By D. Dimitar. Western Maryland College.

It has even been shown that mRNA for tryptophan hydroxylase shows a daily rhythm in cultured eye-cups maintained in the dark discount lotrisone 10mg with visa. Again purchase 10mg lotrisone visa, not a great deal is known about the underlying control mechanisms but the synthesis of tryptophan hydroxylase purchase lotrisone 10mg otc, at least cheap 10mg lotrisone visa, is increased by exposure of 5-HT neurons in vivo to the growth factor purchase lotrisone 10 mg with visa, brain-derived neurotrophic factor (`BDNF; Siuciak et al. Steroid hormones also seem to modulate tryptophan hydroxylase gene transcription but research in this area is confounded by the variation in this effect across different tissues and different hormones, with both increases and decreases being reported. In fact, three such proteins have now been characterised, but only one of them, 45 kDa SBP, appears to be secreted into the synapse along with 5-HT. Whether they serve any role other than forming an osmotically inert storage matrix for 5-HT is unknown. Functional disruption of this transporter, either through competitive inhibition (e. RELEASE Impulse-evoked release of 5-HT, like that of noradrenaline, is subject to fine control by a system of autoreceptors, in particular 5-HT1A receptors on the cell bodies of neurons in the Raphe nuclei and 5-HT1B/1D receptors on their terminals. Because these are all Gi/o protein-coupled receptors, their activation reduces the synthesis of cAMP so that 5-HT1A agonists (or 5-HT itself) decrease neuronal excitability and the firing of Raphe neurons whereas activation of 5-HT1B/1D receptors seems to disrupt the molecular cascade that links the receptor with transmitter release (see Chapter 4). There is some evidence that receptors for other neurotransmitters on 5-HT nerve terminals also modify release of 5-HT. These include nicotinic receptors (increase release from striatal synaptosomes), a2A-adrenoceptors (depress cortical release) and H3-receptors (cortical depression). This compound inhibits 5-HT uptake but its metabolite, d-norfenfluramine, increases 5-HT release as do high doses of d-amphetamine. It is important to realise that this 5-HT release is independent of nerve impulses and the action of such compounds rests on their effects on the 5-HT transporters on the storage vesicles and terminal membrane. Once these drugs have been taken up into 5-HT neurons by the transporter, they cause 5-HT to leak out of its storage vesicles and, ultimately, to be extruded from the neuron by retrotransport (see below and Chapter 4 for further details). Until recently, d-fenfluramine was used to control appetite, in preference to d-amphetamine, because it has a lower affinity for the catecholamine transporter and so its uptake into noradrenergic and dopaminergic neurons is much less than that of amphetamine. This is thought to explain why, at anorectic doses, this compound lacks the psychotropic effects and dependence-liability that are real problems with d-amphetamine. Unfortunately, despite this therapeutic advantage, this compound has had to be withdrawn from the clinic because of worries that it might cause primary pulmonary hypertension, valvular heart disease and even long-term neuropathy. INACTIVATION As with other monoamines, the actions of 5-HT are terminated by its reuptake from the synapse by another member of the family of Na‡/Cl7-dependent transporters. The 5-HT transporter has many features in common with its catecholamine equivalent (described fully in Chapter 8; see Fig. However, the cloned 5-HT transporter has a Km for 5-HT of about 450 nM whereas its Ki for both noradrenaline and dopamine is some ten thousand-fold greater (Povlock and Amara 1997) which means that it is relatively selective for uptake 5-HYDROXYTRYPTAMINE 195 of 5-HT. The uptake process itself requires the inward co-transport of one Na‡ ion and one Cl7 ion while K‡ (or H‡) is carried in the opposite direction. The energy required to maintain the ionic gradients that drive this process is provided by a Na‡/K‡-dependent ATPase. As might be expected, mRNA for the 5-HT transporter is found in high concentrations in the Raphe nuclei but it is also found in other brain regions. Whether this means that non-5-HT neurons can synthesise this protein is unknown but there is some evidence that it is synthesised in astrocytes, at least. One complication is that there are multiple forms of mRNA for the 5-HT transporter, but there is, as yet, no evidence for transporter subtypes in the CNS. However, it must also be remembered that 5-HT transporters are found in the peripheral tissues, notably platelets, mast cells, the placental brush-border and adrenal chromaffin cells and it is possible that these are not all identical. Inhibitors of 5-HT uptake include the tricyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs, which are discussed in detail in Chapter 20) as well as compounds like cocaine and d-amphetamine. Because cocaine is not transported into the neuron it is thought to bind to a site on the transporter protein. This has a negative allosteric effect on the protein and prevents binding of 5-HT to its domain. It has even been suggested that there could be an endogenous ligand for this site which regulates 5-HT uptake. By contrast, d-amphetamine is transported into neurons and so acts as a competitive inhibitor of 5-HT reuptake. Other inhibitors that are transported into the neuron, and which are thought to bind to the same site, include p-chloroamphetamine, MDMA and fenfluramine. Of course, all these transporter inhibitors release 5-HT (see above) but exactly how they do this is uncertain. One suggestion is that, because they can also penetrate the cell membrane directly, they recycle continuously through their active transport into the cell and passive outward diffusion.

