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By: William A. Weiss, MD, PhD

  • Professor, Neurology UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA

https://profiles.ucsf.edu/william.weiss

A number of processes can disturb the normal activity of the endocrine system order geodon 40mg otc, including impaired synthesis or release of hormones effective geodon 80mg, abnormal interactions between hormones and their target tissues cheap geodon 20mg fast delivery, and abnormal responses of target organs cheap 40 mg geodon otc. Endocrine diseases can be generally classified as (1) diseases of underproduction or overproduction of hormones and their resulting biochemical and clinical consequences and (2) diseases associated with the development of mass lesions. Such lesions might be nonfunctional, or they might be associated with overproduction or underproduction of hormones. The study of endocrine diseases requires integration of morphologic findings with biochemical measurements of the levels of hormones, their regulators, and other metabolites. Pituitary Gland Normal the pituitary is a small bean-shaped organ that measures about 1 cm in greatest diameter and weighs about 0. It is located at the base of the brain, where it lies nestled within the confines of the sella turcica in close proximity to the optic chiasm and the cavernous sinuses. The pituitary is attached to the hypothalamus by the pituitary stalk, which passes out of the sella through an opening in the dura mater surrounding the brain. Along with the hypothalamus, the pituitary gland plays a critical role in 1157 Figure 24-1 Hormones released by the anterior pituitary. The adenohypophysis (anterior pituitary) releases five hormones that are in turn under the control of various stimulatory and inhibitory hypothalamic releasing factors. The gland is populated by several distinct cell populations containing a variety of stimulating (trophic) hormones. B, Each of the hormones has different staining characteristics, resulting in a mixture of cell types in routine histologic preparations. Both silent and hormone-negative pituitary adenomas may cause hypopituitarism as they encroach on and destroy adjacent anterior pituitary parenchyma. Clinically diagnosed pituitary adenomas are responsible for about 10% of intracranial neoplasms; they are discovered incidentally in up to 25% of routine autopsies. In fact, using highresolution computed tomography or magnetic resonance imaging suggest that approximately 20% of "normal" adult pituitary glands harbor an incidental lesion measuring 3 mm or more [1] in diameter, usually a silent adenoma. Pituitary adenomas are usually found in adults, with a peak incidence from the thirties to the fifties. Pituitary adenomas are designated, somewhat arbitrarily, microadenomas if they are less than 1 cm in diameter and macroadenomas if they exceed 1 cm in diameter. Silent and hormone-negative adenomas are likely to come to clinical attention at a later stage than those associated with endocrine abnormalities and are therefore more likely to be macroadenomas. Some plurihormonal tumors may arise from clonal expansion of primitive stem cells, which then differentiate in several directions simultaneously. G-proteins are described in Chapter 3 ; here we will review their function in the context of endocrine neoplasms. G-proteins play a critical role in signal transduction, transmitting signals from cell-surface receptors. These are heterotrimeric proteins, composed of a specific subunit that binds guanine nucleotide and interacts with both cell surface receptors and intracellular effectors (Fig. Gs is a stimulatory G-protein that has a pivotal role in signal transduction in several endocrine organs, including the pituitary. Mutations in the G-protein-signaling pathway are seen in a variety of endocrine neoplasms, including pituitary, thyroid, and parathyroid adenomas. This massive, nonfunctional adenoma has grown far beyond the confines of the sella turcica and has distorted the overlying brain. Nonfunctional adenomas tend to be larger at the time of diagnosis than those that secrete a hormone. The monomorphism of these cells contrasts markedly with the mixture of cells seen in the normal anterior pituitary. The tumor cells contain abundant granular endoplasmic reticulum (indicative of active protein synthesis) and small numbers of secretory granules (6000X). Secretion of thyroid hormones (T3 and T4) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. With this disclaimer, we will follow the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably. The three most common causes of thyrotoxicosis are also associated with hyperfunction of the gland and include the following: • Diffuse hyperplasia of the thyroid associated with Graves disease (accounts for 85% of cases) • Hyperfunctional multinodular goiter • Hyperfunctional adenoma of the thyroid Clinical Course. The clinical manifestations of hyperthyroidism are protean and include changes referable to the hypermetabolic state induced by excess thyroid hormone as well as those related to overactivity of the sympathetic nervous system. Excessive levels of thyroid hormone result in an increase in the basal metabolic rate. The skin of thyrotoxic patients tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss. Increased basal metabolic rate also results in characteristic weight loss despite increased appetite. Cardiac manifestations are among the earliest and most consistent features of hyperthyroidism. Patients with hyperthyroidism can have an increase in cardiac output, owing to both increased cardiac contractility and increased peripheral oxygen requirements. Arrhythmias, particularly atrial fibrillation, occur frequently and are more common in older patients. Congestive heart failure may develop, particularly in elderly patients with pre-existing cardiac disease.

