Approaches include comparing (1) the structure arrhythmia 2014 ascoms order altace 10mg mastercard, model inputs and results of one model to another arrhythmia hyperkalemia buy altace 2.5 mg amex, (2) modeled estimates with measured or field data and (3) modeled estimates with biomonitoring data blood pressure 7843 order 2.5 mg altace with amex. Such an evaluation not only indicates the conditions under which a simulation will be acceptable and accurate for its intended purpose hypertension young age buy discount altace 10mg online, but also the conditions under which using the model is unacceptable heart attack troublemaker cheap altace 5 mg amex. Soundness of Assumptions heart attack low vs diamond purchase 1.25mg altace visa, Methods and Conclusions pulse pressure for dengue cheap altace 2.5 mg mastercard, Appropriateness Peer input provides an independent evaluation and review of models used in an exposure assessment heart attack pulse cheap 5 mg altace visa. The purpose of model peer input is to evaluate the assumptions and whether sound scientific principles underlie the methods and conclusions derived from models and to check the scientific appropriateness of a model for informing a specific regulatory or risk management decision (U. The latter objective is particularly important for applications of existing models for purposes other than those intended in their initial design. Researchers and Page 125 practitioners in academia, consulting, private industry and state and local governments-both nationally and internationally-frequently use models and sometimes collaborate in their development. A critical consideration in using models is transparency, including providing rigorous model documentation and promoting unfettered communication among an exposure assessor, modeler and risk manager/decision maker in the application of the model to a specific problem. Attainment of Quality Assurance Objectives For a chosen model, an exposure assessor determines whether the inputs the model requires are available and all parameters the model requires are obtainable or reasonable default values are accessible. After running the model, an exposure assessor needs to evaluate whether the model outputs meet the exposure assessment goal(s) and data quality objectives. If they do not, the model parameters might need adjustment or a different model selected and tested. Qualitative and Quantitative Model Calibration As a standard practice, an exposure assessor verifies model operation and results. Calibration is the process of adjusting selected model parameters within an expected range until the differences between model predictions and field observations are within selected criteria (U. Calibration accounts for spatial variation and temporal variation that the model formulation does not represent; functional dependencies of parameters that are unquantifiable, unknown or not included in the model algorithms; and extrapolation of laboratory measurements to field conditions. Model Uncertainty and Sensitivity Analyses An exposure assessor acknowledges and characterizes important sources of uncertainty in modeled estimates, either qualitatively, quantitatively or both. Uncertainty is the lack of precise knowledge, either qualitative or quantitative, and can refer to the limited knowledge about the factors affecting exposure and adequacy of model outputs for decision making. An exposure assessor characterizes the quality of the input data and the resulting limitations on the uses of the model results. Chapter 8 presents a broader discussion of issues on uncertainty in exposure assessment. Models are mathematical representations of processes that quantify how a system behaves in response to changes in its inputs. Exposure model development entails several choices regarding what to include and at what level of detail. Important sources of uncertainty are measurement error, statistical sampling error, nonrepresentativeness of data and structural uncertainties in scenarios and formulations of models. Omitting any elements of the scenario of interest from the modeling approach can bias the estimates. Uncertainty also might stem from extrapolating beyond conditions for which the model was constructed or calibrated. The extent of verification and validation, whether the model is extrapolated beyond the range of its evaluation and whether alternative theories exist upon which alternative modeling approaches could be developed all influence model uncertainty (Cullen and Frey 1999). Assessments of input and parameter uncertainty can use advanced statistical methods. Such assessments iterate model simulations using alternative sets of variability distributions for key inputs and parameters. Most Monte Carlo applications performed for predicting exposures capture the combined variability and uncertainty associated with each input and variable in the model runs. In models that are more refined, using two-dimensional Monte Carlo methods distinguishes variability from uncertainty. These correlations can be captured, however, by the use of bootstrap-based uncertainty analysis techniques used in Xue et al. Some of the fate and transport, human exposure and integrated fate/transport-exposure models can simulate stochastic processes, which enables assessment of the variability and uncertainty in modeled estimates and input parameters. Variability refers to the heterogeneity or diversity of potential exposures in a population. The models, which can simulate stochastic processes, tend to be higher tier exposure models and some of the integrated fate/transport-exposure models. For these models, such assessments usually involve performing univariate or multivariate Monte Carlo analyses, sensitivity analyses or exposure pathway contribution analyses. The most common model input parameters varied to address variability or uncertainty are exposure factors and chemical residue values in different environmental media. A key challenge for integrated fate/transport-exposure models is the quantification of coupled model uncertainties resulting from propagation of errors from the different model components, linked during an integrated analysis. In other words, for understanding and addressing data uncertainty, the sensitivity analysis is a process of determining which parameter(s) in an exposure assessment drive the results. An exposure assessor uses these analyses to decide when to stop collecting data or Page 127 performing more time-consuming probabilistic analyses. Sensitivity analyses can range from simple to more complex analyses, including modeling and regression analysis. Simpler analysis typically involves a one-at-a-time fixed or percentile scaling approach. Fixed approaches, for instance, might test the variation of results by varying each input up and down by a factor of 2. For each run and simulated individual, modelers determine the mean outputs for each lower and upper percentile simulation and compare them to the reference or base case results. These ratios or ranges provide assessors with the impact and significance of each influential variable on the exposure modeling predictions. The modeler then uses this information in stepwise regression models to examine the relationship between inputs and outputs of the model to determine the impact of the key variables in the presence of others that influence