Friday, July 3, 2020
<h1>Essay Topics For Music - Discover the Best Music Writing Tips</h1><p>In the cutting edge universe of music thankfulness, you have to find out about the best of the present patterns, the most sought after procedures, and techniques for becoming acquainted with better about the distinctions and likenesses between music. Music darlings need to decide why they like music, why they aren't constantly ready to bear the cost of new ones, and what sorts of classifications that will truly accommodate their taste.</p><p></p><p>While there is no uncertainty that your insight into music doesn't really originate from formal instruction, it's useful to set aside some effort to think about your experience as an artist. Do you play on a band or sing lead? Assuming this is the case, what were the advantages to you of your previous occupation? What do you wish you had learned or discovered over the span of your excursion into music?</p><p></p ><p>Another interesting point is the amount of one specific style you're alright with. Do you appreciate having the option to easily mix a few distinct styles into one? Did you generally have an inclination for melodic society or for jazz and rock? It's essential to consider what sort of music you appreciate the most just as what kind of music you're genuinely most certain about.</p><p></p><p>Do you like to hear one out melody at once? Would you like to hear a few pieces on the double? There are numerous approaches to appreciate tuning in to music without focusing on a specific style or sort. When asked the amount you tune in to your preferred groups, in the event that they sound great together, and in the event that you feel content with their music, all things considered, most audience members will express that they appreciate tuning in to melodies. Individuals who appreciate tuning in to music for the most part have an inclination for certain styl es.</p><p></p><p>As you experience this procedure of looking into the best music for your interests, you'll likely need to investigate the many paper themes that are accessible to you. Many article points are explicit to a specific type. Forexample, jazz papers may have to do with melodic styles or how to energize your thoughts and connections. This bodes well, on the grounds that the most ideal approach to find out about these styles is to hear them out. In any case, there are additionally many general subjects to dig into.</p><p></p><p>You can likewise expound on how much cash you've spent on music. A few people utilize this as a contention, yet generally, this means that how much cash you've spent on the past. The cash you spend on music may appear to be immaterial, however then again, it very well may be a marker of where you're at in your imaginative profession. Regardless of what direction you take a gander at it, you have to com prehend what you spent so as to make great decisions.</p><p></p><p>In any case, think about composing regarding your enthusiasm for music. This is a brilliant chance to communicate innovatively, and you won't just be increasingly educated about the theme, yet you'll likewise have a feeling of fulfillment realizing that you have, for one time, expounded regarding the matter of your passions.</p>
Thursday, June 11, 2020
S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications - Health Dissertations - Free Essay Example
S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatment of depression? Abstract In this dissertation we consider the issues surrounding the use of SAMe as an antidepressant. There are many different aspects to this consideration. We start by a consideration of exactly what depression is on a clinical basis and examine the psychological and physiological changes that characterise the condition. We then consider and examine the evolution of the current forms of antidepressant medication. We explore the fields of neurochemistry and pathophysiology of depressive states with particular emphasis on the chemistry of the methylation reaction and its relevance to the SAMe compound. Consideration is then given to SAMe specifically as a medication and the evidence that there is to support its apparent beneficial effect in depression. This is then expanded with a review of the chemistry of SAMe and its intera ctions with other biologically active entities. We conclude the exploration with a critical review of the published literature that is relevant to the role of SAMe as an antidepressant agent. Introduction In order to investigate the full extent of the question at the heart of this dissertation we must examine a number of background issues in some detail first. Depression is a complex clinical state. It has been said that there are as many theories about the aetiology and treatments for depression as there are clinicians thinking about the problem. (LeDoux, J. 1996). A brief examination of the literature on the subject tells us that this comment, although clearly intended to be flippant, may not actually be so very far from the truth. Perhaps it is because of the plethora of hypotheses, ideas and theories on the issue that there are also a considerable number of forms of treatment that are commonly employed. It has to be admitted that some are rational and some appear to be completely irrational. In this dissertation we shall examine some of the more rational forms of psychopharmacology in order to understand the place of SAMe in the