At the level of the flexor muscles of the forearm buy 10mg lotrisone amex, namely lotrisone 10 mg with visa, the wrist buy 10mg lotrisone visa, there is normally an anastomosis round pronator muscle (A3) buy discount lotrisone 10 mg, the radial with the ulnar nerve generic lotrisone 10mg visa. As to the hand, the the anterior interosseous nerve of the forearm thumb, index finger and middle finger can no (AC8) branches off and runs along the inter- longer be flexed at the end and middle phalanges, osseous membrane to the quadrate prona- resulting in a characteristic feature of median pa- tor muscle (A9). On passing long flexor muscle of the thumb (A10) and the carpal tunnel, the nerve can be injured by pressure in older persons (carpal tunnel syn- to the radial part of the deep flexor muscle drome). Autonomic sensory palmar branch of the median nerve zone (dark blue) and maximum zone (light (A–C11) branches off to the skin of the ball blue). After passing through the carpal tunnel, the median nerve divides into three branches: the common palmar digital nerves I–III (A–C12), each of which bifurcates at the level of the metacarpophalangeal joints into two proper palmar digital nerves (A–C13). From the first common palmar digital nerve, a branch extends to the thenar eminence (short abductor muscle of thumb [A14], su- Kahle, Color Atlas of Human Anatomy, Vol. Brachial Plexus 77 A Muscles supplied by the median nerve (according to Lanz-Wachsmuth) 11 1 13 B Skin supplied by the median nerve C 6 C 7 1 C 8 3 T 1 4 5 8 6 7 10 2 9 8 11 16 14 15 12 17 11 D Paralysis of the median nerve 12 (according to Lanz-Wachsmuth) 13 13 C Sequence of branches Kahle, Color Atlas of Human Anatomy, Vol. Medial Fascicle (A–D) Thedeepbranch(AC9)sinksintothedepthof Ulnar nerve (C8–T1). Initially, the ulnar the palm and curves toward the thenar emi- nerve runs in the upper arm in the medial nence. Itgivesoffbranchesforallmusclesof bicipital sulcus without giving off any the hypothenar eminence (C10) (abductor branches. It crosses the lumbrical muscles III and IV (A15), and the elbow joint on the extensor side in a finally, at the thenar eminence, for the ab- bony groove, the sulcus for the ulnar nerve, ductor muscle of thumb (A16) and the deep at the medial epicondyle of the humerus. The Clinical Note: Injury to the ulnar nerve causes nervethenpassesbetweenthetwoheadsof the formation of a so-called clawhand (D), where the ulnar flexor muscle of the wrist to the the fingers are extended in the metacarpo- phalangeal joints but flexed in the proximal and flexor side of the forearm and runs beneath distal interphalangeal joints. It does not posture of the fingers is caused by paralysis of the pass through the carpal tunnel but extends interosseous muscles and lumbrical muscles, over the flexor retinaculum to the palm of which flex the phalanges in the metacarpo- the hand, where it divides into a superficial phalangeal joints but extend them in the proxi- branch and a deep branch. Failure of the flexor muscles causes the fingers to remain in In the forearm, the nerve gives off branches this