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Clinical note — the vitamin D dilemma Determining an adequate dietary intake of vitamin D is complex geodon 80mg sale, as multiple variables influence endogenous production and dietary requirements generic geodon 20mg with mastercard. Factors such as age proven geodon 20mg, season 20mg geodon, geographic latitude, time of day, part of body exposed to sunlight and use of sunscreen affect production of endogenous vitamin D. The successful ‘slip slop slap’ campaign in Australia, which encourages covering up and reduced sun exposure, appears at odds with the vitamin D message and may have put many Australians at risk of poor vitamin D status. Clearly, revision of the current public health messages regarding both vitamin D and safe sunlight exposure has been required for some time. In response, work has Vitamin D 1308 been undertaken to develop a message of compromise (Nowson & Margerison 2002, Working Group 2005). Recent evidence from a study by Samanek et al (2006) © 2007 Elsevier Australia supports the concept that safe sun exposure can yield vitamin D repletion. Their research concluded that from October to March only 10–15 minutes of unprotected exposure to 15% of the body outside of the hours 10 am to 3 pm was sufficient; however, during other seasons, up to 1 hour of exposure was required. In addition to this the authors themselves acknowledge that calculations were based on existing serum values, which have been widely contested by other researchers (Gomez et al 2003). It also suggests varying lengths of time for sun exposure for different skin types in order to achieve adequate levels. Whether these initiatives are sufficient to prevent deficiency in the community remains to be seen. The use of certain anticonvulsants and chronic administration of glucocorticoids increase the risk of vitamin D deficiency. Several rare hereditary forms of rickets develop because the body cannot process (metabolise) vitamin D normally (Beers & Berkow 2003). It is now apparent that much higher concentrations, deemed ‘suboptimal’ status, have deleterious effects (Nowson & Margerison 2002). An association has been suggested between fibromyalgia presenting with generalised muscle weakness and pain and hypovitaminosis (Holick 2004). In deficiency, intestinal absorption of calcium can be halved in adults (Holick 2004). Modelling and remodelling of bone Besides influencing bone by maintaining calcium and phosphorus homeostasis, vitamin D may also contribute to bone health in other ways. Osteocalcin is then secreted by the osteoblasts, which bind calcium in new bone (Groff & Gropper 2005). Vitamin D also appears to play a role in oestrogen biosynthesis by increasing expression of the aromatase enzyme gene. It has demonstrated a synergistic effect in select tissues with the phyto-oestrogen genistein, with co-administration leading to a prolonged half-life of active vitamin D (Harkness & Bonny 2005, Swami et al 2005). Cell differentiation, proliferation and growth Some of the actions already described are the result of the vitamin’s capacity to affect cell differentiation, proliferation and growth in many tissues. This ability has led to its investigation as a treatment for proliferative disorders such as cancer (Brown et al 1999, Groff & Gropper 2005, Kohlmeier 2003). In deficiency, hypersecretion of this hormone can cause excessive growth of the parathyroid gland and secondary hyperparathyroidism (Brown et al 1999). Immunomodulation Vitamin D enhances the immune system’s response to both bacterial and viral agents, primarily through promoting differentiation and activity of the macrophages, which means that immune responses can be tailored through the appropriate cell response (Brown et al 1999). There is also some speculation that through this mechanism, vitamin D will promote a Th-2 dominance and may predispose to the atopic diathesis. Evidence in support of this hypothesis comes from two studies that reveal supplementation with vitamin D in early life to be a potential precipitator of allergic disease (Hypponen et al 2001). Ongoing discovery of previously unidentified receptors on tissues continues to broaden our understanding of its diverse effects. It has also been shown to inhibit clonal cell proliferation in some leukaemia lines and to promote differentiation (Brown et al 1999). Although it has been established that skeletal muscles have receptors for vitamin D, the specific actions of this steroid on muscle are largely unknown. Recently a link between fibromyalgia and vitamin D deficiency has been suggested, with an estimation of 40–60% of cases presenting with generalised muscle weakness and pain being undiagnosed hypovitaminosis (Holick 2004). Enhanced insulin synthesis may be due to vitamin D’s role in controlling intracellular calcium flux in islet cells (Brown et al 1999). Preliminary studies in rats have demonstrated an anti-epileptic action (Kalueff & Tuohimaa 2005). There are tentative links being made between the aetiology/pathophysiology of Parkinson’s disease and poor vitamin D status (Johnson 2001, Kim et al 2005). This review will focus only on oral supplementation of D2 or D3 and not the variety of analogues that continue to be extensively studied. For many conditions that appear to require high doses, the race is on to develop and trial pharmaceutical analogues that retain in particular the antiproliferative nature of the vitamin, but are low-calcaemic in order to minimise the associated toxicity seen at such doses. Vitamin D deficiency results in inadequate calcium and phosphorus levels for bone mineralisation (Beers & Berkow 2003). When this condition occurs in adults it is called osteomalacia, and its first presentation is often chronic lower back pain (Al Faraj & Al Mutairi 2003). Defective vitamin D metabolism may be another cause, and consequently will not Vitamin D 1312 respond to standard oral treatment. In this situation, extremely high doses may be required, which require careful monitoring for toxicity (Beers & Berkow 2003). A recent Australian study investigated the well-documented seasonal variation in birth weight to determine the parameters of anthropometric changes associated with this seasonal variation (McGrath et al 2005). Comparison of over 350,000 mean monthly birth weights of neonates greater than 37 weeks’ gestation revealed overall size, length, head size and skinfold thickness all display seasonal variation, but in particular greater limb length occurred with winter/spring births. Earlier animal studies imply that this may be a consequence of hypertrophy of the cartilage growth plates due to prenatal hypovitaminosis D (McGrath et al 2005).