therapeutic pharmacopoeia. Depression is a commonly occurring illness. It will significantly affect between 10-25% of women and approximately half that number of men during their lifetimes. Approximately 5 million people in the UK will experience significant depression in any given year. (Breggin 1994) If you suffer from an acute or chronic illness you are even more likely to suffer from depressive states with frequencies ranging from 30-50% depending upon the nature and severity of the illness. (Robertson et al 1997) What is depression ? There are many definitions of clinical depression and indeed many different rating scales which purport to try to quantify it. It is important to distinguish between clinical depression and simply feeling down or miserable. Depressive illness typically occurs in episodes al though in some cases it can actually last for many months or even years. (Skolnick, P. 1999). One severe depressive episode is a major independent risk factor for getting further episodes. In other words, having had depression once you are statistically considerably more likely to have another attack. (Post RM. 1992). For our purposes we shall consider a practical overview of the nine classic symptoms that characterise classical depression 1. Depressed mood for most of the day 2. Disturbed appetite or change in weight 3. Disturbed sleep 4. Psychomotor retardation or agitation 5. Loss of interest in previously pleasurable activities; inability to enjoy usual hobbies or activities 6. Fatigue or loss of energy 7. Feelings of worthlessness; excessive and/or inappropriate guilt 8. Difficulty in concentrating or thinking clearly 9. Morbid or suicidal thoughts or actions. (After Zuess 2003) The Diagnostic and Statistical Manual of Mental Disorders (DSM-I V) states that in order to merit a diagnosis of clinical depression you need to demonstrate at least five of these symptoms and that they represent a change in your life. Mood alterations are commonplace in depressive states. The depressed patient will classically feel despair or sadness. Pleasure becomes an alien emotion as they tend to progressively loose interest in activities that they would have previously enjoyed. Mood swings can also occur although they are more commonly found in bipolar states (manic depression). Subjective feelings of tension or irritability are often described as well as just sadness. (Duman et al 1997) In addition to mood changes, depression can also produce changes in the emotional state as well. Feelings of worthlessness and guilt are perhaps the commonest emotions in the clinical spectrum. This is closely followed by both ineptitude and lack of confidence in ones own abilities or capabilities. It is common for depressed people to take action that avoids them having to take responsibility because of an overwhelming fear of failure. (Altar CA 1999) Somatic manifestations of depression are perhaps easier to quantify as they have a qualitative characteristic about them as opposed to the purely subjective. Changes in appetite are commonly found. Generally it is an anorexic change with a decrease in appetite and a loss of interest in food generally. Less frequently, the converse is observed with a voracious increase in appetite (comfort eating) which is normally associated with weight gain. This weight gain can be quite substantial in extreme cases. Sleep disturbances are commonplace. Insomnia and early waking are perhaps the commonest of this type of symptom. This can occur despite severe subjective symptoms of somatic tiredness and fatigue. Some people will find that fatigue is a prominent symptom and may find that this is translated into excessive sleeping and motor retardation generally. Fatigue is actually more diff icult to quantify, but it is commonly experienced by the depressed patient. It can either be an overwhelming tiredness (lack of energy) or perhaps lack of stamina (tiring too easily). Associated with this is often a reduction in libido and, if severe, impotence can also occur. It is not unusual to find sexual avoidance behaviours developing in these circumstances. (Janicak et al 1989) Concentration is commonly impaired. Generally speaking the greater the degree of depression, the greater is the degree of concentration impairment. Thinking and reasoning processes slow down and the attention span is often markedly reduced. Students find they can have an inability to study and if severe, patients report an inability to even sit and watch television. (Bazin et al 1994) Somatic symptoms can occur without the psychological elements of the depression being apparent or obvious. This is a common clinical dilemma. Patients may enter a phase of denial or minimisation where they will not accept that they are actually depressed. They can try to rationalise their physical symptomatology into other disease processes. This can be mistaken for hypochondriasis. (De Vanna et al 1992) If depression is severe (or occasionally part of a symptom complex of another underlying pathology), then psychosis can be found. Delusional states are not uncommon in severe depression. Hallucinations can occur, but they are comparatively unusual. Patients can state that they hear voices telling them that they are worthless or perhaps instructing them to kill themselves. Although this is consistent with a depressive diagnosis, one should note that other illnesses such as schizophrenia must clearly be considered and excluded before