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In fact calan 240mg fast delivery, the incidence of bowel disease generic calan 240 mg amex, there is some evidence that repetitive dy- hip fracture is reduced nearly 50% when older adults are namic exercise may reduce the risk for this illness purchase 120mg calan mastercard. However trusted 240 mg calan, even when Although exercise is often recommended as treatment for activity is optimal, it is apparent that genetic contribu- postsurgical ileus, uncomplicated constipation, or irritable tions to bone mass are greater than exercise. However, of the population variance is genetic, and 25% is due to chronic dynamic exercise does substantially decrease the different levels of activity. In addition, the predominant risk for colon cancer, possibly via increases in food and fiber contribution of estrogen to homeostasis of bone in young intake, with consequent acceleration of colonic transit. These exceptionally active women are typically very thin and exhibit low levels of Chronic Exercise Increases Appetite Slightly circulating estrogens, low trabecular bone mass, and a Less Than Caloric Expenditure in Obese People high fracture risk (Fig. Exercise also plays a role in the treatment of os- Obesity is common in sedentary societies. Controlled clinical trials find that appropriate, creases the risk for hypertension, heart disease, and dia- regular exercise decreases joint pain and degree of disabil- betes and is characterized, at a descriptive level, as an ex- ity, although it fails to influence the requirement for anti- cess of caloric intake over energy expenditure. In rheumatoid arthritis, ex- exercise enhances energy expenditure, increasing physical ercise also increases muscle strength and functional activity is a mainstay of treatment for obesity. For exceptionally active people, exercise expendi- in either rheumatoid arthritis or osteoarthritis is not known. At high levels of activity, appetite and food intake match caloric expenditure (Fig. The biologi- GASTROINTESTINAL, METABOLIC, cal factors that allow this precise balance have never been AND ENDOCRINE RESPONSES defined. In obese people, modest increases in physical ac- The effects of exercise on gastrointestinal (GI) function re- tivity increase energy expenditure more than food intake, main poorly understood. However, chronic physical activ- so progressive weight loss can be instituted if exercise can ity plays a major role in the control of obesity and type 2 be regularized (see Fig. Frank hypoglycemia rarely oc- curs in healthy people during even the most prolonged or in- Lean tense physical activity. When it does, it is usually in association with the depletion of muscle and hepatic stores 2,500 and a failure to supplement carbohydrate orally. Exercise suppresses insulin secretion by increasing sym- pathetic tone at the pancreatic islets. Despite acutely Obese (initially falling levels of circulating insulin, both non-insulin-de- stable weight) pendent and insulin-dependent muscle glucose uptake in- crease during exercise. Exercise recruits glucose trans- 2,000 porters from their intracellular storage sites to the plasma membrane of active skeletal muscle cells. Because exercise increases insulin sensitivity, patients with type 1 diabetes (insulin-dependent) require less insulin when activity in- creases. However, this positive result can be treacherous 1,500 because exercise can accelerate hypoglycemia and increase the risk of insulin coma in these individuals. Chronic exer- 1,500 2,000 2,500 3,000 cise, through its reduction of insulin requirements, up-reg- Caloric expenditure (kcal/day) ulates insulin receptors. This effect appears to be due less to training than simply to a repeated acute stimulus; the effect FIGURE 30. For lean individuals, intake matches expenditure over a wide and can be lost as quickly. For obese individuals during periods of weight gain or peri- people show strikingly greater insulin sensitivity than do ods of stable weight, increases in expenditure are not matched by their sedentary counterparts (Fig. Exercise has other, subtler, positive effects on the energy balance equation as well. A single exercise episode may in- 100 crease basal energy expenditure for several hours and may increase the thermal effect of feeding. The greatest practi- cal problem remains compliance with even the most precise 50 After repeated exercise “prescription”; patient dropout rates from even 100 g glucose daily exercise short-term programs typically exceed 50%. For very short-term exercise, stored phosphagens (ATP and creatine 140 phosphate) are sufficient for crossbridge interaction between actin and myosin; even maximal efforts lasting 5 to 10 seconds 105 require little or no glycolytic or oxidative energy production. When work to exhaustion is paced to be somewhat longer in duration, glycolysis is driven (particularly in fast glycolytic 70 After repeated fibers) by high intramuscular ADP concentrations, and this daily exercise form of anaerobic metabolism, with its by-product lactic acid, 35 is the major energy source.
