Gregory A. Nuttall, MD
Hormones are central to homeostasis since they facilitate chemical control over meta bolic and biochemical processes throughout the entire body breast cancer 49ers shirt buy capecitabine once a day. The endocrine system menstruation ovulation cheap capecitabine 500mg without prescription, which exerts control over chemical processes via hormones pregnancy z pack antibiotic safe capecitabine 500mg, is crucial to homeostasis over an intermediate time scale pregnancy length buy generic capecitabine 500 mg online. The endocrine system is distinct from the nervous system, which employs neurotransmitters to control electrical and electrochemical processes and to influence homeostasis over a shorter time scale. The endocrine system is also distinct from the immune system, which employs immunomodulators to control cellular processes and to influence homeostasis over a longer-term time scale. These organs are diffusely distributed throughout the body and affect the metabolic control of a wide variety of biochemical processes. Accordingly, hormones and hormone receptors are important messenger targets for drug design. The thyroid gland, located in the neck, secretes thyroxine as its messenger hormone; by means of this messenger molecule, the thyroid gland stimulates oxygen consumption at a cellular level, helps to regulate lipid and carbohydrate metabolism, maintains metabolic levels, and influences growth and maturation. The parathyroid glands, located on either side of the thyroid, secrete parathyroid hormone, which is involved in the control of calcium metabolism and bone physiology. The pancreas is located in the upper abdomen near the duodenum; unique clusters of cells within the pancreas, called islets of Langerhans, secrete the polypep tide hormones, glucagon and insulin, which regulate metabolism of proteins, lipids, and carbohydrates. The adrenal glands, located above each kidney, secrete a variety of steroid hormones. The kidneys are themselves endocrine organs, producing renin, a hormonal messenger involved in the regulation of sodium and fluid volumes within the body. The gonads secrete gender-specific steroidal sex hormones and are, of course, involved in the development and functioning of the reproductive system. Even the heart has an endocrine function, producing natriuretic peptides as hormones. Superimposed upon this classification of endocrine organs and classical hormones are the neuropeptides, which may have neurotransmitter and/or neurohormonal effects. The existence of these peptide neurohormones makes the brain a partial endocrine organ as well as a neural organ. The various endocrine organs involved in hormonal metabolism are shown in figure 5. Since hormones are precise chemical messengers influencing specific metabolic function throughout the body, their pharmacological manipulation by the administration of either agonists or antagonists permits therapeutic modulation of a wide range of biochemical events. When broadly categorized on a molecular basis, hor mones may be either steroid-based or peptide-based. Both categories have been and continue to be widely exploited for purposes of drug design. Other pharmacologically interesting steroids, like the heart-active cardeno lides, are compounds of plant origin. Minor changes in the stereochemistry and substitution pattern of the steran skeleton result in vastly different yet specific physiological and pharmacological effects, which in turn influence developmental, metabolic, and behavioral phenomena. The organic chemistry and biochemistry of steroids is the subject of many excellent books and an enormous amount of research and patent literature. This chapter compares and contrasts the structure and mode of action of various steroids, their role in regulating hormonal secretion, and the timing of this regulatory action. One of the most unique and powerful features of steroid hormones is the nature of the steroid receptor. Unlike most other hormones or drugs, which target protein recep tors usually embedded in membranes, steroids target the genes themselves, buried deep within the nucleus of the cell. Within the target organs in which the steroids bind, the steroid molecules exert their influence directly on protein synthesis, at the level of transcription of the genetic message. We can therefore deal with this receptor model in a general way, mentioning specific details as appropriate in the sub sections of this chapter. The currently accepted mechanism is unique and consists of several steps at different subcellular structures: 1. Activation of transcription and influencing protein synthesis the steroid hormones are transported to their target cells via the bloodstream in a protein-bound form, but diffuse into the cell as free steroids. These receptors are large proteins; the estrogen receptor, for example, has a molecular weight of approximately 75,000. The general model of the steroid receptor protein consists of several functional domains. The E domain (ligand binding region) is composed of the C-terminal 250 amino acids; this section has the steroid binding site and additional sites for binding to chaperone proteins (discussed in the next paragraph). This complex con comitantly binds to an additional eight or more other peptides (also via the E domain); these peptides are termed chaperone peptides and consist of macromolecules such as heat shock proteins. The chaperone peptides help to twist and turn the steroid receptor protein into an improved three-dimensional shape for final and optimal binding of the steroid molecule. The activated receptor is then phosphorylated, dimerized, and transported into the nucleus with the aid of the D domain. These early responses can even be triggered by hormones that have a lower than optimal affinity for the receptor (such as estriol in uterus, which binds much more weakly than estradiol). About 40% of the receptors released in this dissociation are recycled and used again; the rest are destroyed and resynthesized. Steroid hormones can even regulate the level of synthesis of their own receptors, and sometimes the synthesis of other steroid receptors as well. All four rings are in the chair conformation in naturally occurring steroids; additionally, rings B, C, and D are always trans with respect to each other, whereas rings A and B can be trans (as in cholestane, 5. It is simple to con ceptualize this ring anellation (fusion) if one observes the relation of substituents (including hydrogen) on the carbon atoms common to the rings in question. For rings A and B, the relative positions of the 19-methyl group (attached to C-10) and the hydrogen on C-5 determine the structure, and their trans or cis configuration is easily visualized. The two methyl groups on C-10 and C-13 are always axial relative to rings B and D, with the C-10 substituent (which is not necessarily methyl) being the conformational reference point. A somewhat obsolete but still valid nomenclature determines substituent conforma tions relative to the plane of a cyclohexane-type ring; thus, the 19-methyl group in the steroid ring system is designated and is above the plane of the molecule, while H-5 in cholestane (5. Since a substituent designated (or) will remain (or) but can be either axial or equatorial, confusion can arise. The stability, reactivity, and spectroscopy of a sub stituent will, however, change, depending on its axial or equatorial position. Equatorial substituents are normally more reactive and less stable than their epimers and show slightly different absorption spectra. The physiological and pharmacological properties of the different molecules are also different, as might be expected. Therefore, steroid substituents maintain their conformation at room temperature, whereas cyclohexane substituents usually do not. Steroids are classified according to their substituents in addition to their occurrence. The primary source of all the compounds involved in steroid synthesis is acetate, in the form of acetyl-coenzyme A. Cholesterol, besides being ingested in food, is synthesized in large amounts, and an adult human contains about 250 g of cholesterol.
By providing ophthalmic educators with the tools to become better teachers menopause 2 order capecitabine on line amex, we will have better-trained ophthalmologists and professionals throughout the world pregnancy on mirena purchase capecitabine amex, with the ultimate result being better patient care menstrual 2 discount capecitabine 500 mg online. The Center enables resources to be sorted by intended audience and guides ophthalmology teachers in the construction of web-based courses breast cancer 6 months to live purchase capecitabine once a day, development and use of assessment tools, and applying evidence-based strategies for enhancing adult learning. The updated Residency Curriculum offers an international consensus on what residents in ophthalmology should be taught. Sixteen global committees, divided by subspecialty and guided by individual subspecialty chairs, updated the existing guidelines and references, reinforcing essential cognitive and technical ophthalmic skills. Refractive Surgery, previously a subset of Cornea, External Diseases, and Refractive Surgery, is now a stand-alone section. Like the 2006 curriculum, which outlined a broad-based curriculum, the learnersexperience and expertise is stratified at Basic, Standard, and Advanced levels of ophthalmic training; but a new fourth level, Very Advanced, corresponding to a subspecialist or fellow level of training, has been added. Within each training level Must Know items are identified by two asterisks (**). These levels of standardization act as a foundation for developing clear and defined milestones and provide benchmarks to gauge progress and performance. Adaptability is important because causes of blindness and reduced vision differ widely, and curricular components essential in one geographical locale may be less important in other regions. Similarly, economic