a confident diagnosis of depression can be made. The actual basis or specific triggering factors for depression are not yet clearly defined but we do know that a number of different biological factors are relevant. Environmental factors, together with both gen etic and neurobiological elements are all capable of influencing the overall clinical picture. (Kendler KS, 1998). Depression is broadly divided into endogenous and reactive types. In general terms endogenous depression is thought to be influenced the genetic and neurobiological factors whereas reactive depression may well have environmental factors as being relevant. This has considerable implications in our considerations of the possible actions of SAMe. (Gold et al 1988) Pharmacology of depression This is a vast subject and is generally considered to be a sub-speciality in its own right. It has long been recognised that certain substances appear to be able to exert a mood elevating effect. The advent of modern psychopharmacology allowed us to develop an understanding into just how some of these substances work. The drugs and medicines that are in common use today are the result of a process of evolution that, arguably, began with the uses of herbs at the beginning of rec orded history and progressed to the chemically and biologically sophisticated compounds that are in use today. (Peinell and Smith 2003) In order to put the SAMe compounds into their appropriate place in the continuum we need to look at some of the evolutionary developments in the field. Most of the currently used antidepressants work by interfering in some way with the actions of the various neurotransmitters in the brain. Many work by slowing down the biological processes of degradation or destruction of these neurotransmitters. In purely simplistic terms, this results in a greater concentration of the neurotransmitter at the critical synaptic interfaces within the brain. (Levine et al 1998) The first real breakthrough with what could be considered to be a major therapeutic agent for depressive states came with the discovery of the MAOI (Monoamine Oxidse Inhibitors), group of drugs. Three were commonly used in clinical practice isocarboxazid, phemelzine and tranlcypromine . For a while they were used extensively but it became obvious that they had serious drawbacks including some potentially fatal side effects. (Saarelainen et al 2003), Headaches dizziness and tremor were not unusual accompaniments of the drug. They also had the ability to interact with other medications and certain types of food (tyrosine containing foods such as cheese could cause hypertensive crises). Despite these drawbacks, many patients were willing to take them because they indisputably worked. (Skolnick 1999) In time, the MAOis were superseded by the Tricyclic group of drugs. There were four in common use, namely amitriptyline, desipramine, imipramine and nortriptyline. These were generally speaking, marginally more effective than the MAOIs but they were without the worst of the side effects. Despite that, they were still able to cause dry mouth and blurred vision in some people. Constipation and drowsiness were not unusual and they were not commonly used if a person al so had hypertension. The pharmaceutical industry then produced a number of different categories of medication in fairly quick succession. SSRIs (Selective Serotonin Reuptake Inhibitors), SNRIs (Serotonin and norepinephrine reuptake inhibitors) and NDRIs (Norepinephrine and dopamine reuptake inhibitors) all emerged into the market place. (Smith et al 2004) It is probably fair to say that they all had their niches in the therapeutic spectrum but the SSRIs were seen to corner the biggest share of the clinical market with citalopram, escitalopram, fluoxetine, paroxetine and sertraline as examples of the group. Fluoxetine was probably the most widely used and its trade name, Prozac was accepted almost as a household word. The side effect profile of this particular group was certainly less significant than their predecessors, but nausea and headaches were not uncommon. (Stewart et al 2000), The SNRIs fell into disuse largely because of their reputation in raising cholesterol l evels and the NDRIs were found to cause unacceptable agitation in certain groups. There was then an emergence of a group of drugs which not only blocked the mechanisms that removed the trophic neurotransmitters from the synapse they also had an effect which effectively enhanced their action by blocking the action of the inhibitory neurotransmitters at the same time. There are several types of medication in this category, but perhaps the best known is maprotilene. Like most of the other types of effective medication, it is not without side effects. Drowsiness, nausea, dizziness and a dry mouth are common accompanying symptoms of a therapeutic dose of this medication. (Harmer et al 2003) Neurochemistry and pathophysiology of depression So far we have take a brief and admittedly comparatively simplistic tour of the nature and pharmacology of depression. We shall now look at the neurochemistry and pathophysiology of certain relevant aspects of the subject in more detail. In general terms, stress and antidepressants appear to have reciprocal actions on neuronal growth and to some extent, on their activity (see on). This appears to be through the mediation of various neurotrophins and the action of synaptic plasticity mainly in the region of the