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Our screens identified multiple genes that impact cellular toxicity of each of the studied chemicals erectile dysfunction medications comparison 2.5mg cialis mastercard. We also revealed a novel cellular link between arsenic toxicity and selenocysteine metabolism impotence support group cialis 2.5 mg low price. We found that disruption of any of the multiple genes involved in selenocysteine biosynthesis increased arsenical resistance and we discuss two possible hypotheses to explain these findings erectile dysfunction doctor in phoenix purchase cialis 10 mg. Further erectile dysfunction treatment in qatar buy discount cialis 2.5 mg on line, we identified key cellular components involved in arsenical uptake and export. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Changes in specific networks are interpreted in the context of changes in the entire set of networks to produce a provisional mode of action hypothesis. Some of these unique modules were highly correlated with liver toxicity phenotypes. The most similar compound was ethionamide, a second line therapy for mycobacterial infection, with hepatotoxicity liability. Notably, module 85 was also induced by both compounds and contains Atf4 and Atf4-target genes. W 1038 Application of Computational Modeling to Risk Assessment of Endocrine Disruptors Q. Endocrine disruption is a major health concern for many persistent environmental chemicals, with adverse outcomes in metabolism, development, reproduction, and cancer. The endocrine systems are robust nonlinear dynamical systems by nature, which can resist perturbations to maintain hormone homeostasis through feedback regulations between multiple organs. Moreover, as toxicity testing is increasingly shifting to cellor organoid-based in vitro assays, the demand for in vivo extrapolation that can predict systems-level hormonal outcomes and apical endpoint consequences in human populations is also rising. This session is organized to present the state-of-the-science in mathematical modeling of endocrine systems in the context of chemical risk assessment through presentations of a series of computational works on thyroid, reproductive, and adrenal systems. The first presenter lays out the general design principles for the homeostatic regulation of the endocrine systems involving feedback interactions between the hypothalamus, pituitary, and endocrine organs. The second talk presents a more detailed model of the thyroid system to understand the effect of iodine nutritional status on thyroid hormone levels during pregnancy and lactation. The fourth talk presents the modeling work on the hypothalamic-pituitary-adrenal axis and how its interaction with the circadian rhythm can affect between-sex and within-sex variability. The final presentation includes a comprehensive modeling framework that links exposure, toxokinetic, and ovarian cycle models. The work illustrates how modeling the exposure-to-outcome continuum through linking these models and incorporating ToxCast assay data can predict the mixture effects of aromatase inhibitors on menstrual cycle length and ovulation. This design minimizes the chance of thyroid hormone alteration by protecting the sensitive signaling part within the blood-brain barrier. Iodine insufficiency remains a public health concern in many regions of the world. Even for developed countries questions are raised about iodine sufficiency during pregnancy and lactation because of the critical importance of iodine during this sensitive life stage. Iodine intake studies were undertaken with pregnant and lactating rats ranging from insufficient to excess. Our model, while generally successful, was unable to explain findings where increased dietary intake of iodine failed to ameliorate human iodine deficiency as measured by serum thyroid hormones and urinary excretion of iodide. W 1041 Biologically Based Computational Models for Endocrine Disruption Incorporating Adverse Outcome Pathways and High-Throughput Toxicity In Vitro Testing H. W 1039 Design Principles of Endocrine Systems and Their Applications to Understanding Endocrine Disruptions: A Case Study with the Hypothalamic-Pituitary-Thyroid Axis Q. The endocrine systems are one of the most robust physiological structures in animals and humans. Although this screening can be useful in examining the potential of chemicals to cause adverse outcomes, it is not enough for estimating health hazard risks to humans. This inadequacy is due to differences in the behaviors and effects of chemicals in vitro vs. In fact, no effects can be expected from typical exposures to individual chemicals when considered alone. The possibility to predict largescale mixture effects for endocrine disrupters with a predictive toxicology approach that is suitable for high-throughput ranking and risk assessment will be introduced. Lastly, the consistency