posture due to the now predominant exten- (C1) to the ulnar flexor muscle of the wrist sor muscles. Since the little finger and the adduc- (A2) and to the ulnar half of the deep flexor tors of the thumb are paralyzed, thumb and little muscle of the fingers (A3). Autonomic arm and runs to the ulnar side of the back of zone (dark blue) and maximum zone (light the hand where it supplies the skin. Another sensory branch, the palmar branch of the ulnar nerve (BC5), branches off in the distal third of the forearm. It extends to the palm and supplies the skin of the hy- pothenar eminence. The superficial branch runs as common palmar digital nerve IV (BC6) toward the interdigital space between ring finger and little finger and divides into the proper palmar digital nerves (BC7), which supply sensory fibers to the volar aspects of the little finger and the ulnar side of the ring finger and reach to the distal phalanges on the extensor side of both fingers. There is a connection to a branch of the median nerve, called the com- Kahle, Color Atlas of Human Anatomy, Vol. Brachial Plexus 79 A Muscles supplied by the ulnar nerve (according to Lanz-Wachsmuth) 5 4 6 7 B Skin supplied by the ulnar nerve (according to Lanz-Wachsmuth) C 8 T 1 2 3 1 9 11 17 5 4 16 12 13 9 15 D Paralysis of the ulnar nerve 10 (according to Lanz-Wachsmuth) 14 14 6 8 7 C Sequence of branches Kahle, Color Atlas of Human Anatomy, Vol. From the nerve fascicle gives rise to the medial cutaneous trunk extending beneath the deltoid muscle nerve of the arm and the medial cutaneous to the front, numerous branches (D6) to the nerve of the forearm; both are exclusively deltoid muscle (D7) branch off and supply sensory nerves supplying the skin on the its various parts. Clinical Note: As a result of its location on the Medial cutaneous nerve of the arm (C8 – capsule of the shoulder joint, the nerve can be in- T1) (A, B). The nerve approaches the ante- jured by dislocation of the humerus or by rior surface of the upper arm below the axil- humeral neck fracture. Here it ramifies and supplies the the skin area over the deltoid muscle. Auto- its anterior branches and to the extensor nomic zone (dark blue) and maximum zone side of the upper arm with its posterior (light blue). The nerve runs below the fascia on the ulnar side of the forearm and passes in the lower third through the fascia with two branches, the anteriorbranch (AC1) and the ulnar branch (AC2). The anterior branch supplies the medial flexor side of the forearm almost up to the midline, and the ulnar branch supplies the upper region of the medial extensor side almost up to the midline. The area innervated by the medial cutaneous nerve of the forearm extends slightly to the upper arm and to the hand. Posterior Fascicle (D, F) The posterior fascicle gives rise to the axil- lary nerve and the radial nerve. This runs deep in- side the axilla and across the capsule of the shoulder joint around the surgical neck on the back of the humerus. It passes through the lateral axillary gap and extends beneath the deltoid muscle to the anterior margin of the latter.

