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Increased from the water on chest and abdomen must quantities of O2 and CO2 therefore diffuse from the also be overcome with each breath order precose 50mg overnight delivery diabetes mellitus headaches. OncethePCO2inbloodrisestoa certain level purchase precose 50mg fast delivery diabetes type 1 kidney disease, the body signals that it is time to resur- Thedepthatwhichasnorkelcanbeusedislimited1) face. Ifthediverresurfacesatthistime,thePO2inthe because an intolerable increase in dead space or air- alveoli and blood drops rapidly (O2 consumption + way resistance will occur when using an extremely pressure decrease) and the alveolar O2 exchange long or narrow snorkel, and 2) because the water stops. Back at the water surface, the PO2 reaches a pressure at lower depths will prevent inhalation. If the diver excessively hy- maximum suction produced on inspiration is about perventilates before the dive, the signal to resurface 11kPa, equivalent to 112cm H O (peak inspiratory2 will come too late, and the PO2 will drop to zero pressure,! Inspiration therefore is no (anoxia) before the person reaches the water sur- longerpossibleataquaticdepthsofabout112cmor face, which can result in unconsciousness and more due to the risk of hypoxic anoxia (! The increased pressure as- tained underwater breathing apparatus) is sociated with diving leads to compression of neededtobreatheatlowerdepths(uptoabout air-filled organs, such as the lung and middle 70m). Their gas volumes are compressed to 1/2 surizedaircylinders)isautomaticallyadjusted their normal size at water depths of 10m, and to the water pressure, thereby permitting the to 1/4 at depths of 30m. The missing volume of air in the lungs is automati- However,theadditionalwaterpressureincreasesthe cally replaced by the scuba, but not that of the partial pressure of nitrogen PN2 (! The middle ear and throat are connected higher concentrations of dissolved N2 in the blood. If volume loss in the ear is not compen- decreases as the diver returns to the water surface, satedforduringadive,theincreasingwaterpressure but the additional N2 does not remain dissolved. The in the outer auditory canal distends the eardrum, divermustthereforeascendslowly,ingradualstages causing pain or even eardrum rupture. As a result, so that the excess N2 can return to and be expelled cold water can enter the middle ear and impair the from the lungs. Resurfacing too quickly would lead organ of equilibrium, leading to nausea, dizziness, to the development of N2 bubbles in tissue (pain! This can be prevented by and blood, where they can cause obstruction and pressing air from the lungs into the middle ear by embolism of small blood vessels. This is called holding the nose and blowing with the mouth decompression sickness or caisson disease (! Once as well as potentially fatal hemorrhage and air 2 a certain P has been reached, chemosensors embolism. Diving with equipment Normal Too deep Gas embolism <40cm N2 N2bubbles Blood Baro- Resurfacing trauma too rapidly Depth N2 >100cm Anoxia Water pressure Depth prevents inhalation ca. Diving unassisted 0 Depth (m) (Water pressure 10 98kPa 0 20 40 Diving time (s) at depth of 10m) Alveolar partial pressures Signal to resurface Hyper- 19. Stimulation of O2 chemosensors at Effects of High Altitude on Respiration high altitudes also leads to an increase in the At sea level, the average barometric pressure heart rate and a corresponding increase in car- (PB)! High altitude also stimulates erythropoiesis However,PBdecreaseswithincreasingaltitude (! Prolonged exposure to high alti- (h, in km): tudes increases the hematocrit levels, al- PB (at h) = PB (at sea level)! PAO2 is an important measure of oxygen above 7000m, where PIO2 is almost as high as supply. Mod- about 4000m above sea level during normal ern long-distance planes fly slightly below this ventilation (! As a result, larger possible without pressurized chambers or volumes of CO2 are exhaled, and the PACO2 and pressurized suits like those used in space PaCO2decrease(seebelow). Otherwise, the body fluids would begin alveolar gas equation, to boil at altitudes of 20km or so (! O2 deficiency ventilation stopsthePAO2frombecomingcriticaluptoalti- Hyperoxia occurs when PIO2 is above normal tudes of about 7000m (altitude gain,! The degree of O2 tox- times the resting rate) during strenuous physi- icity depends on the PIO2 level (critical: ca. Seizures and unconscious- signals from O2 chemosensors to increase the ness occur at PIO2 levels above 220kPa respiratory drive. This helps return the pH of the levels much greater than 40kPa (300mmHg) blood toward normal, and the O2 deficiency- for long periods of time (e. Large devia- + – added H or OH ions per unit volume that tions from the norm can have detrimental ef- change the pH by one unit.