of the size of the predicted effects with an increased risk of infertility in women from everyday exposures to our chemical environment will be demonstrated. Use of this approach to further understand how glycan profiles and glycoproteins respond to therapeutics or xenobiotic exposures also will be discussed. Zhang Epidemiological studies established that exposure impairs the cardiovascular, respiratory and central nervous systems leading to a range of disease states. Persistent disruption of homeostatic glucocorticoid circadian rhythmicity due to chronic exposure is correlated with the incidence of a range of pathological conditions. W 1043 Computational Predictive Analysis of Ovarian Cycle Disruption by Mixtures of Endocrine Disruptors N. Zhang the regulation of menstrual cycle in women is controlled by coordinated hormonal stimulation and inhibition along the hypothalamus-pituitary-ovarian axis. Exposures to endocrine disruptors that interfere directly or indirectly with any of the hormones responsible for this process can induce pathological outcomes such as infertility. In this context, the role of aromatase enzyme is critical as it irreversibly converts testosterone to E2, and androstenedione to estrone, maintaining the dynamic balance between androgens and estrogens. In this talk a computational approach designed to predict the effects of exposure to large-scale. The approach was designed over four computational steps: step one, the ExpoCast dataset of exposure estimates were used to simulate random exposures to potential mixtures of aromatase inhibitors. In step two, a pharmacokinetic model was developed to estimate the intake and disposition of the chemicals and predict their internal concentrations as a function of time (up to 2 yr). Successively in step three, the extent of inhibition of aromatase by the chemical mixture was estimated by using the concentration-inhibition relationships provided in the ToxCast database (86 chemicals). The computed results served as an input for step four, an implementation of the ovarian cycle model. Schnackenberg Few studies have examined in-depth, the metabolic dysregulation and crosstalk which occurs between a pathogenic bacterium or virus and a mammalian host cell/tissue. To a considerable extent, this missing in-depth knowledge is due to the fact that historically, the investigation of metabolic alterations in the host and pathogen during infections posed major experimental challenges. The data generated will be used in computational metabolic network reconstructions to provide a framework for the discovery of novel therapeutic targets or synergies and the prediction of key phenotypes of pathogenesis. This methodology allows for the correlation of analyte tissue distributions with histology images, thereby integrating chemical structures with tissue morphology. Furthermore, this imaging modality offers the potential to further our mechanistic understanding of drug disposition, disease progression and pharmacology (including toxicology) by providing snap shots of temporal and causal changes. W 1049 Mapping Changes in Tissue N-Linked Glycosylation Patterns in Carcinogenesis, Knockout, and Treatment/Drug Resistance Models R. Schnackenberg Glycoproteins account for approximately 80% of the proteins located at the cell surface and in the extracellular environment, and serve as binding ligands for cell adhesion, extracellular matrix molecules, signaling receptors, immune cells, lectins and pathogens. Alterations and changes in cell surface glycosylation during carcinogenesis and other diseases are well documented, but specifics in regards to which glycans and at what sites on glycoproteins are responsible for these changes is still poorly understood. Further, how glycan profiles and glycoproteins respond to therapeutics or xenobiotic exposures is even less characterized. This in turn has generated a database of over 140 N-glycans derived from these tissues. Additional glycans representing different sialic acids detected in rodents, and ethylated derivatives of sialic acids are also included in the database. Using this methodology and data resources, the approach is proving informative for the comparative analysis of tissues in many model systems, including breast cancer drug resistance/sensitivity, gene knock outs of metabolic enzymes, tumor progression and patient derived tumor xenograft models. The goals are to link the disease or phenotypic changes identified for different N-glycan structural classes to metabolic, proteomic and genomic changes associated with each model. Zebrafish (Danio rerio), are quickly becoming a popular model in toxicity studies due to their homogeneity with the human genome, small size, low cost, applicability to environmental studies and large breeding potential. The method was further assessed in a zebrafish model dosed with 10mg/mL gentamicin. In addition to these factors, exposure to environmental metal and nonmetal substances. Experimental studies using animal models of metal toxicity show significant increases in fasting blood glucose levels or disruption of major mediators of metabolism.