the results. The type of sensitivity analysis needed for each situation depends on the complexity of the exposure assessment question (U. The essence of the analysis, however, remains the same: evaluating how changes in the input parameters change the output. Several methodological tools and approaches are available for conducting sensitivity and uncertainty analysis (Cullen and Frey 1999; Mokhtari et al. This section has focused on sensitivity and uncertainty analyses within a selected model. Performing sensitivity analyses across different models is also appropriate to determine whether some models are less sensitive to certain critical parameters. Uncertainty across models is also Page 128 appropriate, for example, to quantify ranges of outputs that reflect the uncertainties of model assumptions for a given set of inputs (Cullen and Frey 1999; Young et al. The assessor determines whether a model to meet those needs is available or if a new model needs to be developed. Models range in complexity from deterministic to probabilistic to advanced probabilistic modeling. The scenarios incorporate environmental measurement data and exposure factor information. The outcome of the scenario evaluation is an exposure estimate that results from combining concentrations with exposure factors. Forward and reverse dosimetry are two approaches for using biomonitoring data to provide quantitative estimates of human exposure to chemicals. The hallmark of the high-throughput screening models is that they trade model complexity and a possible increase in model prediction uncertainty for applicability to thousands of chemicals. Model evaluation is the process that generates information during model application to determine whether the model and its analytical results are of sufficient quality to serve as the basis for a decision. Sensitivity analysis is "any systematic, common sense technique used to understand how risk estimates and, in particular, risk-based decisions, are dependent on variability and uncertainty in the factors contributing to risk. Overview Observational human exposure measurement studies enable exposure scientists and risk assessors to identify agents to which people are exposed; exposure concentrations; important sources, routes and pathways of exposure; and factors that have the greatest influence on exposure. Observational human exposure measurement studies also can be conducted within the context of an epidemiological investigation. Results from observational human exposure measurement studies support the regulatory work of Agency programs and contribute significantly to our understanding of human exposures and risks from environmental agents. In addition, results from these studies have identified major stressors and determined whether mitigation measures have been successful and whether exposures exceeded regulatory standards. Data from an observational human exposure measurement study also can be used to evaluate and refine exposure and dose models. The data collected in the study, however, need to be compatible with the data needs of the model of interest. An iterative relationship exists between the information derived from observational human exposure measurement studies and exposure and dose models (see Section 6. Exposure and dose models then help identify key data needs that observational human exposure measurement studies can provide. Investigated in utero and postnatal organophosphate pesticide exposure and its relationship to neurodevelopment, growth and symptoms of respiratory illness in children. Investigated the aggregate exposures of 257 preschool children and their primary adult caregivers to pollutants commonly detected in their everyday environments. Examined the range of environmental pollutants and chemicals (volatile organic chemicals, metals, pesticides) to which humans are exposed in daily life. Evaluated how air quality information collected at community monitors represents what people living in neighborhoods are exposed to every day. In the exposure assessment process, biological measurements often are combined with environmental, personal and activity pattern data (Bouvier et al. Use of biological measurements in exposure assessments is limited because the potential clinical significance of biomonitoring results. Although this chapter focuses on observational human exposure measurement studies, exposure assessments can use other types of research. Among other provisions, these regulations might require review by the Human Studies Review Board, an advisory board established under the Federal Advisory Committee Act, depending on the purpose and initiation date for the research. More information can be found at the Office of the Science Advisor Human Studies Review Board website. Study Design An adequately developed technical study design will address all parts of a study-from identifying data needs to reporting the results to the study participants. As such, a study design might include planning that considers Budget and logistics Data elements Sample size Criteria for selecting study location Eligibility criteria for study participants Data quality objectives and sampling and analytical protocols Chain of custody, storage and data management Community involvement Engaging stakeholders Human subjects guidelines, informed consent and recruitment Sample collection Sampling schemes Data analysis and database design. Many other published articles and reports can assist when developing the technical study design (Buckley et al. Budget and Logistical Planning Availability of resources is an important consideration in planning an observational human exposure measurement study. Available resources, participant burden, types of sampling methods and specificity of the measurements that need to be collected strongly influence the number of participants and the types of samples collected and analyzed. Sufficient resources need to be available to obtain sample sizes sufficient to meet the study objectives. At some point, the researchers might need to consider how to balance data needs against limited resources. Achieving such a balance could entail reducing the number of study participants, eliminating selected analytical procedures or modifying other study elements. When altering the study plan 13 14 Federal Insecticide, Fungicide, and Rodenticide Act, 7 U. Page 132 to meet resource constraints, the researchers weigh whether the modified study plan is likely to provide the quality of information necessary to meet the study objectives against other options for filling data or informational needs. Planning also needs to consider burdens to both the participants and field technicians. Field studies typically are complex and might require many field staff and extensive travel. Logistical planning is essential for conducting the study within a specified period and using available resources most efficiently. Identifying Critical Data Elements For each specific study objective, hypothesis or scientific question, the critical data elements are those pieces of information that need to be collected to achieve the objective, test the hypothesis or to answer the question. These measurements need to be stratified by site, season, housing stock, geographic location and primary source (U. In addition, models also might be used for identifying critical data