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This will depend on the indication it is being used to cheap geodon 80mg amex treat; however generic 80mg geodon otc, in most instances Calcium 164 long-term administration is required generic geodon 20 mg otc. In very high doses generic 20 mg geodon otc, calcium supplements can cause some side-effects, including constipation, but generally calcium is considered very safe and has a wide therapeutic range. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Long-term effect of calcium supplementation during pregnancy on the blood pressure of offspring: follow up of a randomised controlled trial. Cholesterol-lowering effects of calcium carbonate in patients with mild to moderate hypercholesterolemia. Milk, dairy fat, dietary calcium, and weight gain: a longitudinal study of adolescents. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. A high dairy protein, high-calcium diet minimizes bone turnover in overweight adults during weight loss. Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia. Five year study of etidronate and/or calcium as prevention and treatment for osteoporosis and fractures in patients with asthma receiving long term oral and/or inhaled glucocorticoids. Calcium sensing receptor in human colon carcinoma: interaction with Ca(2+) and 1,25-dihydroxyvitamin D(3). Effect of calcium and cholecalciferol treatment for 3 years on hip fractures in elderly women. Interaction between calcium intake and menarcheal age on bone mass gain: an eight-year follow-up study from prepuberty to postmenarche. Central hypervolemia does not invariably modulate calcium excretion in essential Calcium 165 hypertension. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Effect of supplementation of calcium and Vitamin D on bone mineral density and bone mineral content in periand post-menopause women A double-blind, randomized, controlled trial. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. Influence of maternal bone lead burden and calcium intake on levels of lead in breast milk over the course of lactation. Biochemical effects of calcium supplementation in postmenopausal women: influence of dietary calcium intake. Comparison of the effects of over-the-counter famotidine and calcium carbonate antacid on postprandial gastric acid: A randomized controlled trial. Dietary fiber, potassium, magnesium and calcium in relation to the risk of preeclampsia. Impact of dietary and lifestyle factors on the prevalence of hypertension in Western populations. Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. The influence of dietary and nondietary calcium supplementation on blood pressure: an updated metaanalysis of randomised controlled trials. Calcium and vitamin D status in the adolescent: key roles for bone, body weight, glucose tolerance, and estrogen biosynthesis. Dietary calcium supplements to lower blood lead levels in lactating women: a randomized placebo-controlled trial. Effect of antacids on mineral metabolism in persons with healthy kidneys: Doubleblind study using an antacid containing magnesium aluminum silicate hydrate. High-calcium intake abolishes hyperoxaluria and reduces urinary crystallization during a 20-fold normal oxalate load in humans. Effect of short-term high dietary calcium intake on 24-h energy expenditure, fat oxidation, and fecal fat excretion. Calcium supplementation in patients with essential hypertension assessment by office, home and ambulatory blood pressure. Double-blind, randomized trial of a synthetic triacylglycerol in formula-fed term infants: effects on stool biochemistry, stool characteristics, and bone mineralization. Data do not support recommending dairy products for weight loss [Letter to the Editor]. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. Calcium supplementation and bone mineral density in females from childhood to young adulthood: a randomized controlled trial. Calcium potentiates the effect of estrogen and calcitonin on bone mass: review and analysis. Lactation and bone development implications for the calcium requirements Calcium 167 of infants and lactating mothers. The pathogenesis of age-related osteoporotic fracture: effects of dietary calcium deprivation. Serum calcium and phosphorus associate with the occurrence and severity of angiographically documented coronary heart disease, possibly through correlation with atherogenic (apo)lipoproteins.