Liquirizia (Licorice). Cialis.
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The guidance also provides steps to determine if the material is acceptable for re-use at a variety of sites diabetes obesity and erectile dysfunction cheap 10mg cialis amex. To account for the wide range of chemical concentrations in the dredged material impotence questionnaire 5mg cialis for sale, the screening criteria evaluates various land uses erectile dysfunction natural remedies diabetes order cialis 2.5 mg with visa. Additionally vacuum pump for erectile dysfunction canada generic cialis 5 mg overnight delivery, the guidance allows for the use of the risk assessment process to further evaluate material that exceeds screening criteria but still may be available for re-use by taking into account the location and anticipated land use where dredged material will be placed. By evaluating potential current contamination at the location, planned use or redevelopment of the site, material that previously had to be disposed in a containment facility has the potential to for re-use at sites. We have expanded upon their work with an additional set of 20 compounds (12 in humans and 8 in rats), including both pharmaceuticals and environmental chemicals. For each compound, we then calibrated the appropriate parameter-specific correction factors, which resulted in better prediction of observed pharmacokinetic data: Clmet in humans and rats, for 8 out of 20 compounds needed to be increased by 1. Read-across is a well-established technique utilizing data-rich substances to fill gaps for data-poor compounds. It is particularly useful for the assessment of toxicological endpoints for cosmetic ingredients. In order for read-across predictions to be acceptable, key uncertainties must be established and, where possible, areas of high uncertainty have to be reduced. We demonstrate how in silico tools can be used for reducing uncertainty and increasing confidence in the read-across predictions. The available data were found to be of high quality; as such, maltol is an ideal data-rich "source compound" for read-across. Property-based similarity was addressed by calculating sets of relevant physicochemical and electronic descriptors for source and target compounds. In silico screening was performed to reduce uncertainties related to similarity and mechanistic plausibility. A combination of evidence from structural similarity, physicochemical properties and in silico profiling was able to identify high-quality analogues of maltol. Health implications of residues that may remain following clandestine cannabis (marijuana) grow operations in residential structures are a rising concern of unknown significance. Currently, structures presenting with an extremely pungent ("skunky") cannabis odor are generally torn-down or gutted based on the offensiveness of the odor alone. Questions arise with more moderate situations as there are currently no guidelines available to assist landowners and/or stakeholders to determine whether chemicals are present at levels that could potentially impact human health or to conclude whether cleanup efforts were successful. Because surface wipe sampling can quantitate chemical concentrations on surfaces and Martyny et al. Considered exposure paradigms included incidental ingestion and dermal contact with dust residues present on indoor surfaces for different age groups. Results indicated the hand-to-mouth behavior of young children (ages 1 to <6 yrs) was the most important factor for establishing a screening value. Paired samples taken before and after cleaning surfaces from naпve (vacant following police raid, eviction, etc. Use of the derived screening value will allow stakeholders to evaluate areas that may require remediation and can be used to assess the effectiveness of subsequent cleanup efforts. Ingestion of water containing levels of inorganic arsenic in the 100s to 1000s of ug/L (ppb) has been found to increase the risk of a variety of cancers (Lung, bladder, skin, and possibly prostate). In analyses conducted for areas with median arsenic level less than 60 ug/L, the risk of prostate cancer risk was found to fit a linear-quadratic model with a significantly negative linear coefficient and a significantly positive quadratic coefficient. In analyses limited to areas with median arsenic level less than 30 ug/L, the risk of prostate cancer risk was found to fit a linear model with a significantly negative linear coefficient. The addition of a quadratic term did not significantly improve the fit of the model. Rather the best fitting model for areas with median arsenic level less than 60 ug/L was a linear-quadratic model with a significantly