elements and testing hypotheses. Determining Sample Size for Each Data Element the sample size needed to address the study objectives, hypotheses or scientific questions is determined statistically based on the desired outcome. The number of participants enrolled in a study and the frequency of sample collection from participants often are a compromise between the available budget and the statistical power the study can achieve (Dupont and Plummer Jr. Effect size is a measure of the differences between or within populations used to assess whether the differences are statistically significant. Data from a pilot study could help determine the predicted effect size (Devane et al. The variability within the defined population also needs consideration when determining sample size. Much information is available in the peer-reviewed literature on sample size estimations for studies (Baguley 2004; Dell et al. Developing Criteria and Identifying Potential Study Locations Study location is an integral part of the technical study design and needs to be based on the study objectives, hypotheses or scientific questions. Criteria can include the location of the population group of interest, geographic or built environment considerations, the size of the cohort and the time of year for the study. For example, a study objective to determine exposures to vehicle exhaust in an urban area requires selection of a study location in an urban environment. Developing Eligibility Criteria for Study Participants Eligibility criteria also are essential to the technical study design. Eligibility criteria determine the type of person selected for an observational human exposure measurement study based on the study objectives, hypotheses or scientific questions. For example, an observational human exposure measurement study seeking to understand the variety of fruits and vegetables consumed by the older adult population in the United States would have very different eligibility criteria from an observational human exposure measurement study evaluating exposure to vehicle exhaust associated with bicycle use as a means of transportation in urban areas. Some studies might be designed to sample a representative portion of some larger population. Other studies might select participants based on particular activities or other lifestyle characteristics. Information also is available in the peer-reviewed literature on design issues for these types of studies (Adgate et al. Developing Data Quality Objectives and Identifying Sampling and Analysis Methods After the exposure assessor establishes the data quality criteria (see Section 5. Observational human exposure measurement studies need to follow sampling and analytical protocols that are sufficiently accurate, precise and sensitive to meet the study objectives, test the hypotheses or answer the scientific questions. Selected analytical and sample collection methods will have demonstrated and acceptable performance parameters. If existing or adequate methods are not available, study implementation could depend on additional method development and testing. If method development is required, an assessor determines acceptable performance parameters and evaluation criteria before deeming an analytical or sample collection method ready for implementation. Sample collection methods are tested and evaluated in small-scale pilot studies either in the laboratory or in the field. Evaluating the sample collection methods in a pilot study prior to full study implementation provides an opportunity for an assessor to ensure that the sampling methods will be accurate, precise and sensitive and to reevaluate modifications, if necessary. Evaluation of analytical protocols uses reference standards or previously analyzed samples, if Page 134 available. A comparison of the known results from a reference standard or previously analyzed sample with the results of the analytical protocol can help determine the likelihood of success when following the protocol. In combination, these procedures accurately track the movement of samples before, during and after analyzing, storing and transferring the results. A chain-of-custody record, initiated in the field, captures the field collection information for the sample and all subsequent actions performed. Proper sample storage procedures ensure adequate and appropriate storage space for samples. Storage procedures need to ensure minimal analyte loss, contamination or degradation during shipment and minimize holding times prior to analysis. Adequate storage space also might be required for paper forms collected during a study. Ideally, sample and record storage is secure, with access limited to authorized personnel. Researchers establish data management procedures to process data effectively so that relevant data descriptions. Engaging the Community Community involvement is the process of engaging in dialogue and collaborating with members of the community where the study will take place. Researchers need to define the community for a particular study clearly and consider the extent of the community involvement for the study. Community involvement is founded on the belief that people need to know what the Agency is doing in their community and be able to have input into the decision making process (U. Community representatives bring perspective, value and competence to a research project. Community-based participatory research is an approach in which community members are active partners in all aspects of the study, from the formulation of research questions to the application of findings. Community residents can be involved in the research process as participants, parents of participants, research staff, community consultants, reviewers or members of community advisory boards (Hough et al. Making community involvement a priority helps ensure the research addresses the concerns, needs and priorities of the community and leads to actions and changes that benefit the community.
Primary asexual reproduction of the organisms takes place in the hepatic parenchyma (preerythrocytic schizogony) blood pressure medication how long to take effect 5 mg altace amex. The organisms then invade red blood cells and develop further inside them (intraerythrocytic development) arteriogram cpt code buy 2.5 mg altace mastercard. PrP and amyloid have been found in certain myopathies (such as inclusion body myositis blood pressure line chart purchase 5mg altace with mastercard, p arrhythmia recognition buy altace 5mg online. Early manifestations are not typically seen hypertensive retinopathy cheap altace 10mg fast delivery, but may include fatigability arrhythmia 4279 diagnosis buy cheap altace 2.5mg, vertigo blood pressure keeps rising cheap altace 1.25 mg visa, cognitive impairment heart attack ne demek cheap 5mg altace with amex, anxiety, insomnia, hallucinations, increasing apathy, and depression. The principal finding is a rapidly progressive dementia associated with myoclonus, increased startle response, motor disturbances (rigidity, muscle atrophy, fasciculations, cerebellar ataxia), and visual disturbances. Late manifestations include akinetic mutism, severe myoclonus, epileptic seizures, and autonomic dysfunction. Normal cellular prion protein (PrPc) is synthesized intracellularly, transported to the cell membrane, and returned to the cell interior