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ATTENUATION OF DEGENERATION Even if NT manipulation had provided an effective therapy in AzD it would still be important to stop the progression of degeneration and the disease process itself purchase levitra super active 40mg mastercard erectile dysfunction liver cirrhosis. The activity of b-amyloid might be reduced by: (a) stopping its production by reducing the phosphorylation and proteolysis of APP (b) increasing its breakdown (c) counteracting its toxic effects through plaque formation APP is normally cleaved within the Ab sequence by an unidentified protease order levitra super active 40 mg overnight delivery fda approved erectile dysfunction drugs, so- called a-secretase, so that most of the extracellular APP is released in a soluble form into the extracellular fluid (see Checler 1995). When b-amyloid is formed another protease (b) splits APP so that the complete Ab sequence persists at the extracellular end of the remaining membrane and intracellular APP chain. This is then cleaved by anaother protease (g-secretase) to release the b-amyloid (Fig. Potentiation of a- or blockage of b- and g-secretase could reduce the production of Ab which becomes insoluble and is precipitated (see Hardy 1997). The b-amyloid (Ab4) sequence is partly extracellular and partly in the membrane. NEUROTROPHIC FACTORS Whether or not the production of b-amyloid can be curtailed, it would be desirable to either replace the damaged neurons or encourage the remaining functional ones to ramify further and exhibit more influence. The former, which requires tissue or cell line grafts, is currently not feasible and barely investigated experimentally but there is much interest in the possible use of neurotrophic proteins (neurotrophins) that encourage neuronal growth and differentiation. A number of these have been isolated and identified but the first to be discovered (see Levi-Montalcini 1987), and the most studied, is nerve growth factor (NGF) which, despite its name, is not universally effective on all neurons. In the periphery it is mainly released in tissues containing sympathetic nerves that take it up and transport it retrogradely to the cell body where it acts. In the brain, however, it has more influence on cholinergic than noradrenergic or other neurons so that NGF protein and MRNA expression is highest in cholinergic innervated areas of the brain such as the hippo- campus and cortex while its binding sites (receptors) are mainly in subcortical regions with cholinergic neurons like the nucleus basalis. So it may be assumed that normally the cortically produced NGF is transported back to cholinergic subcortical neurons where it exerts its trophic action. Certainly NGF increases ChAT production when added to cultured cholinergic neurons and its intraventricular infusion in rats and primates prevents the loss of ChAT activity in and degeneration of, cholinergic neurons caused by transection of the septal hippocampal cholinergic pathway, or ibotenic acid injection into the nucleus basalis. Intraventricular NGF has also been shown to improve learning and memory in aged rats and those with lesions to cholinergic pathways. So if NGF is so important for the growth and function of the cholinergic neurons, that appear so vulnerable in AzD, can they be restored and AzD controlled by administering NGF? Before that question can be answered some practical problems have to be overcome, namely how to obtain and administer it. If immune reactions are to be avoided then recombinant human factor should be used and that cannot be produced in large quantities. In any case, it is a large protein that will have to be injected directly into the brain. Even if these problems can be overcome the spread and intensity of any NGF effect has to be restricted so that excessive neuritic growth and inappropriate increases in synaptic connections do not occur. In addition to these problems there is no evidence of reduced NGF in AzD although levels and receptor number are lower in the nucleus basalis. In fact the levels of NGF were found to be increased in the cortex and hippocampus (Scott et al. At least it throws doubt on the value of augmenting NGF as a therapy for AzD. The younger showed no change in memory performance; the older some improvement after one month, which ceased after the infusion was stopped. Both patients had various reversible side-effects such as back pain and weight loss. OTHER DRUG THERAPY In the face of the failure of rational approaches in the treatment of AzD it is perhaps not surprising that there have been many less rational ones. The former, such as hydergine, a mixture of ergot alkaloids, are intended to increase cerebral blood flow and neuronal metabolism despite some reduction in blood pressure, while the latter, like piracetam, are metabolic stimulants that increase cerebral metabolism and ATPproduction. Although there is no evidence that the neuronal degeneration of AzD results, as in cardiovascular ischaemia, from the excitotoxicity of increased intracellular Ca2‡, some calcium channel blockers have been tried in AzD. They have had little effect but surprisingly a pyrrolidone derivative nefiracetam, which opens L-type voltage-sensitive calcium channels (VSCCs) reduces both scopolamine- and b-amyloid-induced impair- ments of learning and memory in rats (Yamada et al. This effect can be overcome by VSCC antagonists, but nefiracetam has not been tried in humans. SUMMARY Clearly there is a long way to go in the treatment of AzD particularly as even the most active of the generally ineffective therapies discussed above have only addressed the early symptoms of memory loss. In such a progressive and debilitating disease that is only a small step. Finding a NT malfunction is obviously a long way from providing an effective treatment, let alone a cure.