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Receptors in the liver mediate the rapid uptake ble vitamins cheap lotrisone 10 mg with amex, particularly vitamin B12 generic lotrisone 10 mg without prescription, are also stored in the of chylomicron remnants generic 10 mg lotrisone with mastercard, which are degraded discount lotrisone 10 mg without a prescription, and the liver discount 10 mg lotrisone amex. These stored vitamins are released into the circulation retinyl ester is stored. When the vitamin A level in blood falls, the liver mobi- lizes the vitamin A store by hydrolyzing the retinyl ester The Liver Has a Central Role in (see Fig. The retinol formed is bound with retinol- Regulating Coagulation binding protein (RBP), which is synthesized by the liver before it is secreted into the blood. The amount of RBP se- Liver cells are important both in the production and the creted into the blood is dependent on vitamin A status. Most of the known clot- tamin A deficiency significantly inhibits the release of RBP, ting factors and inhibitors are secreted by hepatocytes, whereas vitamin A loading stimulates its release. In addition, several coagulation Hypervitaminosis A develops when massive quantities and anticoagulation proteins require a vitamin K–depend- of vitamin A are consumed. Since liver is the storage organ ent modification following synthesis, specifically factors II, for vitamin A, hepatotoxicity is often associated with hy- VII, IX, and X and proteins C and S, to make them effective. The continued ingestion of excessive The monocyte-macrophage system of the liver, pre- amounts of vitamin A eventually leads to portal hyperten- dominantly Kupffer cells, is an important system for clear- sion and cirrhosis. Distur- Vitamin D is thought to be stored mainly in skeletal bances in liver perfusion and function result in the muscle and adipose tissue. However, the liver is responsible ineffective clearance of activated coagulation proteins, so for the initial activation of vitamin D by converting vitamin patients with advanced liver failure may be predisposed to D to 25-hydroxy vitamin D , and it synthesizes vitamin D- 3 3 developing disseminated intravascular coagulation. Vitamin K is a fat-soluble vitamin important in the he- patic synthesis of prothrombin. Prothrombin is synthesized Fat-Soluble Vitamins Are Stored in the Liver as a precursor that is converted to the mature prothrombin, Vitamin A comprises a family of compounds related to a reaction that requires the presence of vitamin K retinol. Vitamin K deficiency, therefore, leads to im- tenance of epithelia, and reproduction. The dietary vitamin K requirement is extremely small and is adequately supplied by the average North American diet. Bacteria in the GI tract also provide vitamin genase releases iron from the heme, which then enters the K. This appears to be an important source of vitamin K be- free iron pool and is stored as ferritin or released into the cause prolonged administration of wide-spectrum antibi- bloodstream (bound to apotransferrin). It is un- vitamin K absorption is dependent on normal fat absorp- clear whether the iron from the hemosiderin granules is ex- tion, any prolonged malabsorption of lipid can result in its changeable with the free iron pool. The vitamin K store in the liver is relatively lim- It was long believed that Kupffer cells were the only ited, and therefore, hypoprothrombinemia can develop cells involved in iron storage, but recent studies suggest within a few weeks. Vitamin K deficiency is not uncommon that hepatocytes are the major sites of long-term iron stor- in the Western world. Transferrin binds to receptors on the surface of hepa- K usually provides a cure. The apotransferrin The Liver Is Important in the Storage (not containing iron) is recycled back to the plasma, and and Homeostasis of Iron the released iron enters a labile iron pool. The iron from transferrin is probably the major source of iron for the he- The liver is the major site for the synthesis of several pro- patocytes, but they also derive iron from haptoglobin-he- teins involved in iron transport and metabolism. When hemo- tein transferrin plays a critical role in the transport and globin is released inside the hepatocytes, it is degraded in homeostasis of iron in the blood. Heme is transferrin level is inversely proportional to the iron load of processed in the smooth ER and free iron released enters the body—the higher the concentration of ferritin in the the labile iron pool. A significant portion of the free iron in hepatocyte, the lower the rate of transferrin synthesis. Dur- the cytosol probably combines rapidly with apoferritin to ing iron deficiency, liver synthesis of transferrin is signifi- form ferritin. Like Kupffer cells, hepatocytes may transfer cantly stimulated, enhancing the intestinal absorption of some of the iron in ferritin to hemosiderin. Haptoglobin, a large glycoprotein with a molecular Iron is absolutely essential for survival, but iron overload weight of 100,000, binds free hemoglobin in the blood. The can be extremely toxic, especially to the liver where it can hemoglobin-haptoglobin complex is rapidly removed by cause hemochromatosis, a condition characterized by ex- the liver, conserving iron in the body. The other protein synthesized by the liver that is involved in the hepatocytes in patients with hemochromatosis are defec- transport of free heme in the blood. The spleen is the organ that removes red blood cells that are slightly altered. Kupffer cells of the liver also have the ENDOCRINE FUNCTIONS OF THE LIVER capacity to remove damaged red blood cells, especially those that are moderately damaged (Fig.