hippocampus and some other brain structures (Reid et al 2001). Various stresses appear to disturb and disrupt the activity, both of individual neurones and also larger functional groups, or networks of neurones whereas antidepressants appear to antagonise this disruptive ability. (Henke 1990) There is a large body of opinion which agrees with the hypothesis that regulation of synaptic activity is a major key to the pathophysiology of depression and related disorders. (Drevets et al 1997) The discovery of the MAOI group of drugs (above) led researchers to speculate that the monoamine group of neurotransmitters were central to the aetiology of depression. As more research is done it is becoming apparent that this may not actually be the case. It is now considered more likely that the fundamental problems lie further along the metabolic cascade from the monoamine oxidase activity. It is also considered likely that the pathology may well not be just a chemical imbalance, but may well involve other functions of neural tissue such as various cellular changes in physiology, genetic factors and the ability of neuronal network to change their characteristics. (Czyrak et al 1992) Observational studies have suggested that early life experiences, the impact of stress and the presence or absence of social support or interactions all have an influence on the development of a depressive state. (Gould et al 1998).Consideration of the monoamine chemistry clearly does not account for all of these factors although it is clearly acknowledged that it does play an important contributory role. Some recent work relating to the chronic use of different classes of antidepressants (Duman et al 1997), has appeared to show that they all are able to increase the production of the neuroprotective groups of proteins which, amongst other actions, play a central role in the plasticity of neurones. Current thinking is that this may well be a common function of a number of different pathways that the different antidepressants exploit. It is known that increases in monoamine levels in the synaptic region result (by a number of different mechanisms) and are associated with the induction of enzyme systems that control gene expression within the neurone. This can be inferred from the finding of increases in the levels of messenger RNA which codes for the cAMP response element binding protein (CREB). These levels slowly increase with chronicity of administration of antidepressants and this mechanism may well account therefore for the commonly observed slow and progressive onset of action of most of the antidepressant drugs. It is proposed that CREB triggers the production of BDNF (Brain Der ived Neurotrophic Factor). This is significant since other work has shown that stress antagonises the levels of BDNF which is opposed by the actions of the antidepressant drugs. (Smith et al 1995). Further credence is given to this theory with the discovery that placing BDNF directly into the brain of experimental animals appeared to relieve many of the behaviour patterns that are associated with depression (Siuciak et al 1997) Some authors have suggested that depression may represent a particularly subtle form of neural degenerative disorder as it has been shown that the hippocampus becomes progressively atrophic in chronic depressive states. This is particularly significant as BDNF is thought to reverse such findings. (Shah et al 1998). There is associated supporting evidence in the form of a study by Vaidya (et al 1999) which shows that ECT treatment (which was always assumed to be detrimental to the neural structure and physiology) is associated with both increased levels of BDNF and trophic changes in the hippocampal neurones. A paper by Czyrak (et al 1992) looked at the antidepressant activity of SAMe in mice and rats in a way that clearly is not possible in humans. It is not always possible to directly extrapolate findings from animals to humans, but there are some pieces of evidence in this work which strongly implicate SAMe in the pathogenesis of depression. The paper itself is extremely long and complex but the relevant parts to our considerations here are the fact that normal geographical exploratory behaviour in rodents tends to diminish if a depressive state is induced. To some extent, exploratory behaviour is therefore considered a marker for the depressive state. It was found that SAMe tended to increase exploratory activity in mice. This, and other more sophisticated testing of the pharmacological interactions of SAMe showed that it tended to have the same psychopharmacological profile as many of the mainstream antidepressants. Man y of the neurotransmitters and for that matter some neuroactive hormones have been variously implicated in the aetiology of depression (eg thyroid hormones and noradrenaline). (Nemeroff, 1998). Modern research has most consistently found that alterations in the levels of serotonin (5-HT) (Melzter H, 1989), system and the chemicals of the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. (Kathol et al 1989), as the most consistently implicated mechanisms that appear to be associated with the control of the mood stabilising and regulating mechanisms. It is in fact very likely that both these mechanisms are in some way interlinked as part of the regulatory mechanism of mood. We have already referred to the role of stress in the aetiology of depression. We know that the adrenal