Similarly levitra super active 20 mg without prescription erectile dysfunction doctor in atlanta, Ley- the luteal phase buy levitra super active 40mg online erectile dysfunction fun facts, when progesterone is increasing, dig cells would need LH to stimulate the production of graafian follicles are not present. FSH decreases when the influence of FSH, are needed to aromatize andro- progesterone is rising. Androgens and estrogens are known gens under the influence of LH, whereas granulosa to stimulate the closure of the epiphyses at puberty. Theca interna cells do Because eunuchs are castrated, they have no testicular contain cholesterol side-chain cleavage enzyme, source of androgen and estrogen, and the closure of which converts cholesterol to pregnenolone. In eunuchs, long bones con- theca cells do not express aromatase, they cannot con- tinue to grow, resulting in a tall stature. The theca interna has a have a positive effect in maintaining bone; however, rich blood supply. Choice B is incorrect, although eunuchs itary portal system leads to a lack of dopamine and may have elevated circulating LH (as a result of the GnRH reaching the pituitary. The absence of testes delays the closure of tion, the lack of GnRH will lead to reduced secretion the epiphyses, and androgen levels are low in eunuchs of LH and FSH, reduced ovarian function, and even- because of the lack of testes. PRL will have no effect on the ovary or inhibit ovarian follicle development. Disrup- Chapter 38 tion of the hypothalamic-pituitary axis will lead to re- duced follicular development, lack of ovulation, and 1. Although crease, but FSH will not increase because there is no LH may stimulate aromatase in granulosa cells, granu- GnRH reaching the pituitary from the disrupted axis. Estradiol synthe- Excessive ovarian androgen usually occurs in the pres- sis in the graafian follicle is unrelated to progesterone ence of excessive LH secretion or an androgen tumor synthesis in the corpus luteum and does not increase in the ovary. Inhibin is produced by granulosa cells between FSH and progesterone in regulating estradiol and inhibits the secretion of FSH. Granulosa cells do not have the en- can have local ovarian effects, it has profound in- APPENDIX A Answers to Review Questions 735 hibitory effects on FSH secretion. Inhibin has two reaction and pronuclei formation occur after the sperm forms, A and B; the subunits are the same, whereas has entered the ovum. Inhibin binds activin and space after penetration; there is no evidence that this decreases FSH secretion. Estrogen induces the formation of a assists in movement of the sperm through the mass of stringy vaginal secretion that is called spinnbarkeit, granulosa cells for the sperm to get to the surface of the observed in the late follicular phase. However, the cumulus cells do not as- dometrium is under the influence of progesterone; sist in actual penetration of the zona. The production of hCG by tro- Spinnbarkeit is not produced in response to proges- phoblast cells stimulates the corpus luteum to continue terone, androgen, or prolactin. Although The oocyte must have entered a second meiotic divi- PRL levels increase throughout pregnancy, PRL is not sion to reduce the chromosome number of the oocyte responsible for maintenance of the corpus luteum of to a haploid state (n) so that it may fuse with the sperm pregnancy. Prostaglandins are generally luteolytic, (also haploid), producing a 2n zygote. Fertilization causing regression of the corpus luteum, termination of does not occur in the uterus, especially not after the the luteal phase, and return to the next cycle; they do first meiotic division when the chromosome number is not prolong the cycle or postpone it. In fact, pregnancy tends Graafian follicles do not enter the oviduct and are not to preserve oocytes, as ovulation ceases during preg- fertilized. Plasma progesterone levels are high during and the oocyte does not implant. The blastocyst will pregnancy as a result of activation of the corpus luteum implant in the uterus. In addition, extrusion of the po- and placental production of progesterone. Elevated lar body is associated with fertilization, but this event progesterone blocks follicular development and the occurs within the oviduct. Fertilization by more than one sperm tase is associated with increasing the most potent an- is prevented by the cortical reaction. Cortical granules drogen, dihydrotestosterone, and reducing LH containing proteolytic enzymes fuse just beneath the secretion.