negative linear coefficient. Increased risks have been observed for multiple health outcomes in populations exposed to inorganic arsenic in water and diet. Comparing and generalizing exposure/dose-response is complicated because varying dose metrics (water arsenic concentration, dietary arsenic intake, urinary arsenic) have been used to analyze exposure-response. In addition, relatively simple, monotonic functional model forms have often been used, making it difficult to discern curve shape, particularly at low exposures. This presentation describes a meta-regression approach undertaken to investigate the shape of arsenic dose-response for bladder cancer, a well-studied health outcome associated with arsenic exposure. Leave-one-out and group-wise analyses were used to identify studies with the most impact on the pooled dose-response estimates. Wound dressings are designed to be in direct contact with the wound, and required a biological evaluation and biocompatibility assessment. Keratinbased wound dressings have been used to help heal a variety of wounds and ulcers. Unlike some other type of wound dressings, keratin-based dressing may be defined as a surface device with permanent contact with breached or compromised skin because the keratin proteins will likely become incorporated in the wound bed and the entire device is unlikely to be removable. Thus, it is necessary to assess if any materials or residuals present in or on the device pose genotoxicity or carcinogenicity risk. A case study is presented for a toxicological risk assessment of chemicals released from a keratin wound dressing. A number of elements and organic compounds were identified in the extractable and leachable (E/L) analysis, where the device was mixed with Purified Water at 50 єC for a minimum of 24 hours, forming a dissolved solution. A carcinogen in the extract, namely benzene, was evaluated to determine the safety thresholds for genotoxicity, margins of safety (MoS) for non-cancer toxicity, and estimated cumulative cancer risks. This evaluation demonstrated that the leachable benzene from the keratin wound dressing is not expected to pose any significant health risks to patients. The oral human cancer potency was derived from the inhalation human cancer potency based on the ratio of the uptake factors for the inhalation versus the oral routes. Human beings are constantly exposed to more than one toxicant; therefore, it is essential to elucidate the mechanism of combined effect from toxicants. Skin sensitization is induced when a susceptible individual is exposed topically to hapten. This chemical sensitizer (hepten) provokes a cutaneous immune response that will subsequently result in the development of contact sensitization. We have analyzed the latest public data set of approximately 3000 chemical substances tested for skin sensitization to further understand the physico-chemical characteristics of chemical substances that are the key determinant(s) for inducing skin sensitization. The measured values of octanol/water partition coefficient (Kow) for sensitizing chemical substances have been found as low as 10-3 and as high as 107, thus encompassing a range of ten orders of magnitude. The mere presence of a reactive functional chemical group(s) within a chemical substance did not represent that the given substance would be a skin sensitizer. However, all sensitizing substances contained at least one reactive functional chemical group(s): aryl halide, quinone, epoxide, (unsaturated) aldehyde/ketone, ester, amide, lactone, lactam, etc. The presence of multiple reactive functional chemical groups or structural alerts did not automatically suggest that the respective substances are highly potent sensitizers. Nevertheless, our analysis of the latest public data set of chemical substances tested for skin sensitization suggests that: (1) the key determinant for skin sensitization is the chemical reactivity of a given substance; a property that is inherently protein-reactive or that can be metabolized in the skin to protein reactive species; and (2) as long as a chemically reactive substance can gain access to the viable epidermis, it can induce sensitization or exhibit high sensitization potency regardless of its ability to penetrate effectively through the skin. The risk characterization ratio was derived using both external and internal dose metrics. Based on the above and accounting for the dynamics of exposure and biokinetics, the daily intake was estimated with median values equal to 0. Had daily intake been estimated solely based on the urinary concentration mass balance, the estimated intake would be lower, due to the assumed simplifications in exposure and elimination time dynamics. In this context, deriving the optimal sampling scheme (number of timing of samples within the day) is crucial for risk characterization in the case of rapidly metabolized compounds. This