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Preliminary evidence suggests that norrin plays a role in INorrie disease directing how cells interact and grow to become more Definition specialized (differentiation) 25 mg precose with visa control diabetes naturally diet. Norrie disease (ND) is a severe form of blindness Many different kinds of mistakes have been that is evident at birth or within the first few months of described in the NDP gene that are thought to lead to ND cheap precose 50mg line managing diabetes sick days. Few associations between Description the type of point mutation and severity of disease have ND was first described in the 1920s and 1930s as an been described. Other occasional errors in the NDP gene inherited form of blindness affecting only males. Individuals with dele- identified that lead to a wasting away or shrinking of the tions in the NDP gene are thought to have a more severe eye over time. One of each kind (23) and progressive deterioration of the lens, iris, and cornea is inherited from the mother and another of each kind cause the eye to appear milky in color and to become (23) is inherited from the father, which makes a total of very small and shrunken. Females therefore have two copies mental retardation, behavior problems, and deafness may of all genes on the X chromosome but males have only also occur. The genes on the Y chromosome are different ND is inherited in an X-linked recessive manner and than those on the X chromosome. The gene for ND was found in one of their X chromosomes to all of their children and the 1990s and genetic testing is available in the year fathers pass on their X chromosome to their daughters 2001. ND has also been referred to as: Males affected with ND have a mutation in their only copy of the NDP gene on their X chromosome and • Norrie-Warburg syndrome therefore do not make any normal norrin protein. As they have one normal copy of the NDP KEY TERMS gene, they usually have a sufficient amount of the norrin protein so that they do not show signs of ND. Women that Cataract—A clouding of the eye lens or its sur- are carriers for ND have a 50% chance of passing the dis- rounding membrane that obstructs the passage of ease gene onto each of their children. Affected males Cochlea—A bony structure shaped like a snail that have children would pass on their disease gene to all shell located in the inner ear. Genetic testing for mutations in the NDP gene is Cornea—The transparent structure of the eye over clinically available to help confirm a diagnosis of ND. As the lens that is continous with the sclera in form- of the year 2001, this testing is able to identify gene ing the outermost, protective, layer of the eye. If such a muta- tion were found in an affected individual, accurate carrier Iris—The colored part of the eye, containing pig- testing would be available for females in that family. Lens—The transparent, elastic, curved structure behind the iris (colored part of the eye) that helps Demographics focus light on the retina. ND has been observed to affect males of many eth- Retina—The light-sensitive layer of tissue in the nic backgrounds and no ethnic group appears to predom- back of the eye that receives and transmits visual inate. The first sign of ND is usually the reflection of a Mental impairment and hearing loss do not necessarily white area from within the eye, which gives the appear- occur together. This is caused by a mass or growth causing mental impairment and hearing loss is unknown. It may also Much variability in the expression of ND within a develop blood vessels that may burst and further damage family as well as between families has been observed. At birth the iris, lens, cornea and globe of the eye rare occasion, carrier females may show some of the reti- are generally otherwise normal. The problems in the nal problems, such as retinal detachment, and may have retina evolve over the first few months and until about ten some degree of vision loss. Cataracts form and the iris is observed to stick Diagnosis or be attached to the cornea and/or the lens of the eye. Pressure in the The diagnosis of ND is usually made by clinical fluid within the eye may increase, which can be painful. Toward the end stages of the disease, the eye mind that as many as 30% of affected males cannot be identified using current methods. The above findings affect The symptoms of ND have considerable overlap both eyes and the changes are usually the same in each with a few other eye diseases and ND must be distin- eye. If speech is devel- • Retinopathy of prematurity (ROP) GALE ENCYCLOPEDIA OF GENETIC DISORDERS 823 • Incontinentia pigmenti type 2 (IP2) The first two dis- ness, and mental retardation, including injury or illness, eases have been shown to also be associated with muta- might shorten the lifespan. General health, however, is tions in the NDP gene and may represent a more mild normal.