and social developments vary globally, and treatments and techniques considered indispensable for one region might be unattainable or unimportant for others. Standards may need to be modified according to local priorities, goals, needs, culture, governmental policies, social systems, financial constraints, varying use of allied care personnel, and differing tangible resources. The International Fellowships were established to help young ophthalmologists from developing nations improve their practical skills and broaden their perspectives of ophthalmology. The Helmerich one-year fellowships offer advanced subspecialty training to ophthalmologists to help transmit new knowledge to the home country. The Conferences cover modern educational theory, methods, and tools with interactive workshops and discussion groups. To see a complete list of 2006 task force members, please go to: icocurriculum. It is not designed to be all-inclusive but rather a guideline for the training of ophthalmic specialists. Educators are encouraged to modify and apply the content as deemed appropriate to meet local, regional, and national priorities. We hope you will enjoy reading, and more importantly, using, the curriculum in your teaching and assessing of ophthalmic knowledge and skills. Online comments and recommendations for future updates are actively encouraged and solicited through: icocurriculum. Stratification the updated Residency Curriculum builds upon the Basic, Standard, and Advanced levels of training by incorporating a new fourth level, Very Advanced, which corresponds to a subspecialist or fellowship level of training. Must Know the updated Residency Curriculum prioritizes and identifies cognitive and technical skills the learner Must Know at each level. Subspecialty Sections the Residency Curriculum consists of the following subspecialty sections: I. Appendix Chair, Section Chairs, and Committee Members Section Reviewers References D. Specialist training is designed to provide a structured learning program facilitating the acquisition of core competencies as well as specialized cognitive and technical skills at a level appropriate for an ophthalmic specialist who has been fully prepared to begin their career as an independent consultant in ophthalmology. Stratification of Levels Basic Level Goals = Year 1 Standard Level Goals = Year 2 Advanced Level Goals = Year 3 Very Advanced Level Goals = Subspecialist the curriculum is intended to be adaptable and flexible, depending upon the needs of the region. While stratifying the curricula by level (ie, Basic, Standard, Advanced, and Very Advanced) is somewhat artificial, it defines clear milestones for learners to progress up the ladder of expertise acquisition. Differentiating various proficiency levels allows local customization of expectation based upon local resources, ability, and geography. For example, in some locations clinical needs are urgent, and marked abbreviations of the training program will be necessary to provide the region with sufficient numbers of practitioners. Years 1, 2, 3, and Subspecialist Though Years 1, 2, 3, and Subspecialist correspond with Basic, Standard, Advanced, and Very Advanced Level Goals respectively, the listing of years are for clarification purposes only and not as a recommendation for duration of training, which is subject to local requirements and regulations. Very Advanced: Subspecialist Level of Training the Very Advanced level has been included to provide a comparison to the three other levels of training (ie, Basic, Standard, Advanced). Prioritization of Content: Must Know the updated Residency Curriculum prioritizes and identifies cognitive and technical skills the learner Must Know at each level. While should know is relevant and important, content defined as should know might be resource dependent or otherwise have some reason for not being learned or taught (eg, we do not see that disease in our particular country). Drafting of Sections and Review Process Drafting of Sections Each committee (referred to by the term Task Force in the 2006 curricula) was responsible for updating their section of the curriculum. If inconsistencies were found, that committee was asked to communicate with the chair or chairs of the relevant sections in order to resolve any discrepancies. Review Process Committee members were asked to identify at least five external colleagues to review their completed draft section. Committee Chairs, Members, and Section Reviewers For a complete list of committee chairs and members, please see the Appendix. Future Updates Ophthalmic curricula worldwide will be improved through the valuable contributions and involvement of global leaders and educators. There are worldwide differences in nomenclature for the general competencies, and the United States version is presented for clarification purposes only. Local customs, practices, resources, and regulatory environments will dictate the application of these competencies for individual programs. Core