nationally-representative survey launched in 2007 by the government of Canada has measured over 250 chemicals in approximately 30,000 Canadians during the last decade. These results suggest that exposure of the Canadian population to these environmental chemicals might be a concern. This screening exercise is useful to help prioritize chemicals for follow-up activities such as risk management actions and show the importance of a continued biomonitoring program to assess population exposures. We distinguished two mode of actions, i) "sensory irritation", characterized by a decrease in breathing rates, and ii) "tissue irritation" characterized by primarily histopathological findings. We based the classification "irritating to respiratory tract" on several data types from in vivo studies with inhalation exposure. The final dataset includes about 2500 irritating and 800 non-irritating compounds.
The laboratory director may reapportion to a technical supervisor erectile dysfunction pill identifier buy 10mg cialis, in writing erectile dysfunction doctor new orleans generic cialis 10mg overnight delivery, the responsibilities in: §§493 xatral impotence buy cialis 2.5mg on line. The only responsibilities that may be delegated to the general supervisor are listed at §§493 erectile dysfunction otc cialis 20mg without prescription. However, an individual may serve as technical consultant, clinical consultant or technical supervisor for any number of laboratories. Surveyors do not normally check for documented competency evaluation on these individuals. However, if you discover problems in the laboratory and you find that a factor in these problems is poor performance of incompetent staff, cite D6030 or D6103 (laboratory director). The term "laboratory training or experience" means that the individual qualifying has the training in and the experience with the specialties and subspecialties in which the individual is performing technical supervision. For technical supervisor, the requirement for training or experience can be met through any combination of training and/or experience in high complexity testing. This can be acquired subsequent to , concurrent with, or prior to obtaining academic requirements. The specified training or experience may be acquired simultaneously in more than one specialty/subspecialty. A year of laboratory training or experience is equivalent to 2080 hours and could extend over more than one 12 calendar-month period. An individual who wishes to qualify as a technical supervisor must supply evidence of this eligibility status. For purposes of the regulations, the individual must meet the education, training or experience required by the board to be eligible to take the examination and must have confirmation of eligibility status. The tests in histopathology include gross examination (macro) and microscopic slide evaluation and interpretation with diagnostic reporting. Note: the technical supervisor requirements for "laboratory training or experience, or both' in each specialty or subspecialty may be acquired concurrently in more than one of the specialties or subspecialties of service. The technical supervisor is not required to be on the premises full-time or at all times tests are being performed in his/her specialty(ies). However, the technical supervisor must be available to provide consultation and is required to spend an amount of time in the laboratory sufficient to supervise the technical performance of the staff in his/her specialty(ies). There should be documentation, such as a log book or notes from training which indicate the technical supervisor performs his/her assigned duties. The laboratory may establish its own format, content, and schedule or provide training on an as-needed basis. The clinical consultant must- (a) Be qualified as a laboratory director under §493. In the absence of the director and technical supervisor, the general supervisor must be responsible for the proper performance of all laboratory procedures and reporting of test results. Teaching experience directly related to a medical technology program, clinical laboratory sciences program, or a clinical laboratory section of a residency program is considered acceptable experience. A year of laboratory training and experience is equivalent to 2,080 hours and could extend over more than one 12 calendarmonth period. Test systems, assays, and examinations not yet classified are considered high complexity. The technical supervisor is ultimately responsible for the diagnosis related to the gross examination and must sign the examination report. All physical examinations/descriptions of tissue including color, weight, measurement and other characteristics of the tissue; or other mechanical procedures including dissection, inking, marking, and specific orientation for diagnostic interpretation performed in the absence of the technical supervisor by individuals