One sub- pressing neurons in response to NMDA receptor activation type cheap calan 240mg with visa, a presynaptic kainate receptor order calan 240mg with mastercard, opens voltage-gated kills adjacent neurons buy generic calan 120mg line. Proposed new treatment strategies promise to enhance Several postsynaptic receptor subtypes depolarize the survival of neurons in brain ischemic/hypoxic disorders generic calan 120mg with amex. Other strategies include drugs that de- lular GLU, leading to the further release of GLU, and of in- stroy oxygen-free radicals, calcium ion channel blocking creased calcium entry, leading to the further mobilization agents, and NOS antagonists. The GABA enters the Krebs cycle in both neu- ronal and glial mitochondria and is converted to succinic semialdehyde by the enzyme GABA-transaminase. This en- zyme is also coupled to the conversion of -ketoglutarate to glutamate. As in the recycling of glutamate, glutamine is transported into the presynaptic terminal, where it is converted into glutamate. Neurally active peptides are stored in synaptic vesicles and undergo exocytotic release in com- mon with other neurotransmitters. Many times, vesicles containing neuropeptides are colocalized with vesicles containing another transmitter in the same neuron, and both can be shown to be released during nerve stimulation. In these colocalization instances, release of the peptide- containing vesicles generally occurs at higher stimulation frequencies than release of the vesicles containing nonpep- tide neurotransmitters. The list of candidate peptide transmitters continues to grow; it includes well-known gastrointestinal hormones, pi- tuitary hormones, and hypothalamic-releasing factors. As a class, the neuropeptides fall into several families of pep- tides, based on their origins, homologies in amino acid composition, and similarities in the response they elicit at GABAergic neurotransmission. Upon release into the synaptic cleft, GABA can bind to GABA receptors (GABAA, GABAB). The conversion of GABA to succinic semialdehyde is coupled to the conversion of -ketoglutarate to glutamate by Neuropeptide Amino Acid Composition the enzyme GABA-transaminase. In glia, glutamate is converted into glutamine, which is transported back into the presynaptic Opioids terminal for synthesis into GABA. Met-enkephalin Tyr-Gly-Gly-Phe-Met-OH Leu-enkephalin Tyr-Gly-Gly-Phe-Leu-OH Dynorphin Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile -Endorphin Tyr-Gly-Gly-Phe-Met-Thr-Glu-Lys-Ser- ization of the postsynaptic membrane. GABAergic neurons Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe- Lys-Asn-Ala-Ile-Val-Lys-Asn-His-Lys- represent the major inhibitory neurons of the CNS, whereas Gly-Gln-OH glycinergic neurons are found in limited numbers, restricted Gastrointestinal peptides only to the spinal cord and brainstem. Glycinergic transmis- Cholecystokinin Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe- sion has not been as well characterized as transmission using octapeptide (CCK-8) NH2 GABA; therefore, only GABA will be discussed here. Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe- The synthesis of GABA in neurons is by decarboxylation Gly-Leu-Met of GLU by the enzyme glutamic acid decarboxylase, a Vasoactive intestinal His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn- marker of GABAergic neurons. GABA is stored in vesicles peptide Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala- and released by exocytosis, leading to the stimulation of Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu- postsynaptic receptors (Fig. Asn-NH2 Hypothalamic and There are two types of GABA receptors: GABAA and pituitary peptides GABAB. The GABAA receptor is a ligand-gated Cl chan- Thyrotropin-releasing Pyro-Glu-His-Pro-NH2 nel, and its activation produces IPSPs by increasing the in- hormone (TRH) flux of Cl ions. The increase in Cl conductance is facili- Somatostatin Ala-Gly-Cys-Asn-Phe-Phe-Trp-Lys- tated by benzodiazepines, drugs that are widely used to Thr-Phe-Thr-Ser-Cys treat anxiety. Activation of the GABAB receptor also pro- Luteinizing hormone- Pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu- releasing hormone Arg-Pro-Gly duces IPSPs, but the IPSP results from an increase in K conductance via the activation of a G protein. Drugs that in- (LHRH) hibit GABA transmission cause seizures, indicating a major Vasopressin Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg- role for inhibitory mechanisms in normal brain function. Gly-NH2 Oxytocin Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu- GABA is removed from the synaptic cleft by transport Gly-NH2 into the presynaptic terminal and glial cells (astrocytes) CHAPTER 3 The Action Potential, Synaptic Transmission, and Maintenance of Nerve Function 57 Peptides are synthesized as large prepropeptides in the Application of somatostatin to target neurons inhibits their endoplasmic reticulum and are packaged into vesicles that electrical activity, but the ionic mechanisms mediating this reach the axon terminal by axoplasmic transport. Recently a novel and by other enzymes that alter the peptides by hydroxy- type of neurotransmission has been identified. The products re- membrane-soluble molecules diffuse through neuronal leased by exocytosis include a neurally active peptide frag- membranes and activate “postsynaptic” cells via second ment, as well as many unidentified peptides and enzymes messenger pathways. Because NOS ac- released peptides appears to be diffusion, a slow process 2 tivity is exquisitely regulated by Ca , the release of NO is that ensures a longer-lasting action of the peptide in the calcium-dependent even though it is not packaged into synapse and in the extracellular fluid surrounding it. There are no mechanisms for the recycling of peptide was also identified as the endothelial-derived relaxing fac- transmitters at the axon terminal, unlike more classical tor in blood vessels before it was known to be a neuro- transmitters, for which the mechanisms for recycling, in- transmitter.