competencies include: Patient Care Medical Knowledge Practice-based Learning and Improvement Communication Skills Professionalism Systems-based Practice Ophthalmic specialists are expected to: Patient Care Provide patient care that is compassionate, appropriate, and effective for the treatment of health problems and the promotion of health; Communicate effectively and demonstrate caring and respectful behaviors when interacting with patients and their families, taking into consideration patient age, gender identification, impairments, ethnic group, and faith community; Gather essential and accurate information about patients; Make informed decisions about diagnostic and therapeutic interventions, based on patient information and preferences, up-to-date scientific evidence, and clinical judgment; Develop and carry out patient management plans; Counsel and educate patients and their families; Use information technology to support patient-care decisions and patient education; Competently perform the medical and invasive procedures considered essential for the area of practice; Provide health care services aimed at preventing health problems or maintaining health; and Work with healthcare professionals, including those from other disciplines, to provide patient-focused care. Medical Knowledge Demonstrate knowledge about established and evolving biomedical, clinical, and cognate (eg, epidemiological and social-behavioral) sciences and apply this knowledge to patient care; Demonstrate an investigatory and analytic thinking approach to clinical situations; and Know and apply the basic and clinically supportive sciences, which are appropriate to ophthalmology. Practice-based Learning and Improvement Investigate and evaluate patient care practices; appraise and assimilate scientific evidence; and improve patient care practices; Analyze practice experience and perform practice-based improvement activities using a systematic methodology; Locate, appraise, and assimilate evidence from scientific studies related to patient health problems; Obtain and use information about regional patient population and the larger population from which patients are drawn; Apply knowledge of study designs and statistical methods to the appraisal of clinical studies and other information on diagnostic and therapeutic effectiveness; and Use information technology to manage information, access online medical information, support ongoing personal professional development; and facilitate the learning of students and other healthcare professionals. Communications Skills Demonstrate communication skills that result in effective information exchange and teaming with patients, patient families, and professional associates; Create and sustain a therapeutic and ethically sound relationship with patients; Use effective listening skills and elicit and provide information using effective nonverbal, explanatory, questioning, and writing skills; and Work effectively with others as a member or a leader of a health care team or other professional group. Professionalism Demonstrate a commitment to carrying out professional responsibilities, adherence to ethical principles, and sensitivity to a diverse patient population; Demonstrate respect, compassion, and integrity; Demonstrate a responsiveness to the needs of patients and society that supersedes self-interest; accountability to patients, society, and the profession; and a commitment to excellence and on-going professional development; Demonstrate a commitment to ethical principles pertaining to provision or withholding of clinical care, confidentiality of patient information, informed consent, and business practices; and Demonstrate sensitivity and responsiveness to patient culture, age, gender identification, and disabilities. Systems-based Practice Demonstrate an awareness of and responsiveness to the larger context and system of health care and effectively call on system resources to provide care that is of optimal value; Understand how patient care and other professional practices affect other health care professionals, the health care organization, and the larger society, and how these system elements affect their personal ophthalmic practice; Know how types of medical practice and delivery systems differ from one another, including methods of controlling health care costs and allocating resources; and practice cost-effective health care and resource allocation that do not compromise quality of care; Advocate for high quality patient care and assist patients in dealing with system complexities; and Know how to partner with health care managers and health care providers to assess, coordinate, and improve health care, and know how these activities can affect system performance. Professional attitudes and conduct require that ophthalmic specialists must also have developed a style of care that is: Humane (eg, compassion in providing bad news, management of the visually impaired, and recognition of the impact of visual impairment