By M. Lester. San Jose State University.

PREG and DHEA are known as 3b-hydroxy-D5-steroids and are also found in peripheral glands as intermediaries between cholesterol and active steroids such as PROG and testosterone malegra dxt plus 160 mg low price. It seems that cholesterol may be the starting point of neurosteroid synthesis in the brain discount malegra dxt plus 160 mg otc. Cytochrome P450scc, the specific hydroxylase needed for cleavage of the cholesterol side-chain to give PREG, has been found widely in white matter and in myelinating oligodendrocytes, but not in neurons. Enzymes are present for the conversion of PREG to PROG and both are reduced in glia and neurons. This does not occur with DHEA and very little is known of either its synthesis or metabolism. Neurosteroids are widely and fairly evenly distributed in the brain with few note- worthy localisations but the concentration of the conjugated forms (sulphated and reduced) of PREG and DHEA can exceed that of the parent compounds. By contrast, although the concentration of progesterone rises some twelvefold in plasma and eight times in hippocampus of animals and humans as they pass from the follicular to luteal phase of the ovarian cycle, it increases by 300 in the cortex, suggesting a considerable variation in the ability of different brain regions to concentrate it. In considering the neurosteroids as possible NTs it should be remembered that neither specific steroid neurons nor an evoked neuronal release of steroids have been demonstrated. There are, however, receptors for them in the CNS and no shortage of actions attributed to them. Given clinically in the therapy of inflammatory conditions, the glucocorticoids are considered to produce euphoria, followed after prolonged or higher dosing by depression and, of course, when we are stressed the corticocosteroids pumped out by the adrenal cortex easily enter the brain and may initiate some of the behavioural response. In women the premenstrual syn- drome (irritability, depression and anxiety) is thought to be associated in some way with progesterone since not only does its concentration rise then fall during that time but in post-menopausal women the use of sequential oestrogen and progestogen hormone replacement therapy (HRT) shows that similar mood changes accompany only the addition of progestogen. More specifically, in women with epilepsy while the incidence of seizures decreases when plasma progesterone is high, it increases during the immediate premenstrual period as progesterone levels fall, rather as with withdrawing 274 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 13. Pregnenolone (PREG) (1) is synthesised from cholesterol and is then either metabolised, reduced to 20a dihydropregnenolone (7) or sulphated (6), or converted by 3b-hydroxysteroid dehydrogenase to progesterone (PROG) (2) or to dehydroepiandrosterone (DHEA) (3). The former (PROG) can then be reduced to allopregnanolone (3a5aThPROG) (4) and DHEA sulphated to dehydroepiandrosterone sulphate (5). The structures of alphaxalone, a steroid anaesthetic and tetrahydrodeoxy- corticosterone, which is formed in the brain from deoxycorticosterone of peripheral origin, are also shown OTHER TRANSMITTERS AND MEDIATORS 275 an antiepileptic drug.

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This can result in raised in- nate in the skeleton and occur in neurofibromatosis generic malegra dxt plus 160mg on-line. The tracranial pressure buy discount malegra dxt plus 160 mg on line, bulging of the anterior fontanelle, biochemical abnormalities will be cured, and the rickets proptosis and papilloedema. Wormian (intersutural) and osteomalacia will heal, with surgical removal of the bones may be identified. Often the tumors are extremely small and In adult onset of the disease, the presenting clinical elude detection for many years. It is important that the af- feature is usually a fracture, occurring after relatively fected patient is vigilant about self examination and re- minor trauma, particularly in the metatarsals. More so- healing is slow or absent with little callus formation, but phisticated imaging (CT, MRI) may be helpful in localiz- will occur following intramedullary nailing. Chondrocalcinosis and extraskeletal os- sification of tendinous and ligamentous insertions to Other Causes of Rickets and Osteomalacia bone may occur. The diagnosis is confirmed by the Not Related to Vitamin D Deficiency or biochemical changes of reduced alkaline phosphatase Hypophosphatemia and raised blood and urine phosphoethanolamine. As there is no effective treatment for hypophosphatasia, se- Hypophosphatasia verely affected patients can prove a challenge to ortho- pedic management. Hypophosphatasia is a rare disorder that was first de- scribed by Rathbun, in 1948. It is generally trans- mitted as an autosomal recessive trait, but autosomal Osteoporosis dominant inheritance has also been reported. The disease is characterized by reduced levels of serum alkaline Introduction phosphatase (both bone and liver isoenzymes), with raised levels of phosphoethanolamine in the blood and Osteoporosis is the most common metabolic bone dis- the urine. Serum calcium and phosphorus levels are not ease, and affects one in three postmenopausal women and reduced; in perinatal and infantile disease there can be one in twelve men in their lifetime. The disease is char- hypercalciuria and hypercalcemia attributed to the im- acterized by reduced bone mass and deterioration in tra- balance between calcium absorption from the gut and becular structure. The clinical consequence is low-trauma defective growth and mineralization of the skeleton. The severity of the condition varies greatly, being fractures cause significant mortality.

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