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By I. Masil. University of Texas Health Center at Tyler.

The method gave satisfactory accuracy and precision buy 25 mg hydrochlorothiazide visa, but had the disadvantage that a large number of standards were necessary for the construction of multivariable standard curves cheap hydrochlorothiazide 12.5 mg without prescription. Nevertheless buy 12.5 mg hydrochlorothiazide with mastercard, it can be seen that data calculated by our technique correlate with those from the original paper. Agreement between the two methods was acceptable, particularly in view of the problems associated with reading data off published material and the fact that the limit of our calculation method is fixed by the lowest binding observed with the least reactive substance. Conclusions The method described in this paper for calculating the concentration of mixtures of cross-reactants is relatively simple. While it could be easily automated all calculations in this paper were performed manually. The approach outlined in this paper is more flexible and technically less arduous than that of Llewlyn et al. Theoretically the model can be extended to permit the measurement of a mixture of two analytes using one assay system (by measuring the sample at two dilutions) and can be extended to allow for the presence of more cross-reacting species. It has long been recognized that many hormones and other substances of biological importance exist in blood partially bound to serum-binding protein. The most well-known examples of this phenomenon in endocrinology are the binding of the thyroid and steroid hormones by a variety of proteins, some of which are generally believed as being “specific” in their binding characteristics. Moreover it has long been believed that - in the case of the steroid and thyroid hormones at least — it is solely the non-protein-bound moiety which is able to permeate capillary walls to exert the hormone’s physiological effect. Observations of this kind have naturally generated a wide demand for simple techniques for the assay, in a clinical context, of serum-free hormone levels — either “directly” or by the measurement of various serum constituents or parameters which, in combination, yield an indirect estimate of the free hormone concentration. The serum “free thyroxine index” — derived following estimation both of the serum thyroxine concentration and of the extent of thyroxine (or triiodothyronine) “uptake” on to a suitable solid absorbant - represents the most widely used example of the latter approach. Such methods - although greatly reducing the diagnostic errors arising from unsuspected abnormalities in serum-binding protein concentration — are nonetheless prone to inaccuracy when binding protein levels are grossly disturbed. However, in the past four years it has become apparent that the direct radioimmunoassay of free hormones in serum is possible using procedures which are no more complex nor technically demanding than the conventional radioimmunoassay of total hormone levels in body fluids. This presen­ tation is primarily intended to provide an objective overview of alternative methodologies for free hormone assay, enabling the radioimmunoassay practitioner to understand the fundamental basis of the various approaches that are possible or, if he so wishes, to develop his own in-house methodology. Nevertheless, it would be insufficient (in the author’s view) to discuss techniques of measurement of free hormones without initial examination of the underlying physico­ chemical ideas governing the free hormone concept and of the mechanisms which are believed to govern hormone delivery to target tissues. Techniques for the direct radioimmunoassay of free hormones in blood are then presented. The most well known examples of this phenomenon in endocrinology are the binding of the thyroid and steroid hormones by a variety of proteins, some of which (e. The fundamental basis for this concept is provided by the large amounts of laboratory and clinical data accumulated over the past two decades demonstrating close correlations between serum free hormone levels and hormonal status. Observations of this kind have naturally generated a wide demand for simple techniques for the assay, in a clinical context, of serum free hormone levels - either "directly" or by the measurement of various serum constituents or parameters which, in combination, yield an indirect estimate of the free hormone concentration. The serum "free thyroxine index" - derived following estimation both of the serum thyroxine concentration and of the extent of thyroxine (or triiodothyronine) "up-take" onto a suitable solid adsorbent - represents the most widely used example of the latter approach. Such methods - although greatly reducing the diagnostic errors arising from unsuspected abnormalities in serum binding protein concentration - are nonetheless prone to inaccuracy when binding protein levels are grossly disturbed. However, in the past four years it has become apparent that the direct radioimmunoassay of free hormones, drugs and other similar ligands in serum is possible using procedures