on the patient and society); Reflective (eg, recognition of the limits of knowledge, skills, and understanding); Ethical; Integrative (eg, involvement in an interdisciplinary team for the eye care of children, patients with long term visual impairment or other disabilities, the systemically ill, the elderly, and with consideration of gender dimensions); and Scientific (eg, critical appraisal of the scientific literature, evidence-based practice, and use of information technology and statistics). Optics and Refraction the general educational objectives are to understand the principles, concepts, instruments, and methods of ophthalmology-related optics and refraction; and to apply these to clinical practice. Define vergence of light, including diopter, convergence, divergence, and vergence formula. Define the term magnification, including linear, angular, relative size, and electronic. Describe the pupillary response and its effect on the resolution of the optical system (Stiles-Crawford effect). Describe the effect of spectacles and contact lens correction on accommodation and convergence (ie, amplitude, near point, far point). Principles of refractive surgery** Clinical Refraction Objective Refraction: Retinoscopy 1. Describe medication concentrations according to age (eg, cyclopentolate, atropine). Illustrate reflection at curved surfaces (ie, focal point and focal length of a spherical mirror). Correct aberrations relevant to the eye, including spherical, coma, astigmatism, and distortion. Illustrate optics of the eye, including the dioptric power of different structures. Prescribe refractive correction based on the obtained objective and subjective measurements. Perform elementary refraction techniques for myopia, hyperopia, and near-vision add. Perform techniques for the correction for presbyopia (ie, measuring for near adds).
Partial removal can significantly increase the risk of bleeding with consequent complications women's health center vancouver wa buy capecitabine 500 mg otc. Total removal of the lesion requires dissection of the lesion from the surrounding brain womens health professionals albany ga purchase capecitabine with a mastercard. Thus breast cancer 2 day atlanta cheap capecitabine 500mg on line, if the cavernoma is located within or beside critical structures of the brain womens health jackson wy order capecitabine without a prescription. Use of the operating microscope and microsurgical instruments is essential in cavernoma removal. Preoperative planning and mapping of eloquent areas adjacent to the cavernoma are the most important part of the surgery, as any inaccuracy in direction of approach can lead to significant difficulties in finding small lesions within parenchyma. The most precise method is to combine knowledge of anatomical landmarks in the affected region and use of stereotactic navigation (frame-based or frameless). Importantly, despite seemingly correct calculations, a neurosurgeon can become lost and fail to find a lesion. Among these are coronal and sagittal suture, external auditory meatus, nasion, and inion, as well as such intracranial structures as Sylvian fissure, sulcal and gyral key points. The first group helps to delineate the approximate location of the lesion and extrapolate it to the surface of the skull for appropriate craniotomy. In these cases, real-time ultrasonography, especially in conjunction with neuronavigation, is particularly useful for lesions that show no surface extensions [46, 165, 311, 323]. Due to achievements in radiological diagnostics and mapping, awake-craniotomy is not necessary. After craniotomy and dural opening, dissection of the cortex is performed through the overlying gyrus or sulcus. The transsulcal approach has been suggested to minimize cortical damage and to 31 expose the lesion in a keyhole fashion [69, 124]. Because the cortex is thicker over the crest of a convolution and thinner at the depth of a sulcus, the transgyral approach sacrifices a larger number of neurons than the transsulcal approach [249]. However, disruption of the arcuate U fibers during transsulcal exposure is not proven to be less detrimental than disruption of vertical projection fibers after the transgyral approach [124, 249, 279]. Meticulous dissection of the arachnoid with sufficiently long preparation of the vessels crossing or lying within the sulcus is crucial to avoid their over-traction, stretching, or kinking, with subsequent ischemic injury to the adjacent or remote cortex. When a patient is operated on soon after overt bleeding, entry to the hematoma provides an initial route to the lesion. Otherwise, appearance of yellowish discoloration indicates an underlying cavernoma. When the lesion is approached, the gliotic plane is identified and circumferential dissection around the lesion is performed until it is free [319]. En bloc resection is recommended, although removal in piece-meal fashion is also suitable since cavernomas do not tend to cause any major intraoperative