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The uncertainty about whether reaction may vary from overdependence disability will be minimal or will progress to overcompensation levitra super active 40 mg cheap impotence at 55, in which they take to severe disability can produce stress and unnecessary risks to test or prove their hardship 20 mg levitra super active amex can you get erectile dysfunction young age. Learning to accept nec- reaction to using a wheelchair, viewing essary assistance from others for basic it instead as a symbol of the inability to needs, such as feeding, personal hygiene, walk. In other instances, even though and bowel and bladder care, requires the disability experienced is minimal, reconstituting views of privacy and self- they may grieve over the lost ability to reliance. Not only are such not only impose permanent loss of func- activities private and mishaps a potential tion, but also involve complex self-con- source of embarrassment, but both may cept and body image changes. Traumatic also be associated with the shame and brain injury, stroke, and spinal cord humiliation experienced in early child- injury provide no time for gradual adjust- hood when control of these most basic ment. Individuals who had been previ- bodily functions was a central issue of ously active are suddenly faced with development. Just as al time for dressing, bathing, and other neurological conditions have a spectrum self-care needs. If wheelchairs are used, of functional consequences, so also the the environment must be made naviga- adjustment of individuals with neurolog- ble. Wheelchairs can provide more free- ical conditions is highly individualized, dom of movement for those with paralysis, and no two individuals with the same dis- for those who have difficulty walking ability will have a reaction that is quite because of problems with coordination, the same. Freedom Lifestyle Issues of movement is limited, however, if there are stairs but no elevator, if bathrooms are The effects of neurological disorders on too small to accommodate a wheelchair, an individual’s lifestyle are varied and or public transportation is unequipped complex. Activities of daily living are of- with lifts or mechanisms for transporting ten altered so that help from family mem- individuals in wheelchairs. Subsequent Individuals with neurological disorders loss of privacy for most intimate details of can usually drive, even with paralysis, if the daily life, such as bathing or other aspects vehicle is equipped with special controls. Even when individuals are able ceptual deficits, however, driving may not to manage their own personal care, the be possible. Although regulations vary from additional time required to carry out most state to state, individuals with epilepsy activities may be considered a liability. When fatigue exacerbates the symp- Although not all neurological conditions toms of a neurological disorder, as in mul- require the use of a wheelchair, most re- tiple sclerosis, or when fatigue is part of quire some consideration of environmen- the symptomatology, as in post-polio tal factors. For example, individuals with syndrome, it may be necessary to space epilepsy may need to avoid environmen- out activities or to arrange for frequent tal conditions such as flashing lights, rest periods during the day. Because times helpful to divide activities that were General Issues in Nervous System Conditions 115 once completed in a short amount of time Although loss or alteration of sexual into a series of smaller tasks, allowing rest function is initially a severe blow to self- periods in between. Generally, needs through a variety of alternate physiologic responses require an intact means. Sexual function may be can develop long-term intimate relation- most disrupted by conditions involving ships that include love, respect, and mu- the spinal cord. Although women with a tually satisfying expression of sexual spinal cord injury are still capable of inter- feelings. The still experience reflex erections but are cost of medical care, rehabilitation, assis- usually incapable of psychologically stim- tive devices, and environmental restruc- ulated erections. The financial may also be a concern after spinal cord adjustments that must be made have a injury. Women with such an injury gen- significant impact on the individual’s gen- erally remain fertile and are capable of eral lifestyle. Social Issues Sexual intercourse may be more diffi- cult in conditions involving spasticity, Many factors associated with disorders such as cerebral palsy or multiple sclero- of the nervous system can affect social sis. A supportive environment, in- and arousal experienced as part of sexual cluding the family, plays an instrumental excitement may make the spasms worse. In other instances, special arrangements Misinterpretation or misperception of the for positioning or other technical assis- individuals’ disability and associated tance may be necessary for sexual inter- functional limitations, however, can act course to occur. Some form of sexual expression is possible Although some functional limitations for almost all individuals with a disabili- associated with neurological conditions ty. Individuals may need to learn new are visible, such as the mobility restric- forms of sexual expression to meet their tions indicated by use of a wheelchair, needs, or in other instances they may others are not so readily recognizable. Those who do not understand instead coddling the individual or hiding the consequences of multiple sclerosis their own displeasure over the individ- may interpret fatigue as laziness or at- ual’s actions.

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