by endocytosis. Part of the PrPc is then broken down by proteases, and another fraction is transported back to the cell surface. Another mutated form of PrP (PrPsc) causes the infectious spongiform encephalopathies. PrPsc induces the conversion of PrPc to PrPsc in the following manner: PrPsc enters the cell and binds with PrPc to yield a heterodimer. The resulting conformational change in the PrPc molecule (-helical structure) and its interaction with a still unidentified cellular protein (protein X) transform it into PrPsc (-sheet structure). Protein X is thought to supply the energy needed for protein folding, or at least to lower the activation energy for it. PrP and PrPsc cannot be broken down intracellularly and therefore accumulate within the cells. Hemiparesis, aphasia, apraxia, ataxia, cranial nerve palsies, or incontinence may occur depending on the type and location of the tumor. Papilledema, if present, is not necessarily due to a brain tumor, nor does its absence rule one out. Specific Manifestations Some tumors produce symptoms and signs that are specific for their histological type, location, or both. These tumors include craniopharyngioma, olfactory groove meningioma, pituitary tumors, cerebellopontine angle tumors, pontine glioma, chondrosarcoma, chordoma, glomus tumors, skull base tumors, and tumors of the foramen magnum. In general, these specific manifestations are typically found when the tumor is relatively small and are gradually overshadowed by nonspecific manifestations (described above) as it grows. Symptoms and Signs the clinical manifestations of a brain tumor may range from a virtually asymptomatic state to a constellation of symptoms and signs that is specific for a particular type and location of lesion. Patients may complain of easy fatigability or exhaustion, while their relatives or co-workers may notice lack of concentration, forgetfulness, loss of initiative, cognitive impairment, indifference, negligent task performance, indecisiveness, slovenliness, and general slowing of movement. More than half of patients with brain tumors suffer from headache, and many headache patients fear that they might have a brain tumor. If headache is the sole symptom, the neurological examination is normal, and the headache can be securely classified as belonging to one of the primary types (p. Neuroimaging is indicated in patients with longstanding headache who report a change in their symptoms. The clinical features of headache do not differentiate benign from malignant tumors. Focal or generalized seizures arising in adulthood should prompt evaluation for a possible brain tumor. There may be a relatively long history of headache, abnormal gait, visual impairment, diabetes insipidus, precocious puberty, or cranial nerve palsies before the tumor is discovered. Fibrillary astrocytoma is more common than the gemistocytic and protoplasmic types. It tends to arise at or near the cortical surface of the frontal and temporal lobes and may extend locally to involve the leptomeninges. Tumors of mixed histology (oligodendrocytoma plus astrocytoma) are called oligoastrocytomas. They may involve not only the dura mater but also the adjacent bone (manifesting usually as hyperostosis, more rarely as thinning) and may infiltrate or occlude the cerebral venous sinuses. They may arise in the ventricular system (usually in the fourth ventricle) or outside it; they may be cystic or calcified. Central Nervous System 257 Brain Tumors Tumors in Specific Locations Supratentorial Region Colloid cyst of 3rd ventricle. These cysts filled with gelatinous fluid are found in proximity to the interventricular foramen (of Monro). Small colloid cysts may remain asymptomatic, but large ones cause acute or chronic obstructive hydrocephalus (p. Sudden obstruction of the foramen causes acute intracranial hypertension, sometimes with loss of consciousness. Symptomatic colloid cysts can be surgically removed with stereotactic, neuroendoscopic, or open techniques. Adamantinomatous craniopharyngioma is suprasellar tumor of children and adolescents that has both cystic and calcified components. It produces visual field defects, hormonal deficits (growth retardation, thyroid and adrenocortical insufficiency, diabetes insipidus), and hydrocephalus. Papillary craniopharyngioma is a tumor of adults that usually involves the 3rd ventricle. In addition to possible hormone secretion, these tumors have intrasellar (hypothyroidism, adrenocortical hormone deficiency, amenorrhea reflecting anterior pituitary insufficiency, and, rarely, diabetes insipidus), suprasellar (chiasmatic lesions, p. Hemorrhage or infarction of a pituitary tumor can cause acute pituitary failure (cf. Prolactinomas can cause secondary amenorrhea, galactorrhea, and hirsutism in women, and headache, impotence, and galactorrhea (rarely) in men. Growth hormone-secreting tumors cause gigantism in adolescents and acromegaly in adults. Headache, impotence, polyneuropathy, diabetes mellitus, organ changes (goiter), and hypertension are additional features. Early manifestations include hearing impairment (rarely sudden hearing loss), tinnitus, and vertigo. This group of tumors includes pheochromocytoma (arising from the adrenal medulla), sympathetic paraganglioma (arising from neuroendocrine cells of the sympathetic system), and parasympathetic ganglioma or chemodetectoma (arising from parasympathetically innervated chemoreceptor cells). They usually involve the cerebral hemispheres, but are sometimes found in infratentorial locations (brain stem, cerebellum, spinal cord). They are occasionally multicentric or diffuse (gliomatosis cerebri is extremely rare). Infiltrative growth across the corpus callosum to the opposite side of the head is not uncommon ("butterfly glioma"). Headache, cranial nerve palsies, polyradiculoneuropathy, meningismus, and ataxia suggest (primary) leptomeningeal involvement. Ocular manifestations: Infiltration of the uvea and vitreous body (visual disturbances; slit-lamp examination). They produce local symptoms and also such general symptoms as psychosis, dementia, and anorexia. Dural-based metastases may compress or infiltrate the adjacent brain tissue, or exude fluid containing malignant cells into the subdural space. Pituitary metastases (mainly of breast cancer) cause endocrine dysfunction and cranial nerve deficits. Spinal Metastases the clinical manifestations of vertebral metastases, including vertebral or radicular pain, paraparesis/paraplegia, and gait ataxia, are mainly due to epidural mass effect. The bone marrow itself being insensitive to pain, pain arises only when the tumor compresses the periosteum, paravertebral soft tissue, nerve roots, or spinal cord. Leptomeningeal Metastases (Neoplastic Meningeosis, "Carcinomatous Meningitis") Seeding of the meninges may be diffuse or multifocal. Meningeal metastases may spread into the adjacent brain or spinal cord tissue, cranial nerves, or spinal nerves. Cerebral leptomeningeal involvement produces headache, gait ataxia, memory impairment, epileptic seizures, and cranial nerve deficits. Spinal involvement produces neck or back pain, radicular pain, paresthesia, paraparesis, and atony of the bowel and bladder. Aside from direct metastatic involvement, the nervous system can also be affected by local tumor infiltration. Only a small fraction of proliferating