glucocorticoid hormones subtly interact with the 5-HT system and these are produced in direct response to stress. (Lopez et al 1999) (I). We also know that the glucocorticoids have a number of direct effects on the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. It may be that this is the mechanism by which stress antagonises the changes brought about by SAMe. (Lopez et al 1999) (II) We do not need to consider the effects of the corticoids on the LHPA axis in detail as it is only of peripheral relevance to our considerations here. The important consideration in this regard is that the LHPA axis is intimately connected to the hippocampus. It is this structure that is the intermediate step and connection between the bodys hormonal response to stress and the response of the higher functions of the brain. (Dallman et al 1987). The immediate relevance of all this to the actions of SAMe are that hyperactivity of both the hippocampus and the LHPA axis are both well documented in cases of clinical depression. This has been shown to also be associated with high levels of corticosteroid production (Kalin et al 1987), but one study has shown that in suicide cases who have had profound dep ression the hippocampus has fewer corticosteroid receptor sites than one might normally expect (Lopez et al 1998). One further piece of clinical evidence in the role of the corticosteroids in depression is that patients with Cushings disease have a high incidence of depression. This incidence returns to normal when their hormonal over-activity is treated and returned back to physiological levels. (Murphy 1991) SAMe as a medication SAMe was discovered in Italy in 1952 during research into the chemistry of neurotransmitters. It was not, however, introduced in a useable form for patient benefit until 1974 (as SAMe sulphate-paratoluene-sulphonate). It is for this reason that the majority of the early papers and work on the subject are almost exclusively Italian in origin. (De Vanna et al 1992) SAMe has been used clinically in a number of conditions including cholestasis, osteoarthritis and depression. (Carney et al 1987) Although there is a wealth of literature on the first two elements it is not relevant to our considerations here. We shall therefore restrict this discussion to the spectrum of its use in the field of depression. A number of studies have shown that SAMe has useful activity in depressive illness. Studies that have compared it to placebo have found that it can consistently produce about a 6 point increase on the Hamilton rating scale after about three weeks of optimum treatment. This finding is approximately in line with the results that are found with most of the other clinically effective antidepressant medications. (Cooper et al 1999) (De Vanna et al 1992) Some studies have found that using SAMe in a large dose has produced an unusually rapid onset of beneficial effects (Kagan 1990) One could argue that, because it is a naturally occurring substance, it would not be likely to have a high side-effect profile. Although these two statements do not always follow, it is generally true. A study by Bressa (1994) on the issue showed that it did have a particularly low side-effect profile, particularly when compared to the other antidepressants (Tricyclics). To demonstrate this point further, we can point to the study by Caruso (et al 1987) where there were a greater number of patient withdrawals due to the side effects of the placebo than withdrew because of the SAMe drug. For the record, that particular trial was in its use as an antiarthritic rather than an antidepressant, but the point is made. The two major unwanted clinical effects are nausea and hypomania. The nausea is not a local effect on the gut lining but appears to be a centrally mediated effect and is possibly caused by the same phenomenon of over-stimulation of the neuronal networks which causes the other major clinical manifestation of hypomania. For this reason it is generally not used in cases of bipolar disorder. (De Vanna et al 1992) It is probably not strictly accurate to refer to SAMe as a drug as it is normally found in the cellular matrix. It has been found to be effective in patients who have been unable to tolerate other forms of antidepressants or, for that matter, have had minimal response to them. (Reynolds et al, 1984) Young (1993) produced a particularly interesting review of dietary treatments for depression. A lot of his article is not relevant to our considerations here, but he makes a number of interesting and relevant observations. Low serotonin levels are known to be associated with depression even though low levels on their own do not appear to cause the condition. It appears that it needs to be in combination with a low level of folic acid. We know that low levels of folic acid are also often found in combination with depressive illness and that low levels of folate are often associated with low levels of SAMe. The evidence points to the fact that the low levels of serotonin are more likely to be a result of the low SAMe levels in neural tissue and that this is more likely to be nearer to the root of the main anomaly that causes depression. Pregnancy is known to be associated with low levels of folate and post natal depression is a well recognised clinical entity. Salmaggi (et al 1993) considered the effects of SAMe in the postnatal period. This was a well considered and constructed study. It was a double