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Rules are applied on the data collected using an inference engine order precose 25mg with mastercard diabetes type 2 lifestyle, decisions are suggested precose 50 mg generic diabetes symptoms in children age 6, and explanations supplied (Turban & Aronson, 2000). For example, DARWIN, a renal decision support system, uses rule-based reasoning to advise dialysis technical staff regarding the response to bacteriologic monitoring of fluids used during hemodialysis. Another example of a rule-based or expert system is the use of clinical protocols to generate suggestions regarding anemia treatment using erythropoietin and iron protocols. On the basis of knowledge of new and historical laboratory results and medications, the expert system can suggest the modification of drug doses or the discontinuation of a medication. The inference engine can also provide an explanation of the basis of the recommendation in the protocol. A decision algorithm is a set of instructions that is repeated to solve a problem. Highly intelligent algorithms include the capability to learn and to perform several iterations of the algorithm or of parts of the algorithm until an optimal solution is reached (Turban & Copyright © 2005, Idea Group Inc. Copying or distributing in print or electronic forms without written permission of Idea Group Inc. A very simple decision algorithm may alert physicians on receipt of out- of-range laboratory results. In the next sections, we will discuss about the characteristics of a medical decision support systems, generic components, problem areas in which decision support systems are used and knowledge sharing standards. Characteristics of M edical Decision Support Systems To understand the characteristics of a medical decision support system, it is important to analyze the medical decision making process. A clear understanding of the medical decision making process is essential to appreciate the value and the characteristics of a medical decision support system. It is an extremely complex sequence of inter related and differentiated activities that occur over a period of time. The vastness of the knowledge area presents itself infinite paths to reach a decision. Thus, the importance of finding an optimal path is extremely important in the decision making process. Any assistance in this critical step can be of immense value to the medical decision makers. The second is the beliefs and opinions about the objective states, and the processes including input and outcomes states. The third is the values and consequences attached to each outcome of the event-choice-action combination. The decision support literature classifies problems into three major categories: struc- tured, semi-structured, and unstructured (Gorry & Morton, 1971). Structured problems are routine and repetitive: solutions exist, are standard, and pre-defined. Unstructured problems are complex and fuzzy; they lack clear and straight-forward solutions. Semi- structured problems combine the features of the two previous categories; their solution requires human judgment as well as the application of standard procedures (Simon, 1971). Thus the complexity involved in a decision making process can be grouped as a knowledge gathering process, knowledge storage, knowledge retrieval, and information processing. The literature categorizes the decision making process into four distinct phases: intelligence, design, choice, and review (Stohr & Konsynski, 1992). During the intelligence phase of the decision making process, the need for a decision making (or the trigger) event is recognized and the clinical problem or opportunity is properly identified and defined. This is done by eliciting two different types of knowledge domains: public and private. Private knowledge generally is heuristic and experience- based knowledge that usually comes from the clinical practitioners. Public knowledge can be gathered from standards, guidelines, text books and journals. The office of technology assessment (1995) suggests usage of the following questions in identifying the problems and opportunities for medical decision support. Copying or distributing in print or electronic forms without written permission of Idea Group Inc.