tumor cells are capable of metastasizing; thus, the biological behavior and drug response of metastasizing cells may differ from that of the primary tumor. Local invasion of surrounding tissue by the primary tumor makes it possible for tumor cells to break off and metastasize by way of the lymphatic vessels, veins, and arteries. Metastatic cells often settle in a vascular bed just downstream from the site of the primary tumor, thus (depending on its location) in the lungs, liver, or vertebral bodies. The nervous system may become involved thereafter in a second phase of metastasis (cascade hypothesis), or else directly, in which case the metastasizing cells must have passed through the intervening capillary bed without settling in it. Metastases may also bypass the lungs through a patent foramen ovale (paradoxical embolism). Intracranial Metastases Of all intracranial metastases, 85 % are supratentorial, 15 % infratentorial. The primary process in men is usually a tumor of the lung, gastrointestinal tract, or urogenital system, in women a tumor of the breast, lung, or gastrointestinal tract. Prostate, uterine, and gastrointestinal tumors metastasize preferentially to the cerebellum. The clinical manifestations of intracranial metastases are usually due to their local mass effect and surrounding cerebral edema. Brain metastases of melanoma, choriocarcinoma, and testicular cancer tend to produce hemorrhages. Central Nervous System Leptomeningeal metastasis Brain Tumors takes effect several hours after they are administered; thus, acute intracranial hypertension must be treated with an intravenously given osmotic agent (20 % mannitol). Pain often requires treatment (headache, painful neoplastic meningeosis, painful local tumor invasion; cf. Restlessness: treatment of cerebral edema, psychotropic drugs (levomepromazine, melperone, chlorprothixene). Residual tumor after surgery can often be treated radiosurgically (if indicated by the histological diagnosis). As these tumors grow slowly, they are often less aggressively resected than malignant tumors, so as not to produce a neurological deficit (partial resection, later resection of regrown tumor if necessary). There are still inadequate Classification and Treatment As the treatment and prognosis of brain tumors depend on their histological type and degree of malignancy, the first step of management is tissue diagnosis (see Table 31, p. The subsequent clinical course may differ from that predicted by the histological grade because of "sampling error". Other factors influencing prognosis include age, the completeness of surgical resection, the preoperative and postoperative neurological findings, tumor progression, and the site of the tumor. The overall incidence of pituitary tumors (including pituitary metastases), craniopharyngioma, and intracranial lymphoma and sarcoma is low. Treatment the initial treatment is often neurosurgical, with the objective of removing the tumor as completely as possible without causing a severe or permanent neurological deficit. The resection can often be no more than subtotal because of the proximity of the tumor to eloquent brain areas or the lack of a distinct boundary between the tumor and the surrounding tissue. Brain Tumors data on the potential efficacy of chemotherapy against malignant forms of meningioma, plexus papilloma, pineocytoma, schwannoma, hemangiopericytoma, and pituitary adenoma. Cerebral metastases: Solitary, surgically accessible metastases are resected as long as there is no acute progression of the underlying malignant disease, or for tissue diagnosis if the primary tumor is of unknown type. Solitary metastases of diameter less than 3 cm can also be treated with local radiotherapy, in one of two forms: interstitial radiotherapy with surgically implanted radioactive material (brachytherapy), or stereotactic radiosurgery. The latter is a closed technique, requiring no incision, employing multiple radioactive cobalt sources (as in the Gamma Knife and X-Knife) or a linear accelerator. Solitary or multiple brain metastases in the setting of progressive primary disease are generally treated with whole-brain irradiation. Chemotherapy is indicated for tumors of known responsiveness to chemotherapy in patients whose general condition is satisfactory. Spinal metastases: Resection and radiotherapy for localized tumors; radiotherapy alone for diffuse metastatic disease. Leptomeningeal metastases: Chemotherapy (systemic, intrathecal, or intraventricular); irradiation of neuraxis. Aftercare Follow-up examinations are scheduled at shorter or longer intervals depending on the degree of malignity of the neoplasm and on the outcome of initial management (usually involving some combination of surgery, radiotherapy, and chemotherapy), with adjustment for individual factors and for any complications that may be encountered in the further course of the disease. Central Nervous System Trauma less the neurological examination is completely normal. A cervical spine series from C1 to C7 is needed to rule out associated cervical injury. In multiorgan trauma: Blood should be typed and cross-matched and several units should be kept ready for transfusion as needed. Physical examination and ancillary studies for any fractures, abdominal bleeding, pulmonary injury. Primary Injury the primary injury affects different parts of the skull and brain depending on the precipitating event. The traumatic lesion may be focal (hematoma, contusion, infarct, localized edema) or diffuse (hypoxic injury, subarachnoid hemorrhage, generalized edema). Vomiting or an epileptic seizure in the acute aftermath of the event should be noted. Also important are the past medical history, current medications (particularly anticoagulants), and any history of alcoholism or drug abuse. General: Open wounds, fractures, bruises, bleeding or clear discharge from the nose or ear. Neurological: Respiration, circulation, pupils, motor function, other focal signs. Laboratory: Blood count, coagulation, electrolytes, blood glucose, urea, creatinine, serum osmolality, blood alcohol, drug levels in urine, pregnancy testing if indicated. Prognosis Head trauma causes physical impairment and behavioral abnormalities whose severity is correlated with that of the initial injury. Reliable data on the long-term prognosis are not available Age-dependent mortality ranges from 30 % to 80 %. Late behavioral changes (impairment of memory and concentration, abnormal affect, personality changes) Severe 268 1 For severity of head trauma, cf. Bleeding into the tissue of the brain (intraparenchymal hematoma) under the site of impact, on the opposite side (contre-coup), or in the ventricular system (intraventricular hemorrhage) (pp. The scene should be secured to prevent further injury to the injured person, bystanders, or rescuers. Documentation: Time and nature of accident, general and neurological findings, drugs given. Systematic assessment and treatment by organ system, with documentation of all measures taken. Cardiovascular system: Central venous access, administration of fluids and pressors as needed. Posttraumatic Headache Posttraumatic headache may be acute (8 weeks after head trauma) or chronic (8 weeks). The duration and intensity of the headache are not correlated with the severity of the precipitating head trauma. It often worsens with physical exertion, mental stress, and tension and improves with rest and stress avoidance. If the headache gradually increases in severity, or if a new neurological deficit arises, further studies should be performed to exclude a late posttraumatic complication, such as chronic subdural hematoma (p. Pathogenesis of Traumatic Brain Injury Direct blunt or penetrating injuries of the head and acceleration/deceleration injuries can damage the scalp, skull, meninges, cerebral vasculature, ventricular system, and brain parenchyma.