Toward the end of inactive water-soluble derivatives suitable for excretion fetal life buy lotrisone 10 mg line, the descent of the testes into the scrotum is pro- by the kidneys generic 10 mg lotrisone with amex. The major products of testosterone me- moted by testosterone and insulin-like hormones from tabolism are two 17-ketosteroids purchase 10 mg lotrisone with mastercard, androsterone and etio- Leydig cells (see Chapter 39) buy lotrisone 10mg online. These discount lotrisone 10mg online, as well as native testosterone, are The onset of puberty is marked by enhanced androgenic activity. Androgens promote the growth of the penis and conjugated in position 3 to form sulfates and glu- scrotum, stimulate the growth and secretory activity of the curonides, which are water-soluble and excreted into the epididymis and accessory glands, and increase the pigmen- urine (see Fig. Enlargement of the testes occurs un- der the influence of the gonadotropins (LH and FSH). Androgens Have Effects on Reproductive Spermatogenesis, which is initiated during puberty, de- and Nonreproductive Tissues pends on adequate amounts of testosterone. Throughout adulthood, androgens are responsible for maintaining the An androgen is a substance that stimulates the growth of structural and functional integrity of all reproductive tis- the male reproductive tract and the development of sec- sues. Castration of adult men results in regression of the re- ondary sex characteristics. Androgens have effects on al- productive tract and involution of the accessory glands. Shortly after treat- gens for cellular proliferation; therefore, physicians at- ment, testicular concentrations of androgens decline be- tempt to totally ablate the secretion of androgens by the cause of the low levels of circulating LH and FSH. Generally, two options for those patients are surgi- expectation is that androgen-dependent cancer cells will cal castration and chemical castration. Lupron]) are usually used in combination with other drugs One option for chemical treatment of these patients is in order to block most effectively androgenic activity. For the use of analogs of GnRH, the hormone that regulates the example, one of the androgen-blocking drugs includes 5 - secretion of LH and FSH. Long-acting GnRH agonists or an- reductase inhibitors that prevent the conversion of testos- tagonists reduce LH and FSH secretion by different mecha- terone to the highly active androgen dihydrotestosterone nisms. In addition, desensitization of the pituitary gonadotrophs to GnRH, antiandrogens, such as flutamide, bind to the androgen leading to a reduction of LH and FSH secretion. GnRH antagonists the treatment requires nonhormonal therapies, including bind to GnRH receptors on the pituitary cells, prevent en- chemotherapy and radiation. Androgens Are Responsible for Secondary Sex drogens have multiple effects on skeletal and cardiac mus- Characteristics and the Masculine Phenotype cle. Because 5 -reductase activity in muscle cells is low, the androgenic action is due to testosterone. Testosterone Androgens effect changes in hair distribution, skin texture, stimulates muscle hypertrophy, increasing muscle mass; pitch of the voice, bone growth, and muscle development. Hair is classified by its sensitivity to androgens into non- Testosterone, in synergy with GH, causes a net increase in sexual (eyebrows and extremities); ambisexual (axilla), muscle protein. Hair follicles metabolize testos- kidneys, adipose tissue, and hematopoietic and immune terone to DHT or androstenedione. The kidneys are larger in males, and some renal the growth of facial, chest, and axillary hair; however, enzymes (e. Normal axillary and pubic hair growth triglyceride concentrations higher in men, compared to in women is also under androgenic control, whereas excess premenopausal women, a fact that may explain the higher androgen production in women causes the excessive prevalence of atherosclerosis in men. In- creased sensitivity of target cells to androgenic action, es- pecially during puberty, is the cause of acne vulgaris in The Brain Is a Target Site for Androgen Action both males and females. Most of those areas also contain ing of the vocal cords are also androgen-dependent. Eu- aromatase and many of the androgenic actions in the brain nuchs maintain the high-pitched voice typical of prepuber- result from the aromatization of androgens to estrogens. The pituitary also has abundant androgen receptors, but no The growth spurt of adolescent males is influenced by a aromatase. The enzyme 5 -reductase is widely distributed complex interplay between androgens, growth hormone in the brain, but its activity is generally higher during the (GH), nutrition, and genetic factors. Sexual dimorphism in the cludes growth of the vertebrae, long bones, and shoulders.

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