blind placebo controlled trial over a 30 day period and had an entry cohort of 80 women. The degree of depression was assessed before, during and after the trial on the Hamilton Scale. The results showed a statistically significant improvement in the SAMe group when compared to the placebo group. The authors comment that there were no significant side effects of the medication encountered. Because we know that any beneficial effect that SAMe is likely to have on a patient tends to be seen more quickly than with the other antidepressants, and also, by virtue of what we suspect about its probable mode of action in the hippocampus and elsewhere in the brain, i t seems a logical step for someone to look into the effects of giving SAMe alongside a conventional antidepressants to see if there is either any synergistic effect or possibly a speeding up of the clinical onset of the secondary medication. The study by Berlanga (et al 1992) did exactly that. Unfortunately the trial was not particularly rigorous in its design as although it was double blind, it was not placebo controlled, which would appear to have been the method of choice in this type of investigation. Its other problem as that it only had an entry cohort of 40 patients. Despite these limitations it was indeed shown that depressed patients who took SAMe in conjunction with other antidepressant medication found that the depressive symptoms resolved faster with the SAMe added to their normal treatment regime. There are one or two other less important papers which we shall only mention in passing. Kagan (et al 1990) ran a small trial on 15 inpatients (with very severe depressi on) and found SAMe to be a safe, effective antidepressant with few side effects and a rapid onset of action. This particular trial is notable as it was the first to report the side effect of mania in a patient who didnt have a previous history. Another is the trial by Rosenbaum (et al 1990). This particular trial is notable for the demonstration of the fact that about 20% of other treatment resistant patients experienced benefit with SAMe. Faya (et al 1990) (II) considered the fact that SAMe is thought to exert its effect through its action in increasing dopamine levels in the synaptic cleft. It is known that dopamine inhibits the production of both Thyroid stimulating hormone (TSH) and Prolactin from the pituitary gland. Faya considered measuring the levels of both TSH and Prolactin during treatment with SAMe. His findings constituted something of a surprise insofar as in the men in the trial group had their levels of TSH and Prolactin reduced which is consistent with the hyp othesis that SAMe increases the dopamine levels in the brain. Much to everybodys surprise, this effect was not seen in the female group. The authors do not offer any explanation of this fact. For the record, there is another trial (Thomas et al 1987), which obviously considered the same phenomenon and their trial did not show any sex linked difference in the suppression of the Prolactin levels With regards to efficacy, a trial by Carney (et al 1986) suggests that the beneficial action of SAMe is restricted to endogenous depression and it does not appear to have any action above placebo on reactive depression. As far as we can ascertain, this is the only trial published that has made this suggestion, although from a first principles basis, one can see the biochemical rationale for believing that it might well be the case. On a purely empirical grounds, some authors have recommended (on the basis of scant hard evidence), that SAMes action can be maximised by the addition of B 12, B6 and folic acid. It is known that SAMe is required to convert these agents into their active form as a coenzyme. (Morrison et al, 1996). The same author also recommends the simultaneous adminstration of Trimethylglycine (TMG) which is necessary for the intracellular conversion of methionine into SAMe by the provision of the necessary methyl- groups. Comment has to be made that again, this appears to be a completely empirical (and logical) suggestion, but we cannot find any hard evidence to substantiate its clinical use. Chemistry SAMe is a basic component of cellular biochemistry. It occurs in every living cell and is second in importance only to ATP in both the number variety and significance of the reactions in which it serves as a cofactor. (Stramentinoli 1987). It is central in the chemistry of the transmethylation reactions. In essence its cellular function is to transfer the active methyl group form carrier molecules to a multitude of other molecules. In general terms, this methylation makes inert molecules biologically active. In addition to the transmethylation reactions it also plays a central role in transsulfuration and aminopropylation reactions It is involved in the synthesis of proteins including the nucleic acids, fatty acids, lipids and phospholipids, porphyrins and polysaccharides. In terms of our considerations here, perhaps the most significant reaction type that SAMe is involved in is the generation of the neurotransmitter amines. In this regard it is considered to be the most biologically significant provider of methyl groups within the cell. (Baldessarini 1987). Significantly it is also involved in the pathways to produce a number of other neurologically active compounds such as adrenaline, the neuronutrients acetyl l-carnitine and phosphatidyl choline (Mathews et al 1990) It is also