern. In no instance is it appropriate to withhold treatment in the setting of active tuberculosis to await susceptibility testing. The size of the reaction to the tuberculin skin test determines whether individuals should receive treatment for latent tuberculosis. Thus, the reaction of 7 mm is not a positive result, and treatment is not required. A size of ≥10 mm is considered positive in individuals who have been infected within 2 years or those with high-risk medical conditions. The individual working in an area where tuberculosis is endemic has tested newly positive by skin testing and should be treated as a newly infected individual. High-risk medical conditions for which treatment of latent tuberculosis is recommended include diabetes mellitus, injection drug use, end- stage renal disease, rapid weight loss, and hematologic disorders. There are two situations in which treatment for latent tuberculosis is recommended re- gardless of the results on skin testing. First, infants and children who have had close con- tact with an actively infected person should be treated. In tropical areas, the prevalence of tinea versicolor is 40–60%, whereas in temperate areas it is about 1%. In general, most individuals seek evaluation for cosmetic reasons as the lesions in tinea versicolor are asymptomatic or only mildly pruritic. The lesions typi- cally appear as patches of pink or coppery-brown skin, but the areas may be hypopig- mented in dark-skinned individuals. Diagnosis can be made by demonstrating the organism on potassium hydroxide preparation where a typical “spaghetti and meatballs” appearance may be seen. Selenium sul- ﬁde shampoo, topical azoles, terbinaﬁne, and ciclopirox have all been used with success. A 2-week treatment regimen typically shows good results, but the infection typically re- curs within 2 years of initial treatment. Sporotrichosis develops after inoculation of the organism into the skin with a contaminated puncture or scratch. The disease typically presents as a ﬁxed cutane- ous lesion or with lymphocutaneous spread. Options include oral itraconazole, saturated solution of potassium iodide, and terbinaﬁne. However, terbinaﬁne has not been approved for this indication in the United States. In cases of serious system disease such as pul- monary sporotrichosis, amphotericin B is the treatment of choice. Epiglottitis can cause life-threatening airway obstruction due to cel- lulitis of the epiglottis and supraglottic tissues, classically due to H. The initial evaluation and treatment for epiglottitis in adults includes airway management and intravenous antibiotics. The patient presented here is demonstrating signs of impending airway obstruction with stridor, inability to swallow secretions, and use of accessory muscles of inspiration. A lateral neck x-ray shows the typical thumb sign indicative of a swollen epiglottis. In addition, the patient has evidence of hypoventilation with carbon dioxide retention. Thus, in addition to antibiotics, this patient should also be intubated and mechanically ventilated electively under a controlled setting as he is at high risk for mechanical airway obstruction. Antibiotic therapy should cover the typical organisms outlined above and include coverage for oral anaerobes. In adults presenting without overt impending airway obstruction, laryngoscopy would be indicated to assess airway patency. Endotracheal intubation would be recommended for those with >50% airway obstruction. In children, endotracheal intubation is often recommended as laryngoscopy in children has provoked airway obstruction to a much greater degree than adults, and increased risk of mortality has been demonstrated in some series in children when the airway is managed expectantly. Currently, however, it cannot be recommended as ﬁrst-line therapy as data are limited in regards to its efﬁcacy relative to gentamicin, but can be considered if an individual is unable to tolerate gentamicin. To date, there have been no clinical trials of ﬂuoroquinolones to deﬁnitively demonstrate equivalency with gentamicin. However, use of ceftriaxone in children with tularemia resulted in almost universal fail- ure.