bleeding [279]. Dural-based cavernomas in the middle fossa are an exception: they may cause profuse bleeding during resection and therefore require careful handling in terms of avoiding damage to the integrity of the nidus [319]. The resection bed should be carefully inspected under high magnification for small satellite lesions [319]. Gliotic fringe discolored by blood breakdown products should be removed only when a lesion is located out of eloquent areas. The extent of resection of perifocal hemosiderotic parenchyma still remains controversial for cure or prophylaxis of epileptic disorder. After removal of the perifocal parenchyma, precise hemostasis is performed using bipolar coagulation with minimal voltage to avoid inadvertent injury to normal vasculature. Cavernomas of the brain stem represent one of the most challenging neurosurgical pathologies requiring thorough knowledge of the functional anatomy of the region and superior dexterity of the operating surgeon. Traversing of even a very thin fringe of healthy tissue between the lesion and brain stem surface during the approach may lead to devastating deficits. Risk of postoperative deterioration may be similar to having an overt hemorrhage from cavernoma [236]. A more favorable outcome is expected when a cavernoma extends to the pial surface and myelotomy is not necessary or only minimal [236]. Summarizing their recent experience of brain stem cavernoma surgery, Garrett and Spetzler recommended a supracerebellar infratentorial or lateral supracerebellar infratentorial approach for lesions involving the posterior or posterolateral midbrain [99]. To access lesions involving the anterior or 32 anterolateral midbrain, a full or modified orbitozygomatic craniotomy is recommended [99, 177, 342]. Lateral and anterolateral pontine lesions may be safely reached using the retrosigmoid approach. A safe entry zone, located between the fifth cranial nerve and the corticospinal tracts provides a reasonable pathway to the lesion of the anterior pons. A posterior pontine and posterior medullary cavernoma abutting the floor of the fourth ventricle is best approached via a suboccipital craniotomy, whereas lateral and anterolateral medullary lesions are reached using a far-lateral suboccipital approach [99]. When a cavernoma is large and/or hemorrhage causes significant mass-effect with displacement of the tracts and nuclei, superficial anatomical landmarks, such as the facial colliculus or the stria medullaris, are not concordant with the presumed location of intrinsic structures [203]. The mechanism of response to radiosurgery is thought to be a chronic inflammatory process, including endothelial cell proliferation, vessel wall hyalinization and thickening, and eventual luminal closure with a latency interval ranging from two to three years [161]. Sex, age, and duration of epilepsy had no prognostic value, whereas extratemporal location and history of only simple partial seizures was related to better seizure outcome. Radiation-induced complications include edema, necrosis, increased seizure frequency, and recurrent bleeding [4, 133, 294]. Expectedly, greater dosimetry is associated with a higher risk of complications [231]. Many questions regarding these entities still have no answers or are under debate. To date, there is no explanation in the literature why cavernomas are commonly located supratentorially, accounting for 70% of all lesions, but affect the spine very rarely. Furthermore, what limits the size of the lesion and why gigantic lesions are extremely rare are not fully understood. The growing number of patients with incidentally found lesions tends to increase the number of patients with lesions previously considered rare. A clearer understanding of the basic pathological features and treatment results of these cases is essential when making clinical decisions and planning management adequately. Among unusual cavernomas treated at our department, we analyzed intraventricular, multiple and spinal cavernomas; we supplemented these with a literature review. Intraventricular Cavernomas Patients and symptoms Intraventricular cavernomas constitute 2. Furthermore, authors noted that incomplete surgical remove can exacerbate extensive growth after long period of being stable [5, 213, 335]. Surgical or autopsy findings suggested that such growth may be attributable to repeated intralesional hemorrhages rather than to confluence of vascular channels [213]. Improved 45 (58) Persistent deficit 18 (24) Clinical manifestations are related to the Died 8 (10) location within the third ventricle. Lesions in Not defined 6 (8) the suprachiasmatic region tend to cause visual field restriction or endocrine dysfunction, 38 whereas cavernomas involving the lateral wall or floor of the ventricle can affect short-term memory functions [181]. There are observations showing enlargement of cavernomas during pregnancy and shrinkage after delivery [335, 345]. Some authors believe that cavernomas in the third ventricle