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With pears to be inducible by phenobarbital administration discount precose 25 mg on-line diabetes type 1 5 years old, respect to the drug inducer purchase precose 50 mg on line diabetic diet for quick weight loss, drugs with a shorter half- and UGT1A7 is induced by the chemopreventive agent life will reach equilibrium concentrations sooner (less oltipraz. Little is known about the substrate specificities of the other The flavin monooxygenases (FMOs) are a family of five UGT2B isoforms or the inducibility of this enzyme enzymes (FMO 1–5) that operate in a manner analo- family. Though they possess broad substrate specificity, N-Acetyltransferases in general they do not play a major role in the metabo- As their name implies, the N-acetyltransferase (NAT) lism of drugs but appear to be more involved in the me- enzymes catalyze to a drug molecule the conjugation of tabolism of environmental chemicals and toxins. The net result of this conjugation is an increase in CONJUGATIVE ENZYMES: water solubility and increased elimination of the com- PHASE II REACTIONS pound. The NATs identified to date and involved in hu- Phase II conjugative enzymes metabolize drugs by at- man drug metabolism include NAT-1 and NAT-2. Little taching (conjugating) a more polar molecule to the overlap in substrate specificities of the two isoforms original drug molecule to increase water solubility, appears to exist. Little is known about the substrate exists on the regulation of the NAT enzymes, such as specificity of SULT1C1. However, re- zymes appears to be controlled by levels of the avail- ports have suggested that disease states such as ac- able sulfate pool in the body or that of PAPS. Patients quired immunodeficiency syndrome (AIDS) may who consume a low-sulfate diet or have ingested multi- down-regulate NAT-2, particularly during active dis- ple SULT substrates may be susceptible to inadequate ease. The methyltransferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as Sulfotransferases and drugs, hormones, and neurotransmitters, but they are Methyltransferases also responsible for the methylation of such macromol- Sulfotransferases (SULTs) are important for the me- ecules as proteins, RNA, and DNA. A representative tabolism of a number of drugs, neurotransmitters, reaction of this type is shown in Figure 4. The co- MTs use S-adenosyl-L-methionine (SAM) as the methyl substrate for these reactions is 3 -phosphoadenosine donor, and this compound is now being used as a di- 5 -phosphosulfate (PAPS) (Fig. Like the afore- etary supplement for the treatment of various condi- mentioned enzymes, sulfate conjugation typically ren- tions. For example, catechol-O- However, this process can also result in the activation of methyltransferase (COMT) is responsible for the bio- certain compounds, such as the antihypertensive minox- transformation of catecholamine neurotransmitters idil and several of the steroid hormones. N-methylation is isoforms identified in humans, including SULTs 1A1 to a well established pathway for the metabolism of neu- 1A3, possess activity toward phenolic substrates such as rotransmitters, such as conversion of norepinephrine to dopamine, estradiol, and acetaminophen. SULT1B1 epinephrine and methylation of nicotinamide and hista- possesses activity toward such endogenous substrates as mine. SULT1E1 has substan- MT activity involves S-methylation by the enzyme tial activity toward steroid hormones, especially estra- thiopurine methyltransferase (TPMT). Likelihood of adverse topurine so that the dose may be adjusted downward if events, such as the dyskinesias associated with certain they are found to be deficient in this enzyme. To mini- TISSUE SPECIFICITY OF HUMAN DRUG mize adverse events and toxicity, care should be exer- METABOLISM ENZYMES cised when prescribing drugs that depend on CYP2D6 metabolism. Though most drug metabolism enzymes reside in the Recently, variant alleles (and thus polymorphisms) liver, other organs may also play an important role. For of the enzymes previously mentioned are found in the example, six alleles of CYP2C9 have been discovered, human liver, but other tissues and organs may have and several of them profoundly affect therapy. CYP3A4 and ant allele CYP2C9*3 occurs in fewer than 1% of the CYP3A5 have been found in the human gut and can population, but affected individuals generally require contribute to substantial metabolism of orally adminis- doses of the anticoagulant warfarin that are 10–25% of tered drugs, even before the compound reaches the those required by unaffected individuals. For example, CYP3A4 may play a substantial role polymorphism also has been identified in 2–3% of cau- in the low bioavailability of cyclosporine. In this case, individuals olizing enzymes have also been found in measurable who are CYP2C19 deficient are more likely to have quantities in the kidney, brain, placenta, skin, and lungs. PHARMACOGENETICS OF DRUG- METABOLIZING ENZYMES One of the most interesting and heavily researched ar- EXCRETION OF DRUGS eas of drug metabolism today is genetic polymorphism Despite the reduction in activity that occurs as a drug of drug-metabolizing enzymes (pharmacogenetics). As leaves its site of action, it may remain in the body for a early as the late 1950s it was recognized that individuals considerable period, especially if it is strongly bound to might differ in whether they could acetylate certain tissue components. In this case, activity and drug elimination are to be seen as related the individuals studied appeared to segregate into two but separate phenomena. Excretion, along with metabolism and tissue redis- It was later discovered that this polymorphism ex- tribution, is important in determining both the duration isted in the N-acetyltransferase-2 gene and thus the of drug action and the rate of drug elimination. More important, it has become clear Excretion is a process whereby drugs are transferred that slow acetylators (about 50% of the caucasian popu- from the internal to the external environment, and the lation) are more prone to adverse effects following ad- principal organs involved in this activity are the kid- ministration of certain drugs than fast acetylators.

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