There is evidence that choline deficiency may also compromise brain development heart attack 19 years old generic 10 mg altace, memory function blood pressure chart calculator generic altace 2.5 mg, and cardiovascular health arrhythmia in 7 year old order altace 5 mg without prescription. Phosphatidylserine is normally concentrated on the cytosolic face of the plasma membrane; cellular damage may result in inappropriate phosphatidylserine exposure on the cell surface blood pressure medication nightmares generic altace 5mg with amex, giving rise to antibody formation hypertension quality improvement cheap altace 1.25 mg with mastercard. In lupus pulse pressure sensor buy cheap altace 5 mg on-line, antibodies are sometimes also directed against cardiolipin blood pressure medication replacement order 10mg altace mastercard, another acidic phospholipid blood pressure chart during the day order altace 10 mg with mastercard, which is normally localized to the inner mitochondria1 membrane. Type A Niemann-Pick disease is more severe, with early death resulting from excess deposition of sphingomyelin in the central nervous system. Patients with type B Niemann-Pick have more residual enzyme activity than those with type A Niemann-Pick disease, generally do not exhibit neurologic involvement, and usually survive into adulthood. Types A and B Niemann-Pick, should not be confused with type C1 or C2 Niemann-Pick Disease, in which the underlying molecular defect involves mutation in the gene N P C l, which is required for the transport of cholesterol and other lipids out of the lysosome. Eicosanoids are local-acting autocrine and paracrine hormones that stimulate cells adjacent to their site of synthesis. They are not stored in cells but instead are released as soon as they are synthesized. I Prostaglandins Are Eicosanoids with Ring Structures the term prostaglandin reflects the original isolation of these molecules from seminal fluid, into which they are secreted by the seminal glands (rather than the prostate). Prostaglandins act to modulate many physiological functions, including blood pressure, uterine contraction, and the production of pain and fever. Thromboxanes have a six-membered oxygen-containing ring instead of the cyclopentane ring of classic prostaglandins. The term thromboxane refers to the platelet-aggregating activity, which has thrombus-forming potential. The term leukotriene derives from their cell of origin (leukocytes) and the fact that their structures contain three carbonxarbon double bonds in conjugation. The lipoxins are another class of linear eicosanoids that are derived from arachidonic acid. Although eicosanoids can also be synthesized from dihomo-y -1inolenic acid (20:306), the immediate precursor of arachidonic acid, there is little synthesis of 1-series prostaglandins and 3-series leukotrienes in humans. The cyclooxygenases and related enzymes in the eicosanoid synthesis pathways are localized to the cytoplasmic surfaces of the nuclear envelope and endoplasmic reticulum. For this reason, synthetic prostaglandins are helpful in promoting the healing of gastric ulcers. During parturition, prostaglandins soften tissues in the cervix and stimulate uterine contractions to expel the fetus. One is a cytosolic enzyme that is activated in response to signal-transduction cascades. Lipoxygenases are dioxygenases that attach both atoms of molecular oxygen to a particular carbon atom of arachidonic acid. Lipoxins are synthesized by multicellular processes involving the sequential actions of two lipoxygenases. In addition to the lipoxygenase family of enzymes, linear eicosanoids are also synthesized by cytochrome P450 epoxygenases. The products differ from those of the lipoxygenase pathway in that they contain three rather than four double bonds. Within the cell, prostaglandins are often inactivated by the action of a prostaglandin 15-hydroxydehydrogenase. The 15-keto prostaglandins are then oxidized further by oxidation from the omega (w) end as well as by P-oxidation from the carboxy end, and the resulting more polar molecules are excreted by the kidney. Steroidal anti-inflammatory drugs such as prednisone and betamethasone block prostaglandin release in part by inducing the synthesis of members of the phospholipase A2-inhibitory family of proteins called lipocoi-tins or anne. Low-dose aspirin regimens are often used to decrease the risk of thrombosis and coronary heart disease in older persons. This therapy is effective because circulating platelets are unable to synthesize more prostaglandin synthase to replace that which has been inactivated. Conversely, if the ductus remains open after birth in an otherwise normal infant, closure can be hastened by the cyclooxygenase inhibitor indomethacin. The carbohydrate domains of glycoconjugates often contain modified amino or acidic sugar derivatives that contribute to their strongly hydrophilic nature and structural specificity. Glycosphingolipids in the plasma membrane tend to concentrate along with sphingomyelin, cholesterol, and phosphatidylinositolanchored proteins in lipid domains called rafts, which are involved in receptormediated plasma-membrane signal transduction and cell-cell adhesion. Cerebrosides are ceramide monohexosides, the most common of which is galactocerehroside, also called galactolipid. Most galactocerebroside is found in the brain, where it is a major component of the myelin sheath. Medical Biochemistry: Human Metabolism in Health and Disease Copyright 02009 John Wiley & Sons, Inc. Globosides are sphingolipids that contain two or more sugar residues, usually a combination of galactose, glucose, and N-acetylgalactosamine. The oligosaccharides of globosides are uncharged and contain no free amino groups. Gangliosides are sialic acid-containing glycosphingolipids which are highly concentrated in ganglion cells of the central nervous system, particularly in the nerve endings. Lesser amounts of gangliosides are present in the plasma membrane of cells of most extraneural tissues. Sialic acid, which is found in glycoproteins and mucins as well as gangliosides, is the N-acetyl derivative of the nine-carbon amino sugar neuraminic acid (Neu). The carbohydrate domains of the various gangliosides serve as receptors for many different classes of ligands, including cytokines, microbial toxins. Gangliosides play roles in diverse cellular processes, such as cell-cell recognition, cell homing and adhesion, and growth regulation and differentiation. Glycoproteins also play important roles in cell growth and development, and in the communication that occurs between cells. A particular glycoprotein can have one or as many as 30 oligosaccharide chains, with the carbohydrate accounting for as little as 1% to as much as 70% of the mass of the glycoprotein. The oligosaccharide chains of a particular