qualified under §493. The name does not necessarily need to be included in the final report because the final report is under the responsibility of the technical supervisor. The grossing information should be recorded and maintained to show who performed the test, somewhere in the test record. The general supervisor in cytology must possess a current license issued by the State in which the laboratory is located, if such licensing is required, and must- (a) Be qualified as a technical supervisor under §493. The criteria used to determine the adequacy of the testing personnel involves evaluating testing personnel responsibilities, ensuring that these responsibilities are specified by the director in writing and are appropriate to ensure compliance with the reporting and recordkeeping requirements, quality control monitoring, quality assessment activities, and proficiency testing participation. Cite this deficiency only when problems are found in areas that can be directly related to insufficient numbers of testing personnel. Refer to "A Guide to the Evaluation of Educational Experience in the Armed Services," American Council on Education, Washington, D. Such training must ensure that the individual has- (b)(5)(i)(B)(1) the skills required for proper specimen collection, including patient preparation, if applicable, labeling, handling, preservation or fixation, processing or preparation, transportation and storage of specimens; (b)(5)(i)(B)(2) the skills required for implementing all standard laboratory procedures; (b)(5)(i)(B)(3) the skills required for performing each test method and for proper instrument use; (b)(5)(i)(B)(4) the skills required for performing preventive maintenance, troubleshooting, and calibration procedures related to each test performed; (b)(5)(i)(B)(5) A working knowledge of reagent stability and storage; (b)(5)(i)(B)(6) the skills required to implement the quality control policies and procedures of the laboratory; (b)(5)(i)(B)(7) An awareness of the factors that influence test results; and (b)(5)(i)(B)(8) the skills required to assess and verify the validity of patient test results through the evaluation of quality control values before reporting patient test results; and 397 (b)(5)(i)(B)(8)(ii) As of September 1, 1997, be qualified under §493. This training should be such that the individual can demonstrate that he/she has the skills required for proper performance of preanalytic, analytic, and postanalytic phases of testing. For example, if the individual performs a manual differential, he/she should be able to demonstrate the skills for: · Proper specimen handling prior to testing. Documentation may consist of, but is not limited to , letters from training programs or employers, attestation statements by the laboratory director, a log sheet initialed by the attendees indicating attendance at a training session/in-service, certificates from organizations providing the training session, workshop, conference, or specialty course. Therefore, only moderate complexity personnel requirements are applicable to them. In the case of gross examinations, the technical supervisor may delegate to individuals qualified under §493. The technical supervisor is not required to provide direct on-site supervision but is responsible for the accuracy of all test results reported. All physical examinations/descriptions of tissue including color, weight, measurement and other characteristics of the tissue; or other mechanical procedures performed in the absence of the technical supervisor by individuals qualified under §493. All microscopic tissue examinations must be performed by individuals qualified under §493. At least 24 semester hours in chemistry and biology courses of which- (b)(4)(i)(A)(1) At least 6 semester hours were in inorganic chemistry and at least 3 semester hours were in other chemistry courses; and (b)(4)(i)(A)(2) At least 12 semester hours in biology courses pertinent to the medical sciences; or (b)(4)(i)(B) For those whose training was completed after September 14, 1963. If the laboratory continues to refuse a survey, refer to Subpart R Enforcement Procedures beginning at §493. For complaint or revisit surveys, you may phone the laboratory to confirm the hours of testing prior to a survey without revealing your identity or the scheduled date. During the survey, the laboratory must be able to retrieve copies of all records and necessary information upon request. Determine what constitutes a reasonable timeframe based on the information requested. A laboratory must have all records and data accessible and retrievable within a reasonable time frame during the course of the inspection. For complaint or 407 revisit surveys, you may phone the laboratory to confirm the hours of testing prior to a survey without revealing your identity or the scheduled date. When authorized to perform a survey of waived tests, in addition to the