to be found in the metabolic pathways of both serotonin and dopamine. Oral administration has been shown to increase the metabolites of these compounds in the CSF (implying increased turnover). It is thought to exert its antidepressive effect partly through the mechanism of increasing the levels of both dopamine and serotonin as neurotransmitters, but it also appears to have some form of trophic action on some of the neurones in the brain cortex. (Baldessarini 1987) It has been demonstrated that the tissue levels of SAMe tend to diminish with age and blood levels are also found to be low in some cases of clinical depression (Baldessarini 1987) A methyl group (CH3) is a group of three hydrogen atoms bound to one carbon atom. It does not exist in a stable isolated form and is transported between molecules by intermediaries such as SAMe. Methylation is the process by which this group is transferred from the methyl donor molecule to the recipient molecule. In general terms this process is central to the control of many of the intracellular pathways. Giving a methyl group to an enzyme is often the key to a ctivating it, and thereby beginning a synthesis or degradation process elsewhere in the cell. Equally removing the methyl group will render the enzyme inactive and stop that particular pathway. Similar mechanisms are involved in the expression of genes and therefore the production of proteins within the cell. Some specific methylation reactions include the methylation of phenols which detoxify them and thereby aid in their excretion. (Stramentinoli 1987) In the context of this dissertation, methylation is also central to the metabolic chemistry of serotonin (and therefore also melatonin). The activity of both these compounds is effectively regulated by the presence of a methyl group. SAMe is synthesised from methionine, a naturally occurring amino acid. As the name implies (METH-ionine), it contains a methyl group. By utilising the energy supplied by ATP and in the presence of magnesium, it is converted into SAMe. The process is catalysed by the intervention of the enzyme M AT (methionine adenosyl transferase) (Bigger et al 1990) As we have discussed, SAMe is a methyl donor. When it has donated its methyl group to the recipient molecule it becomes homocysteine. The cycle is completed when homocysteine (which is a methyl sink or potential recipient) accepts back a methyl group to become methionine once again. The relevance of this association of SAMe with homocysteine is of great importance, as homocysteine has recently become recognised as a source of major morbidity. High levels of homocysteine are associated with cardiovascular disease, hypertension and a number of degenerative illnesses. It is thought to be associated with a high incidence of spina bifida and a number of other neurologically based birth defects. High levels of homocysteine have been found in some cases of severe depression It is at this point that the significance of the relevance of folate and B12 becomes clear. It is one of the biochemical pathways that can supply methyl groups to homocysteine, thus detoxifying it. There are other potential pathways involving choline and other molecules but it is thought that the B12 and Folate pathways are the most clinically significant. Another way that homocysteine can be remethylated is through the mediation of B6 and magnesium. This allows the homocysteine to be converted back to the clinically safe cysteine. It may well be relevant, but we cannot find any work to support it directly, that methylation is also vital in the removal of many of the heavy trace metals that find their way into the body. This may well be relevant to our considerations here because it is well known that many of the heavy metal group are potent neurotoxins and neuroinhibitors. It is not surprising that such a centrally important molecule as SAMe is affected by a number of other clinically important molecules. B2, B6, B12 and folic acid deficiencies will all impair the ability of SAMe to be produced in sufficient quantities for optim um action. Equally it follows that SAMe is required to convert both folic acid and B12 to their active co-enzyme forms cyanocobalamin and methylcobalamin, both of which are important in maintaining the structural integrity of the myelin sheaths of the peripheral nerves and the membranes of the CNS neurones. We have discussed traumatic experience evidence for SAMe increasing the action of some of the neurotransmitters (specifically Noradrenaline, serotonin and dopamine). It appears to do this by improving or facilitating the binding mechanisms between these entities and the cell receptor sites. (Cohen et al 1989) It also appears to have a direct action on the neural cell membrane. Functionally it is not clear exactly what this action is, but structurally it increases the synthesis of a major structural ingredient of the membrane (phosphatidylcholine). By means of its ability to methylate enzymes, it is able to influence the production of polyamines which are vital in the pro cesses of phosphorylation of proteins within the CNS neurones. This appears to be a mechanism which is central to the mode of action of many of the more conventional categories of antidepressants. Brain tissue is unique amongst the tissues of the body in that it runs at 100% metabolic activity 100% of the time. Mitochondrial function is therefore vital to the integrity and continued proper