could be under stronger hormonal influences because of their location [149], but no data exist to confirm this. The location of a cavernoma in the lateral ventricle is also frequently associated with raised intracranial pressure. In 22 of 38 cases (58%) with lateral ventricle cavernomas reported in the literature, patients suffered from mass-effect and hydrocephalus as leading symptoms. These patients suffered from sensorimotor paresis in the extremities [66], drop attacks [104], diplopia and ataxia [152, 335], and dysartria [137]. All patients with fourth ventricle lesions experienced intermittent headaches frequently accompanied by nausea and vomiting. However, in one case, a lesion located in the temporal horn of the lateral ventricle caused severe intraventricular bleeding and intracerebral hematoma [226]. However, in lesions with subependymal origin, a hemosiderotic fringe could be detected [146]. Surgery is advocated when re-hemorrhages are frequent, and the mass-effect causes progressive neurological deficits. In cases of acute hydrocephalus, temporary external ventricular drainage was usually applied before surgical excision of the lesion, and in five reported cases (6%) a permanent shunt was indicated [68, 128, 149, 213, 285]. In this group, the cavernoma was in the third ventricle in four patients, and one newborn had a giant lesion in the lateral ventricle. Patients with cavernomas close to the brain stem frequently present with cranial nerve deficits.
As for the Maxwell body women's health boutique houston buy capecitabine 500mg on line, we solve for the creep response by imposing a step force and considering times t > 0 breast cancer test purchase 500 mg capecitabine visa, in which case F(t) = F0 and F= 0 menstrual cycle at age 7 buy capecitabine 500mg otc. Once again we recognize that the displacement of the dashpot is zero at time t = 0+ pregnancy quotes and sayings cost of capecitabine,so that the force must be carried by the springs only, i. The model predictions can be further improved by adding a dashpot in series with the Kelvin body. The creep response for this model is simply the superposition of the response of the Kelvin body and the series dashpot, and therefore is given 58 Cellular biomechanics h k 0 0 h 1 F F k 1 Figure 2. The quality of the t suggests that there must be (at least) two components of the cell that are responsible for generating viscous responses and (at least) two components that generate an elastic response. It is even possible that all of the viscous behavior could come from a single component that relaxes with two different time scales. From such ts, viscoelastic constants that describe the creep response of a cell can be estimated and used to compare the response of one cell with that of another cell, or to determine the response of a cell to a variety of inputs. The viscoelastic constants estimated by the lumped parameter model are indicative of the properties of the whole cell, but those properties are determined in part by the properties of the cell membrane, in part by the properties of the cell cytoplasm, and in part by the structure of the cytoskeleton. We will show in the next two sections that these structural differences can have profound effects on the mechanical properties of the whole cell, explaining some of the variations seen in the viscoelastic properties from one cell to another. An alternate way of forcing magnetic beads attached to a cell is to subject them to an oscillating 59 2. The dashed line represents the instantaneous elongation of the body (1/(k0 + k1)) and the solid line is fit to the data using Equation (2. It can be shown that the displacement has both exponential and harmonic components, being given byF0 k0 t/x(t) = 1 e k1 k0 + k1 2 0 t/0 1 (e cos t) + 1 + sin t k0k0 + 1 + 2 (2. It is based on the somewhat controversial theory of tensegrity and is largely a mechanical theory. This is a building technique in which the mechanical integrity of a structure is maintained by internal members, some of which are under tension and others of which are under compression. More formally, tensegrity structures can be de ned as the interaction of a set of isolated compression elements with a set of continuous ten sion elements [with] the aim of providing a stable form in space [71]. Examples of tensegrity structures include geodesic domes and our bodies, where the muscles play the role of the tension elements and the bones are in compression. At the level of the cell, it has been proposed by Ingber and co-workers [72] that actin micro laments play the role of tension elements and microtubules are the compression elements. There is some experimental evidence that supports this general idea [72]: r actin micro laments can generate tension r there are interconnections between actin micro laments and microtubules r microtubules may be under compression. One difficulty in evaluating the implications of the tensegrity model is that the topology of the interconnected laments within the