Whereas order calan 240mg, originally discount calan 240 mg online, features of XLH is now the most common cause of genetically in- vitamin D deficiency (rickets/osteomalacia) and sec- duced rickets buy calan 120 mg amex. The disease is characterised by phospha- ondary hyperparathyroidism (erosions buy calan 240mg without a prescription, osteosclerosis, turia throughout life, hypophosphatemia, rickets and os- brown cysts) predominated, improvement in management teomalacia. Clinically affected individuals may be short and therapy have resulted in such radiographic features in stature, principally due to defective growth in the legs, being present in a minority of patients. New complications (amyloid depo- and large pharmacological doses of vitamin D (hence the sition, noninfective spondyloarthropathy, osteonecrosis) term “vitamin D-resistant rickets”) may heal the radio- are now seen in long-term hemodialysis and/or renal logical features of rickets, and also increase longitudinal transplantation. The radiological features of XLH are char- imaging techniques, but occasionally other imaging and acteristic. The metaphy- In extreme cases of soft-tissue calcification, there may seal margin tends to be less indistinct than in nutritional be ischemic necrosis of the skin, muscle and subcuta- rickets and the affected metaphysis is not as wide. This condi- Changes are most marked at the knee, wrist, ankle, and tion can occur in patients with advanced renal disease, in proximal femur. Healing can be induced with appropriate those on regular dialysis, and also those with functioning treatment (phosphate supplements, l,25(OH)2D). Although Looser’s zones may heal with appropriate treatment, those that have been pre- sent for many years persist radiographically and are pre- sumably filled with fibrous tissue. Although there is defective mineralization of osteoid in XLH, the bones are commonly and characteristically increased in density, with a coarse and prominent trabec- ular pattern. This is a feature of the disease and is not re- lated to treatment with vitamin D and phosphate supple- ments, as it is present in those who have not received treatment. This bone sclerosis can involve the petrous bone and structures of the inner ear, and may be respon- sible for the hydropic cochlea pattern of deafness that these patients can develop in later life. X-linked hypophosphatemia is characterised by an en- thesopathy, in which there is inflammation in the junc- tional area between bone and tendon insertion that heals by ossification at affected sites. This may result in complete ankylosis of the spine, resembling ankylos- ing spondylitis, and clinically limiting mobility. However, the absence of inflammatory arthritis, with normal sacroiliac joints, serves to differentiate XLH from anky- losing spondylitis. Ossification can occur in the in- terosseous membrane of the forearm and in the leg be- b tween the tibia and the fibula. Separate, small ossicles may be present around the joints of the hands and ossifi- cation of tendon insertions in the hands cause “whisker- ing” of bone margins. A rare, but recognized, complication of XLH is spinal cord compression caused by a combination of ossifica- tion of the ligamentum flavum, thickening of the laminae, and hyperostosis around the apophyseal joints. Ossification of the ligamentum flavum causes the most significant narrowing of the spinal canal and occurs most commonly in the thoracic spine, generally involving two or three adjacent segments. Affected patients may be asymptomatic, even when there is severe spinal-canal narrowing. It is important to be aware of this tubulated, with ricketic changes at the metaphyses. The extent of in- bones with a coarse trabeular pattern traspinal ossification cannot be predicted by the degree of paraspinal or extra skeletal ossification at other sites. Computed tomography is a useful imaging technique for demonstrating the extent of intraspinal ossification. Extraskeletal ossification is uncommon in patients The bones are often short and under-tubulated (shaft with XLH before the age of 40 years. The extent to which wide in relation to bone length) with bowing of the femur radiographic abnormalities of rickets and osteomalacia, and tibia, which may be marked. Following skeletal mat- osteosclerosis, abnormalities of bone modeling and ex- uration, Looser’s zones appear and persist in patients with traskeletal ossification are present varies between affect- XLH. In some, all the features are present those in nutritional osteomalacia and often affect the out- and are thus diagnostic of the condition. In others, there er cortex of the bowed femur, although they also occur may only be minor abnormalities and the diagnosis of along the medial cortex of the shaft.