requirements in 408 this subpart, refer to the requirements at §493. Make every effort to minimize the impact of the survey on the laboratory operations and patient care activities. D8203 (c) the laboratory must comply with the basic inspection requirements of §493. When authorized to perform a survey of waived tests, in addition to the requirements in this subpart, refer to the requirements at §493. The inspection sample for review may include testing in the subcategory of provider-performed microscopy procedures. Do you have to use other resources, such as on-line resources, to teach your lessons? Do your students believe they can get current information from sources such as the internet rather than their textbook? It contains 25 chapters covering cell biology, genetics, ecology, evolution and human biology (chapters 1-18 and 35-41). Together, the two books provide a complete educational tool for the high school student. These lessons, written by renowned experts in high school biological science education, are designed to address both state and national standards. It is the first time a comprehensive on-line searchable resource for the high school student has been developed. When utilized properly, this tool should completely revolutionize the methods of teaching. As a teacher, you know how time-consuming it can be to have to search for on-line resources. Many times, textbooks are developed by individuals who have never taught at the high school level; this is not the case for these books.
Hypertension occurs because cortisol has weak mineralocorticoid activity and because cortisol increases the responsiveness of arterioles to catecholamines (by up-regulating 1 receptors) erectile dysfunction pills at cvs generic 5 mg cialis otc. In Cushing syndrome erectile dysfunction treatment penile implants proven 20 mg cialis, the primary defect is in the adrenal cortex erectile dysfunction drugs that cause cialis 20 mg without prescription, which is overproducing cortisol impotence nerve damage buy cialis 10 mg online. As already described, the dexamethasone suppression test, in which a synthetic glucocorticoid is administered, can distinguish between the two disorders. Treatment of Cushing syndrome includes administration of drugs such as ketoconazole or metyrapone, which block steroid hormone biosynthesis. If drug treatment is ineffective, then bilateral adrenalectomy coupled with steroid hormone replacement may be required. Conn Syndrome Conn syndrome, or primary hyperaldosteronism, is caused by an aldosterone-secreting tumor. The symptoms of Conn syndrome are explainable by the known physiologic actions of aldosterone: Na+ reabsorption, K+ secretion, and H+ secretion. Treatment of Conn syndrome consists of administration of an aldosterone antagonist such as spironolactone, followed by surgical removal of the aldosterone-secreting tumor. Several congenital abnormalities are associated with enzyme defects in the steroid hormone biosynthetic 440 · Physiology pathways. The most common enzymatic defect is deficiency of 21-hydroxylase, which belongs to a group of disorders called adrenogenital syndrome. In other words, the adrenal cortex does not synthesize mineralocorticoids or glucocorticoids, resulting in predictable symptoms (as previously discussed). If the defect is present in utero in a female fetus, the excess androgens cause masculinization of the external genitalia, with a penis-like clitoris and scrotum-like labia. If untreated in childhood, the androgen excess will cause an acceleration of linear growth, the early appearance of pubic and axillary hair, and suppression of gonadal function. The endocrine pancreas also secretes somatostatin and pancreatic polypeptide, whose functions are less well established. The endocrine cells of the pancreas are arranged in clusters called the islets of Langerhans, which compose 1% to 2% of the pancreatic mass. There are approximately 1 million islets of Langerhans, each containing about 2500 cells. The islets of Langerhans contain four cell types, and each cell secretes a different hormone or peptide. The central core of the islet of Langerhans contains mostly cells, with cells distributed around the outer rim. As a result, neither glucocorticoids nor adrenal androgens will be produced by the adrenal cortex. The resulting high levels of mineralocorticoids then cause hypertension, hypokalemia, and metabolic alkalosis. Interestingly, the levels of aldosterone itself are actually decreased in 17-hydroxylase deficiency. Why would this be so, if steroid intermediates are shunted toward the production of mineralocorticoids? These gap junctions permit rapid cell-to-cell communication via either ionic current flow or transfer of molecules (up to 1000 molecular weight). The blood supply of the endocrine pancreas is arranged so that venous blood from one cell type bathes the other cell types. Small arteries enter the core of