glycoprotein usually influence one or more of its biological properties, including intracellular transport, solubility, viscosity, susceptibility to inactivation (by heat, extremes of pH, and proteolysis), and the tendency to aggregate. The carbohydrate chains of glycoproteins are grouped into two classes, depending on how they are linked to the protein. Figure 16-5 illustrates two types of N-asparaginelinked oligosaccharide chains commonly found in mammalian glycoproteins: the high-mannose type and the complex type. They are high molecular weight (200 to 10,000 kDa) glycoproteins that contain dozens to several hundred oligosaccharides 0-linked to serine or threonine residues. Secreted mucins (such as salivary mucin) aggregate into oligomeric gels which form a protective layer over the digestive, respiratory, and reproductive tracts and provide lubrication as well as a barrier against pathogens and toxins. Cancer cells often synthesize abnormal mucins, whose structures can perturb the normal function of a cell, including its immunologic and adhesive properties and its potential to invade and metastasize. For example, in heparan sulfate the disaccharide repeat unit glucuronic acid-N-acetylglucosamine. Both glycolipids and glycoproteins are integral components of the asymmetrical plasma membrane, with the carbohydrate moieties facing outward. Other glycoproteins and proteoglycans are adsorbed onto the extracellular surface of the membrane. Heparan sulfate proteoglycan also serves as the ligand that binds lipoprotein lipase to the luminal surface of the capillary endothelium. For example, chondrocytes (cartilage cells) secrete a variety of proteoglycans, of which a major component is a particular chondroitin sulfate named aggl-ecan. Following its secretion, aggrecan molecules aggregate spontaneously to form a supramolecular structure known as hyaluronan which endows cartilage with its load-bearing properties. Hyaluronic acid is a component of the extracellular matrix of skin and connective tissue where its viscous and elastic nature allows it to function as a lubricant and shock absorber in the synovial fluid of joints. These include the lysosomal-associated membrane glycoproteins as well as lysosomal acid hydrolases. Following its incorporation into glycosaminoglycans, glucuronate may be isomerized to iduronate. Synthesis of amino sugars is initiated by glutamine: fructose 6-phosphate amidotransferase, which catalyzes the synthesis of glucosamine 6-phosphate. Sialic acid (N-acetylneuraminic acid) is synthesized by condensation of the carbon backbone of phosphoenolpyruvate with N-acetylmannosamine 6-phosphate. Galactocerebroside is the major cerebroside found in membranes; by contrast, glucocerebroside is primarily an intermediate in the synthesis of more complex sphingolipids. Sulfatides Galactocerebroside 3-sulfate, a sulfuric acid ester of galac6322 tocerebroside, is the major sulfolipid of brain, accounting for about 15% of the lipids of white matter. Globosides and gangliosides are synthesized in the Golgi apparatus by enzymes that transfer sugars sequentially onto a cerebroside. One such example is the synthesis of the glycosphingolipids containing A, B, and 0 blood group antigens. The core structure of the 0 (or H) oligosaccharide is formed by sequential addition of N-acetylglucosamine, galactose, and fucose to galactocerebroside. Persons with a gene for the type A transferase are able to transfer N-acetylgalactosamine to the core structure to synthesize the A antigen from the 0 core structure, while those with the type B transferase transfer galactose to synthesize the B antigen. Some people have genes for both the A and B transferases and therefore synthesize both A and B antigens. The "0 gene" is actually a mutation which results in premature termination of translation so that no active transferase A or B is formed; persons homozygous for the gene for the 0 blood group therefore synthesize only the core 0 antigen. Additional sugars, including sialic acid, are then added stepwise to the growing glycan chain. Humans contain at least five different sialyltransferases, each with a different specificity with regard to the acceptor. By contrast, the synthesis of N-linked oligosaccharide chains involves a more complex sequence of reactions which is initiated in the endoplasmic reticulum and continues in the Golgi complex. The first phase of N-linked oligosaccharide synthesis takes place on an isoprene lipid, dolichol pyrophosphate. The core oligosaccharide, containing two N-acetylglucosamine, nine mannose, and three glucose residues, is assembled on dolichol pyrophosphate by the successive transfer of glycosyl residues from their respective nucleoside diphosphate sugar donors. The asparagine that accepts the core oligosaccharide always occurs in the sequence AsnX-Thr/Ser, where X is any amino acid except proline. The next phase of N-linked oligosaccharide-chain processing involves aglucosidase-catalyzed stepwise removal of the three glucose residues and one mannose from the core oligosaccharide. The properly folded glycoprotein then moves by vesicular transport to the Golgi complex, where it undergoes a variety of additional posttranslational modifications, including the removal of additional mannose residues and the sequential addition of single residues each of N-acetylglucosamine, galactose, fucose, and sialic acid. A xylose residue is attached to the hydroxyl group of a serine, followed by addition of two galactose residues to form what is called the liizk trisaccharide. Two glycosyltransferases enzymes then alternate adding sugar residues to generate the repeating disaccharide units. The glycosphingolipids are catabolized in lysosomes by sequential, irreversible removal of the carbohydrate residues-one at a time-followed by the hydrolysis of ceramide to sphingosine and a free fatty acid. This pathway requires enzymes that cleave specific bonds, including a - and P-galactosidases, a p-glucosidase, a neuraminidase, a hexosaminidase, a sphingomyelinase, a sulfatase, and a ceramide-specific amidase (ceramidase). The enzymes that hydrolyze glycosphingolipids often require sphingolipid activator proteins, which promote interaction between these enzymes and their water-insoluble lipid substrates. Sphingolipid catabolism normally functions smoothly, all of the glycosphingolipids and sphingomyelin being degraded to their constituents. However, when the activity of one enzyme in the pathway is markedly reduced due to a genetic error, the substrate for that defective enzyme accumulates within the lysosomes of the tissue in which catabolism of that sphingolipid normally occurs. Gaucher disease is caused by a genetic deficiency of lysosomal glucocerebrosidase. The accumulation of glucocerebroside, primarily in macrophages of the reticuloendothelial system, results in hepatomegaly, splenomegaly, anemia, and bone pain. Gaucher disease is now treated effectively by enzyme replacement therapy using recombinant glucocerebrosidase, which is produced in human cells so as to obtain appropriate glycosylation of the enzyme with oligosaccharide chains terminating in mannose residues. Mannose receptors on the surface of macrophages bind the mannose-terminated enzymes and through a process of endocytosis deliver them into lysosomes, where they degrade the accumulated lipid, glucocerebroside. Deficiency