which are no more complex nor technically demanding than the conventional radioimmunoassay of total hormone levels in body fluids. My own laboratory was probably amongst the first to perceive that such methods were feasible, and has both independently developed its own "in-house" methodologies and explored the theoretical and experimental basis of a number of alternative approaches. In general, however, the bulk of the technical development of individual direct free hormone assay methods has been conducted in the laboratories of large commercial kit manufacturers, albeit, these have often, unfortunately, not been over anxious to divulge the fundamental principles or experimental details governing their own procedures. The field therefore remains one which is almost totally outside the methodological competence of non-commercial institutions, and in which public discussion is therefore generally restricted to the purely empirical assessment of the relative merits of the various commercial kits. Nevertheless, it would be insufficient (in the present authors view) to discuss techniques of measurement of free hormones without initial examination of the underlying physico­ chemical ideas governing the "free hormone" concept per se and of the mechanisms which are believed to govern hormone delivery target tissues (into the framework of which the free hormone concept is inextricably woven). For this reason the first part of this presentation will address itself specifically to the "free hormone hypothesis" and attempt to clarify the molecular events which are thought to underlie the relationships observed between physiological effects and the concentration of free hormone measured in blood. Basic Physico-chemical concepts The fundamental physico-chemical events underlying the free hormone concept are relatively well known, and only the most basic ideas will be discussed here. This portrayal of molecular events underlines the fact that, in many circumstances, it is irrelevant whether the particular protein involved in the interaction is present in high concentration but possesses low affinity (i. In practice, the situation existing in serum is generally considerably more complicated than has been here described. A number of different binding proteins, characterised by differing association and dissociation rate constants (and hence equilibrium constants) may be present, and the equations governing the relative concentration of free and bound hormone (and the distribution of hormone between the individual binding hormones present) are consider­ ably more complex than equation iii. Moreoever (as in the case of the thyroid hormone/binding protein interactions) two or more different hormones may bind to identical protein binding sites, adding further complexity to the form of the equations governing the distribution of hormone in an undisturbed medium. The essence of the free hormone hypothesis - at least in its currently accepted form - is that the free hormone concentration per se determines the rate of hormone delivery to target cells, implying that the distribution of hormone between the various binding proteins that may be present in serum is essentially irrelevant. The Kinetics of Hormone Delivery to Target Tissues: Concepts compatible with the "free hormone hypothesis". In the preceding section we have discussed the basic physico-chemical events whkl: result in the existance of a free hormone concentration in serum in conditions of undisturbed equilibrium. The situation arising in blood in vivo is, however, somewhat different from that described above. In the latter circumstances, we must envisage serum and blood cells passing along the individual capillaries within individual target organs, from which hormone is permeating across the capillary walls into adjacent extra-cellular fluids and thence into target cells. A net flow of hormone from capillary blood will thus exist implying, in turn, a disturbance to the equilibrium otherwise existing between the free and bound hormone moieties within serum. The free (steroid) hormone falls essentially to zero in consequence o f target organ clearance; the albumin-bound hormone moiety is also partially or totally cleared. No significant dissociation o f specifically-bound hormone occurs during capillary transit. These contrary postulates have been primarily advanced by Robbins and Rail (4) and by Tait and Burstein (5) respectively in major reviews, and will accordingly be termed the "Robbins and Rail" and "Tait and Burstein" models in this presentation.