the islet, distributing blood through a network of fenestrated capillaries and then converging into venules that carry the blood to the rim of the islet. The cells even have a "neuronal" appearance and send dendrite-like processes onto the cells, suggesting intraislet neural communication. Insulin Insulin, which is synthesized and secreted by the cells, boasts an impressive array of "firsts. Structure and Synthesis of Insulin During this packaging process, proteases cleave the connecting peptide, yielding insulin. Insulin and the cleaved connecting peptide are packaged together in secretory granules, and when the cell is stimulated, they are released in equimolar quantities into the blood. The secretion of connecting peptide (C peptide) is the basis of a test for cell function in persons with type I diabetes mellitus who are receiving injections of exogenous insulin. The A chains and B chains are released, now inactive, and are excreted in the urine. Increases in blood glucose concentration rapidly stimulate the secretion of insulin. Because of the preeminence of glucose as a stimulant, it is used to describe the mechanism of insulin secretion by the cell, as illustrated in Figure 9. The circled numbers in the figure correlate with the steps described as follows: 1. Once inside the cell, glucose is phosphorylated to glucose6-phosphate by glucokinase (Step 2), and glucose6-phosphate is subsequently oxidized (Step 3). Two disulfide bridges link the A chain to the B chain, and a third disulfide bridge is located within the A chain. The synthesis of insulin is directed by a gene on chromosome 11, a member of a superfamily of genes that encode related growth factors. The signal peptide is cleaved early in the biosynthetic process (while the peptide chains are still being assembled), yielding proinsulin. Proinsulin is then shuttled to the endoplasmic reticulum, where, with the connecting peptide still attached, disulfide bridges form to yield a "folded" form of insulin. Briefly, when the K+ channels close, K+ conductance decreases and the membrane potential moves away from the K+ equilibrium potential and is depolarized. Ca2+ channels, also in the cell membrane, are regulated by changes in voltage; they are opened by depolarization and closed by hyperpolarization. Ca2+ flows into the cell down its electrochemical gradient and the intracellular Ca2+ concentration increases (Step 7). Increases in intracellular Ca2+ concentration cause exocytosis of the insulin-containing secretory granules (Step 8). Insulin is secreted into pancreatic venous blood and then delivered to the systemic circulation. C peptide is secreted in equimolar amounts with insulin and is excreted unchanged in the urine. Therefore the excretion rate of C peptide can be used to assess and monitor endogenous cell function. Recall from Chapter 8 that oral glucose is a more powerful stimulant for insulin secretion than intravenous glucose. The insulin receptor is a tetramer composed of two subunits and two subunits. The subunits lie in the extracellular domain, and the subunits span the cell membrane. A disulfide bond connects the two subunits, and each subunit is connected to a subunit by a disulfide bond. Insulin binds to the subunits of the tetrameric insulin receptor, producing a conformational change in the receptor. Activated tyrosine kinase phosphorylates several other proteins or enzymes that are involved in the physiologic actions of insulin including protein kinases, phosphatases, phospholipases, and G proteins. Phosphorylation either activates or inhibits these proteins to produce the various metabolic actions of insulin. The insulin receptor is either degraded by intracellular proteases, stored, or recycled to the cell membrane to be used again. Insulin down-regulates its own receptor by decreasing the rate of synthesis and increasing the rate of degradation of the receptor. In addition to the previously described actions, insulin also binds to elements in the nucleus, the Golgi apparatus, and the endoplasmic reticulum. For example, the stimulatory effects of amino acids and fatty acids on insulin secretion utilize metabolic pathways parallel to those utilized by glucose. Glucagon activates a Gq protein coupled to phospholipase C, which leads to a rise in intracellular Ca2+. When the availability of nutrients exceeds the demands of the body, insulin ensures that excess nutrients are stored as glycogen in the liver, as fat in adipose tissue, and as protein in muscle. These stored nutrients are then available during subsequent periods of fasting to maintain glucose delivery to the brain, muscle, and other organs. The effects of insulin on nutrient flow and the resulting changes in blood levels are summarized in Table 9. The two subunits are connected by disulfide bonds; each subunit is connected to a subunit by a disulfide bond.
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