cell is very complex. However, insight into the tensegrity mechanism can be obtained if we consider a very simple model, rst introduced by Stamenovic and Coughlin [71]. In this approach, the cell is assumed to have only six compression elements (struts), oriented as shown in. This is the smallest number of struts that can provide a non trivial tensegrity system that is spatially isotropic. These six compression elements are joined by 24 tension elements, as shown in. We will assume that the compression members are perfectly rigid and of equal length L0. Further, we will assume that the tension elements act as linear springs, so that the tension force that they generate can be written as F = k(l lr), (2. B B T/2 A A T/2 o X T/2 A A /2 B B Z C C where lr is the relaxed length of the element, l is its actual length, and k is a constant. We will assume that the length of the tension elements is l0 (for all elements) when the cell is at rest. Note that even when the cell is at rest, there is tension in the actin laments; that is, the tension elements are not relaxed when the cell is at rest. If we de ne coordinate axes as shown, then everything is symmetric about the origin. If we specify T, we can then solve the system for the displacements and lengths of the tension elements, although it is algebraically messy. The easiest way is to consider the energy stored in the cell owing to an incremental extension sx caused by a small applied tension T acting in the x direction. When an object experiences elongation from length s0 to length sx caused by a uniaxial force T acting in the x direction, then the work done on that object may sx be written as s T dx. We introduce the strain energy per unit mass, W, which 0 represents the amount of energy stored in the body (per unit mass) owing to defor mation. The resting cell volume (at T = 0) can be computed as V = 5L3/16, and the reference length is 0 0 s0 = L0/2. One of the essential features of the tensegrity model is the existence of a non-zero force in the cytoskeletal tension elements, even when the cell is in the resting state. In computing the prestress, we only consider the component of force in the direction perpendicular to the cross-sectional area. If all the actin laments in the cell were aligned and under uniform tension F0, then the prestress in the direction of the actin laments would be nF0 P = (2. In the more realistic case of randomly oriented actin laments, the right-hand side of the above equation has to be divided by a factor of three to account for the component of the force F0 that is normal to the area A [74]. Furthermore, it is convenient to write F0 as a c, where a is the cross-sectional area of a tension member and c is the stress in that member, to obtain na c P =. We could cal culate an upper bound on P from an estimate of the yield stress of actin for F0 and assumptions on the characteristic lengths of the actin laments (l0). However, this estimate would be rather crude because of uncertainty in these quantities. Recently, experimental estimates of the prestress in human airway smooth muscle cells cultured on exible substrates have been made [75,76] and compared with experimentally measured stiffnesses in these cells. So what does all this mean, and what are the implications for the tensegrity model First, the linear relationship between E0 and P observed experimentally agrees with that predicted by the analytical model, suggesting that the tensegrity model correctly describes at least some of the physics of the small stress response of the cytoskeleton. Unfortunately, it is diffi cult to assess further the tensegrity model predictions because of at least two major sources of uncertainty: 1. The answer seems to be that it can: prestress in a cell is the net result of forces generated by active contractile forces in the actinomyosin apparatus, and it is balanced by forces 67 2. The range predicted analytically is based on the simple tensegrity model and experimental measurements of prestress [75,76]. Changing any of these parameters will change the prestress, and it is likely that these parameters varied signi cantly between experiments performed by different investigators using different substrates, cell types, cell densities, and experimental conditions. Comparisons of exper imental data from different sources are further complicated by the fact that the measured stiffness of a cell depends on the applied stress or strain because cells exhibit prestress-dependent strain stiffening. The mechanical loading applied to a cell during an experiment depends rather strongly on the measurement technique used. Also, for a given strain, cell stiffness increases with increasing prestress (prestress-induced stiffening). For instance, under large applied compres sive stresses, actin laments may actually bend; this feature is not taken into account in the tensegrity model, although it is in the foam model presented in the next section. Buy capecitabine 500 mg with visa. womens health. |