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As neurons in the substantia nigra die buy 12.5 mg hydrochlorothiazide amex, less dopamine is transported to the striatum 25 mg hydrochlorothiazide visa. Eventually a low threshold level of dopamine leads to the neurologi- cal symptoms (Fig discount 12.5mg hydrochlorothiazide overnight delivery. There is freezing of movement when the movement is stopped and often the inability to resume motion. There is also a loss of fine motor skills and hand writing takes on distinctive features. A variety of reciprocal connections are made between neurons joining the substantia nigra with the striatum (putamen). Death of substantia nigra neurons results in reduced levels of dopamine transported to the putamen and causes the neurological symptoms of Parkinson’s. A mutation in the a-synuclein gene (a substitution of alanine to threonine at position 53), which codes for a presynaptic nerve terminal protein, was identified to be at fault in a large Italian family in 1997 by Mihael Polymeropoulos and co- workers at the National Human Genome Research Institute in Bethesda, Maryland. Basic research and gene therapy initiatives are directed at preventing the loss of neurons that synthesize dopamine (possibly by supplying a neurotrophic factor) or by engineering cells to increase the dopamine concentration in the striatum. Magnetic resonance imaging and electrophysiologically monitoring during surgery permits detailed localization within the brain. The presence of high-frequency stim- ulation through electrodes placed deep in the brain appears to produce a functional lesion in the desired target area (deep brain stimulation). Huntington’s In 1872, George Huntington described a disease that he, his father, and his grand- father had observed in several generations of their patients. However, 150,000 individuals are at a 50% risk of inheriting the disease from an affected parent. It usually develops in a subtle fashion in the fourth to fifth decade of life and gradually worsens over a course of 10 to 20 years until death. The motor symptoms develop gradually, initially characterized by involuntary movements. Uncontrolled movements increase until the patient is confined to a bed or wheelchair. The movement symptoms appear in the form of clumsiness, stiffness, and trouble with walking. Aspects of dementia include a decline in memory, concentration, and problem solving. If psychiatric symptoms appear, there are episodes of depression, instability, and even personality changes associated with mood swings. At the neuropathological level, there is a selective loss of neurons that is most aggressive in the striatum (caudate and putamen regions). Although the genetic defect causing Huntington’s was assigned to chromosome 4 in 1983, it took 10 additional years of intense research to identify the gene in ques- tion. The gene has been implicated as a tran- scription factor to regulate the expression of other genes. Therefore, each of their children has a 50/50 chance of receiving the gene and a 50/50 chance of inheriting the condition. Since the 1930s, this disease has been widely referred to as Lou Gehrig’s disease. In this condition, there is a system degeneration of the upper and lower motor neurons in the brain and spinal cord. Lower motor neurons constitute the large neurons in the anterior horn of the spinal cord that connects with the skeletal (voluntary) muscles of the body. The upper motor neurons refer to the pyramidal neurons in the cerebral cortex that interact and modulate the activity of the lower motor neurons. Neurons affected usually show accumulations of phosphorylated neurofilaments in swollen proximal regions of axons and in cell bodies. There are signs of axonal degeneration leading to a reduction in the number of motor neurons in the spinal cord and brain stem nuclei. A loss in the number of pyramidal neurons in the brain motor cortex is asso- ciated with degeneration of the corticospinal pathways (responsible for voluntary movement). This condition is very progressive, resulting in muscle weakness and an atrophy of muscle mass due to the degenerating neurons. These enzymes provide cellular defense against the radical ·O2 and its toxic derivatives. Life expectancy from the time of diagnosis is about 2 to 5 years, but there is a wide range because some patients have prolonged survival. This condition presents in different ways, depending on the muscles initially affected. Symptoms may include stumbling, a loss of dexterity and strength in the hands, or difficulty in swallowing. The degeneration of the neuromuscular components may be present for some time before the symptoms cause real concern. In the majority of cases, all voluntary muscles become affected, leaving the patient completely paralyzed. Multiple, randomly scattered lesions (referred to as plaques), representing sites of myelin destruction, accumulate in the brain and spinal cord and cause a variety of neurological problems. When the myelin is damaged, neurological transmission may be slowed or blocked completely, leading to dimin- ished or lost function. Astrocytes contribute to the scar tissue in the plaques throughout the brain and spinal cord. The mediator of the autoimmune attack is the patients’ T lymphocytes—a type of white blood cell derived from the thymus gland that normally responds to infection and offers long-term immunity. The abnormal autoimmune response involves activation of helper T cells and cyto- toxic T cells, with a corresponding decrease in suppressor T-cell activity (see Chapters 11 and 12 for immune cell functions). A number of limited clinical trials have been conducted to evaluate the effects of neurotrophic factors for central as well as peripheral neural disorders.