Plasma osmolality is low- lated from the amount of solute present (7 calan 240 mg mastercard,980 3 quality 80 mg calan,990 ered discount 80 mg calan with mastercard, and water moves into the cell compartment along the 1 buy calan 80 mg amex,580 mOsm) divided by the final volume (28 14 1 L); osmotic gradient. The entry of water into the cells causes it is equal to 315 mOsm/kg H2O. The final volume of the them to swell, and intracellular osmolality falls until a new ICF equals 7,980 mOsm divided by 315 mOsm/kg H2O or equilibrium (solid lines) is achieved. The dashed lines indicate 0 0 the normal condition; the solid 0 28 44 0 25. Arginine Vasopressin Is Critical in the Control of Renal Water Output and Plasma Osmolality WATER BALANCE Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is a nonapeptide synthesized in the body People normally stay in a stable water balance; that is, wa- of nerve cells located in the supraoptic and paraventricular ter input and output are equal. The hormone travels by axoplasmic flow down the excretion of water by the kidneys, and habit and thirst. When the cells are brought to 2 threshold, they rapidly fire action potentials, Ca enters A balance chart for water for an average 70-kg man is pre- the nerve terminals, the AVP-containing vesicles release sented in Table 24. The person is in a stable balance (or their contents into the interstitial fluid surrounding the steady state) because the total input and total output of wa- nerve terminals, and AVP diffuses into nearby capillaries. On the input The hormone is carried by the blood stream to its target tis- side, water is found in the beverages we drink and in the sue, the collecting ducts of the kidneys, where it increases foods we eat. Solid foods, which consist of animal or veg- water reabsorption (see Chapter 23). Wa- ter of oxidation is produced during metabolism; for exam- Factors Affecting AVP Release. Many factors influence ple, when 1 mol of glucose is oxidized, 6 mol of water are the release of AVP, including pain, trauma, emotional produced. In a hospital setting, the input of water as a result stress, nausea, fainting, most anesthetics, nicotine, mor- of intravenous infusions would also need to be considered. These conditions or agents pro- On the output side, losses of water occur via the skin, lungs, duce a decline in urine output and more concentrated urine. We always lose water by Ethanol and atrial natriuretic peptide inhibit AVP release, simple evaporation from the skin and lungs; this is called in- leading to the excretion of a large volume of dilute urine. The main factor controlling AVP release under ordinary Appreciable water loss from the skin, in the form of circumstances is a change in plasma osmolality. When plasma osmolality rises, neu- Sweat, which is a hypoosmotic fluid, contains NaCl; exces- rons called osmoreceptor cells, located in the anterior hy- sive sweating can lead to significant losses of salt. This stimulates the nearby neurons in trointestinal losses of water are normally small (see Table 24. The kidneys are the sites of adjustment of water output Supraoptic nucleus from the body. Renal water excretion changes to maintain Posterior Anterior hypothalamus hypothalamus balance. If there is a water deficiency, the kidneys diminish the excretion of water and urine output falls. If there is wa- Hypothalamic neurohypophyseal ter excess, the kidneys increase water excretion and urine Optic tract flow to remove the extra water. The renal excretion of wa- chiasm Hypophyseal ter is controlled by arginine vasopressin. Chil- Median eminence Mammillary dren have, for their body weight, a larger body surface area body Pars tuberalis Pars Central Daily Water Balance in an Average intermedia cavity TABLE 24. AVP is syn- Water in beverages 1,000 mL Skin and lungs 900 mL thesized primarily in the supraoptic nucleus and Water in food 1,200 mL Gastrointestinal 100 mL to a lesser extent in the paraventricular nuclei in the anterior hypo- Water of oxidation 300 mL tract (feces) thalamus. It is then transported down the hypothalamic neurohy- Kidneys (urine) 1,500 mL pophyseal tract and stored in vesicles in the median eminence and Total 2,500 mL Total 2,500 mL posterior pituitary, where it can be released into the blood. CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 409 Thirst volume. An increased blood volume inhibits AVP release, whereas a decreased blood volume (hypovolemia) stimu- lates AVP release. Intuitively, this makes sense, since with 12 excess volume, a low plasma AVP level would promote the excretion of water by the kidneys. With hypovolemia, a high plasma AVP level would promote conservation of wa- ter by the kidneys.