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  • What other symptoms do you have?
  • Inflammation
  • Fatigue
  • Clotting problems
  • Alcohol consumption in excess
  • When did you first notice a change in urine color and how long have you had the problem?
  • High blood pressure
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  • Excess body weight (especially around the waist)

The responding cells are in close proximity to buy geodon 40 mg with mastercard the ligand-producing cell and are generally of a different type generic geodon 20mg line. Paracrine stimulation is common in connective tissue repair of healing wounds order geodon 80 mg free shipping, in which a factor produced by one cell type order geodon 80 mg with visa. Paracrine signaling is also necessary for hepatocyte replication during liver regeneration (see below). A special type of paracrine signaling, called juxtacrine, occurs when the signaling molecule. In this type of signaling, receptor-ligand 98 interaction is dependent on and promotes cell-cell adhesion. Several cytokines, such as those associated with the systemic aspects of inflammation discussed in Chapter 2, also act as endocrine agents. Figure 3-8 General patterns of intercellular signaling demonstrating autocrine, paracrine, and endocrine signaling (see text). Shown are receptors with intrinsic tyrosine kinase activity, seven transmembrane G-protein-coupled receptors, and receptors without intrinsic tyrosine kinase activity. The figure also shows important signaling pathways transduced by the activation of these receptors through ligand binding. Binding of the growth factor (ligand) causes receptor dimerization and autophosphorylation of tyrosine residues. Partial hepatectomy removes two thirds of the liver (median and left lateral lobes), and only the right lateral and caudate lobes remain. After 3 weeks, the right lateral and caudate lobes enlarge to reach a mass equivalent to that of the original liver. Note that there is no regrowth of the median and left lateral lobes removed after partial hepatectomy. Mitosis presented as the percentage of hepatocytes undergoing mitosis (right-side scale). Expression of the proto-oncogenes c-fos, c-jun, and c-myc corresponds to the immediate early gene phase of gene expression during liver regeneration. Lower panel, A scan of the liver 1 week after performance of partial hepatectomy to remove the right lobe. Note the great enlargement of the left lobe (outlined in the panel) without regrowth of the right lobe (Courtesy of R. Norepinephrine, insulin, thyroid hormone, and growth hormone act as adjuvants for liver regeneration. The factors that determine the termination of cell replication are not known but are likely to involve cell cycle inhibitors, shut-off of growth factor production, and decreased metabolic demand on the liver. Morphologically, elastic fibers consist of a central core made of elastin, surrounded by a peripheral network of microfibrils. Substantial amounts of elastin are found in the walls of large blood vessels, such as the aorta, and in the uterus, skin, and ligaments. The microfibrils serve as scaffolding for deposition of elastin and the [86] assembly of elastic fibers. Inherited defects in fibrillin result in formation of abnormal elastic fibers in a fairly common familial disorder, Marfan syndrome, manifested by changes in the cardiovascular system (aortic dissection) and the skeleton (Chapter 5). These proteins are located in the cell membrane, where they function as receptors, or they are stored in the cytoplasm. The integrins have [87] [88] broader ligand specificity and are responsible for many events involving cell adhesion. Fibronectin is a larger protein that binds to many molecules, such as collagen, fibrin, proteoglycans, and cell-surface receptors. The plasma form binds to fibrin, forming the provisional blood clot that 105 Figure 3-15 Steps in collagen synthesis (see text). This can initiate the production of intracellular messengers or can directly mediate nuclear signals. Cell-surface receptors for growth factors may activate signal transduction pathways that overlap with those activated by integrins. Collectively, these are integrated by the cell to yield various responses, including changes in cell growth, locomotion, and differentiation. This is a trichrome stain that stains collagen blue; minimal mature collagen can be seen at this point. B, Trichrome stain of mature scar, showing dense collagen, with only scattered vascular channels. In angiogenesis from pre-existing vessels, endothelial cells from these vessels become motile and proliferate to form capillary sprouts (lower panel). Regardless of the initiating mechanism, vessel maturation (stabilization) involves the recruitment of pericytes and smooth muscle cells to form the periendothelial layer. A telling proof of the importance of these molecules is the existence of a genetic disorder caused by mutations in Tie2 [103] that is characterized by venous malformations. Proteinases can also release inhibitors such as endostatin, a small fragment of collagen that inhibits endothelial proliferation and [106] angiogenesis. Fibroblast Migration and Proliferation Granulation tissue contains numerous newly formed blood vessels. The sources of these growth factors and cytokines include platelets, a variety of inflammatory cells (notably macrophages), and activated endothelium. Macrophages are important cellular constituents of granulation tissue, clearing extracellular debris, fibrin, and other [108] foreign material at the site of repair. If the appropriate chemotactic stimuli are present, mast cells, eosinophils, and lymphocytes may also accumulate. Each of these cells can contribute directly or indirectly to fibroblast migration and proliferation. Fibrillar collagens form a major portion of the connective tissue in repair sites and are important for the development of strength in healing wounds.

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