of lysosomal a-galactosidase A results in Fabry disease and accumulation of globotriaosylceramide (Cer -+ P-Glu -+ pGlu -+ a-Gal) in tissues, mainly the walls of blood vessels. Unlike the other sphingolipidoses, which are autosomal recessive diseases, Fabry disease is X-linked. Tay-Sachs disease is a gangliosidosis caused by the absence of P-hexosaminidase A and results in neural accumulation of the ganglioside G M. The disease is characterized by mental retardation, ~ a cherry-red spot on the macula which reflects ganglioside accumulation in retinal ganglia, blindness, and for the most severe, infantile form, death before age 3. Because of the primary involvement of ganglion cells of the central nervous system, effective enzyme replacement therapy has not proven feasible. Since there is some digestion of the oligosaccharide chains by lysosomal endoglycosidases, urinary excretion of shorter oligosaccharides is often diagnostic. The mucopolysaccharidoses are classified according to the substrate that accumulates (Table 16-1). They can result from deficiencies in any one of a number of enzymes, including a-mannosidase, P-mannosidase, a-fucosidase, and a-sialidase. Oligosaccharidoses are usually named for the deficient enzyme; for example, a deficiency in a-mannosidase is called a-mannosidosis. Patients with I-cell disease secrete large amounts of many different lysosomal enzymes into body fluids but have deficient enzyme activity within the lysosomes. Two enzymes are required to attach a phosphate group to a mannose moiety of oligosaccharide chains of lysosomal enzymes. The second enzyme in the pathway, N-acetylglucosamine- 1-phosphodiester-a-N-acetylglucosaminidase, removes the terminal a-N-acetylglucosamine residue, leaving the phosphate group attached to the underlying mannose residue. Lysosomal enzymes bearing the mannose 6-phosphate marker bind to the mannose 6-phosphate receptor in the trans Golgi, are packaged into clathrin-coated vesicles, and are transported to late endosomes, where the low pH causes the lysosomal enzymes to dissociate from the receptors. Patients with I-cell disease have a deficiency of the phosphotransferase, which impairs targeting of enzymes to the lysozyme. This leads to activation of adenylyl cyclase, which stimulates secretion of chloride ion and produces diarrhea. Cholesterol has a hydroxyl group at C3, a C5-C6 carbonsarbon double bond, and two methyl groups, attached at positions C 10 and C13 of the sterol ring. In addition, cholesterol has a branched eight-carbon hydrocarbon chain attached to the D ring at C17. In contrast to plasma, where most of the circulating cholesterol exists esterified to a fatty acid, most cholesterol in cellular membranes is present in the free (unesterified) form. The fluidity of membranes is regulated in part by changing their cholesterol content. The solubilization of free cholesterol in bile is achieved Medical Biochemistry: Human Mefaholism in Health and Disrase Copyright 02009 John Wiley & Sons, Inc. Bile acids, which are metabolites of cholesterol, also aid in solubilizing cholesterol in bile. Increased biliary secretion of cholesterol or decreased secretion of phospholipids or bile acids into bile may lead to deposition of cholesterolrich gallstones. Indeed, the name cholesterol was derived some 200 years ago from the Greek words chole (bile) stereos (solid). Cholesterol and phospholipids in bile protect gallbladder membranes from potentially irritating or harmful effects of bile salts. Posttranslational prenylation of these proteins increases their tendency to associate with membranes, and prenylation is usually required for their full activity. Covalent attachment of cholesterol to protein is required for the membrane tethering that is necessary for the activation of the Hedgehog family of proteins, which are essential to embryonic patterning; the cholesterol moiety is attached via an ester bond to the C-terminal glycine during autocatalytic cleavage and maturation of the initially soluble protein. The brain is the most cholesterol-rich organ of the body; however, since plasma lipoproteins that transport cholesterol in the circulation do not cross the blood-brain barrier, all cholesterol in the brain must be synthesized within the central nervous system. Cholesterol synthesis in the brain occurs at a high rate during the period of active myelination and declines substantially thereafter. Within the cell, cholesterol synthesis takes place in the cytosol and endoplasmic reticulum. Although there is wide individual variation, on average about half of the cholesterol that enters the small intestine is absorbed into the body. Animal products contain both cholesterol and cholesteryl esters; the latter are hydrolyzed in the small intestine by pancreatic cholesteryl esterase: cholesteryl ester + H20 + cholesterol + fatty acid Cholesterol is absorbed by the cells of the intestinal mucosa and incorporated into the surface of chylomicrons. Cholesterol in excess of that required for the chylomicron surface is esterified to cholesteryl esters and incorporated into the triacylglycerol-rich chylomicron core. Both free and esterified cholesterol are delivered to the liver as components of chylomicron remnants. Cholesterol that is not secreted from the intestinal mucosa in chylomicrons is returned to the intestinal lumen as a component of sloughed mucosal cells and excreted. The fecal sterols are a mixture of cholesterol and cholesterol metabolites, such as cholestanol and coprostanol, generated by intestinal bacteria. As with fatty acid synthesis, nearly all of the acetyl-CoA used for cholesterogenesis is generated in the mitochondrion; the acetyl moieties are transported to the cytosol in the form of citrate. Synthesis starts with the as condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA in a reaction catalyzed by acetoacetyl-CoA thiolase (acetyl-CoA:acetyl-CoA acetyltransferase). The two reactions are catalyzed by mevalonate kinase and phosphomevalonate kinase, respectively. A second prenyltransferase then adds another 3-isopentenyl pyrophosphate unit to form the 15-carbon intermediate, farnesyl pyrophosphate, with the release of a second molecule of pyrophosphate. The last condensation step in cholesterol synthesis involves head-to-head fusion of two molecules of farnesyl pyrophosphate to form squalene. Cholesterol synthesis from squalene proceeds through the intermediate lanosterol, which contains the fused tetracyclic ring system and an eight-carbon side chain. The endoplasmic reticulum enzyme that catalyzes this cyclization reaction is bifunctional and has both squalene epoxidase and lanosterol cyclase activity. Transformation of the 30-carbon lanosterol to the 27-carbon cholesterol molecule requires at least eight different enzymes which catalyze removal of the methyl group at C14, removal of two methyl groups at C4, migration of the double bond from C8 to C5, and reduction of the double bond between C24 and C25 in the side chain. In this reaction, the source of the fatty acid is the phospholipid phosphatidylcholine: phosphatidylcholine + cholesterol + cholesteryl ester + 2-lysophosphatidylcholine 17. The other is a cytosolic enzyme that acts on cholesteryl esters in lipid droplets present in steroidogenic cells and which releases free cholesterol for synthesis of steroid hormones.