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In general purchase hydrochlorothiazide 25 mg mastercard, a genetically reces- sive mutation correlates with a loss of function order hydrochlorothiazide 12.5mg with amex, such as in a tumor suppressor gene buy hydrochlorothiazide 25mg online. A dominant mutation correlates with a gain in function, such as the overexpression of a normally silent oncogene. It is the manipulation of these genetic mutations and the enhancement of normal cellular events that is the goal of cancer gene therapy. Thus, gene therapy for the treatment of cancer has been directed at (1) replacing mutated tumor suppressor genes, (2) inactivating overexpressed oncogenes, (3) delivering the genetic com- ponent of targeted prodrug therapies, and (4) modifying the antitumor immune response. Diagrammatic representation of sequential mutations needed to develop colorectal carcinoma from normal epithelial cells. Tissue- specific and cellular-specific factors as well as other gene products mediate the processes of differentiation, growth, and apoptosis. Alterations in these gene prod- ucts can lead to premalignant, benign tumors or malignancy. Thus, numerous genes can be implicated in oncogenesis, or the development of a malignant tumor. These include oncogenes, or the activation of growth-promoting genes, and tumor suppressor genes, or the inactivation of growth-suppressing genes. Two important characteristics in carcinogenesis are integral to the genetic alterations: (1) multistep oncogenesis and (2) clonal expansion. The mulitstep formation of tumor develop- ment requires that several genetic alterations or,“hits,” occur in sequence for normal cells to progress through various stages to malignancy, as represented in Figure 10. Clonal expansion indicates that a growth advantage is conferred to a cell by virtue of a genetic alteration (mutation) that occurs as part of the multistep carcinogenesis. Cell Cycle The cell cycle is comprised of five phases based on cellular activity (Fig. Cells commit to a cycle of replication in the G1 phase at the R (restriction) point. Regulation of the cell cycle is critical at the G1/S junction and at the G2/M transition. For instance, cyclinD1 has been shown both in vitro and vivo to initiate oncogenic properties and is amplified and overexpressed in certain esophagus squamous cell carcinomas as well as other head, neck, bladder, and breast cancers. The cyclin A gene is the site of integration of the hepatitis B virus (Chapter 6), thereby promoting hepatitis virus integration into the genome. Cip1 is activated by the p53 tumor suppressor gene product and by cell senescence. In esophageal and pancreas tumors, deletion or point mutations at this locus are observed. Apoptosis Apoptosis,genetically programmed cell death,involves specific nuclear events. These include the compaction and segregation of chromatin into sharply delineated masses against the nuclear envelope, condensation of cytoplasm, nuclear fragmentation, convolution of the cellular surface, and formation of membrane-bound apoptotic bodies. However, another protein, termed bax, forms a dimer with bcl-2, and bax contributes to programmed cell death. It is the cellular ratio of bcl-2 to bax that determines whether a cells survives or dies. Alternatively, bak,a proapoptotic member of the bcl-2 gene family has been recently described. On the other hand, localized immune cells fighting malignant cells could provide added pro- tection through the transfer of genes that protect from apoptosis. Cellular Transformation Cells are said to be “transformed” when they have changed from a normal pheno- type to a malignant phenotype. Malignant cells exhibit cellular characteristics that are distinguished from normal cells. In the transformation to a malignant phenotype, epithelial cells become nonpolar, pleo- morphic, display variable levels of differentiation, contain mitotic figures, rapidly divide, and express tumor-associated antigens on the cell surface. The expression of tumor-associated antigens has been used to target tumor cells via monoclonal anti- bodies, liposomes, and the like for drug- or toxin-induced cell death. Cells can also be transformed by chemical treatment, radiation, spontaneous mutations of endoge- nous genes, or viral infection. Transformed cells generated by these mechanisms display rounded morphology, escape density-dependent contact inhibition (clump), are anchorage independent, and are not inhibited in growth by restriction point reg- ulation of the cell cycle (Fig. In addition, transformed cells are tumorgenic when adoptively transferred to naïve animals. Note the rounded morphology, aggregation, clumping, and satellite colonies of growth. Although replication- defective viral vectors are used in viral vector gene transfer (see Chapter 4), the remote possibility of viral recombination of vector with naturally occurring patho- genic virus to produce a competent transforming virus remains. Oncogenes Cellular oncogenes are normal cellular genes related to cell growth, proliferation, differentiation, and transcriptional activation. Cellular oncogenes can be aberrantly expressed by gene mutation or rearrangement/translocation, amplification of expression, or through the loss of regulatory factors controlling expression. The aberrant expression results in the development of cellular proliferation and malignancy. There have been over 60 oncogenes identified to date and are associated with various neoplasms. Oncogenes can be classi- fied in categories according to their subcellular location and mechanisms of action. An example of an oncogene is the normally quiescent ras oncogene which com- prises a gene family of three members: Ki-ras, Ha-ras, and N-ras. In association with the plasma membrane, p21 directly interacts with the raf serine- theonine kinase. This pathway provides signaling for cell cycle progression, differentiation, protein transport, secretion, and cytoskeletal organization.