function of the neurones. SAMe is necessary to maintain mitochondrial activity. It is theoretically possible that there is another pathway by which SAMe can influence depressive symptomatology. (Evans et al 1998) One other strand of evidence comes from the fact that the methylation process is important in the production of many of the anti-oxidants which are now realised to be vital in the protection of neural tissues. Specifically SAMe is vital to the production of glutathione which is a strong antioxidant and normally found in high concentrations in neural tissue. (De La Cruz et al 1992) Following our discussions so far we have to consider the issue of why is the process of methylation so important biologically? We have already examined the processes of pathway control by methylating (or activating) rate limiting enzymes. And we have mentioned the role of DNA and RNA in protein production. The process by which genes are switched on and off is, in part, a process of methylation. There is a genetic component in depression and therefore this becomes a relevant consideration (Janicak et al 1989) The methylation of cytosine is comparatively easily measured in biological samples and as such, it represents a marker for the methylation status of the body. At birth, a child has cytosine methylation rates of between 2-6% (range depends upon the particular type of cell measured). This is a reflection of the level of activity of the genes in the DNA which are currently active. In numerical terms the nuclear portion of the cells DNA would have about 90 million methyl gro ups. (Smith et al 1998). As life progresses, the reduction of the measurable levels of methylated cytosine is a measure of the ageing process. The cellular controls and the ability to access genetic information reduce as the methylation levels drop. Certain cancers seem to develop once the methylation level drops below about 80% of maximal methylation and auto immune diseases also appear to have a correlation with this level. It is postulated that depression might also be a part of this spectrum. For the record degeneration reaches a point which is incompatible with life once about 40% of the methyl groups in cellular DNA are lost Studies relating to SAMe efficacy as an antidepressant. Literature Review As we have commented above. SAMe became available for use on prescription in 1974. Since then a number of trials (of variable quality) have looked at its indices of action. One of the major clinical features of SAMe is the unusual speed of onset of action when it is co mpared to other antidepressants. For reasons that we have explored above, most of the other antidepressants would not be expected to exert any significant beneficial effect until about two or three weeks after beginning the course at a therapeutic dose. Faya (et al 1995) looked at enhancing the speed of onset of action by using SAMe parentally. The trial design was neither blinded nor controlled as it was a simple study of 195 patients receiving the drug by this method. The authors observed that a measurable response was found to the extent that the symptoms remitted between 7 and 15 days. This particular trial is not very satisfactory, not only for the reasons of trial design mentioned above, but also because the authors do not tell us how they measured the degree of resolution of the symptoms. They did however, comment on the fact that even when giving the patients a comparatively large dose (400mg IM) they found no evidence of serious adverse effects. One way to avoid the s hortcomings of small cohorts in a trial is to perform a meta-analysis of a number of trials. Bressa (1994) provided us with the most recent reliable work in this respect. He conducted a meta-analysis of all of the major double blind placebo controlled trials that had been published up to that date. One of the problems that he experienced was that different trials defined their particular endpoint in different ways. For that reason he gives the overall response rate as between 17 and 38% (when compared to placebo results), and the degree of the response is comparable to that of the tricyclic group of antidepressants. Bottiglieri (et al 1994) (I) produced a paper which gave an overview of the currently known activity and significance of SAMe in the neuropsychiatric disorders. It covers much of the same ground that we have already explored above but it is significant in that it refers to evidence that deficiencies of both Vit B12 (cyanocobalamin) and folate have been found to be ass ociated with reductions in the concentrations of SAMe in the CSF. Sadly he does not give any references to where he found this information so we cannot check its credentials. He does, however, draw attention to the fact that it is well known that deficiencies of both cyanocobalamin and folate are associated with a number of other neurological manifestations, namely depression myelopathy, a number of forms of dementia and peripheral neuropathy. He comments on the fact that it is unlikely to be a coincidence that the metabolic pathways of these substances are intimately related to those of SAMe and that SAMe is demonstrated to be of clinical value in depression and some forms of dementia insofar as it can improve their cognitive function. It equally follows that the same statement is true when you consider the fact that treatment with methyl group donors (such as SAMe ) are found to be beneficial in treating the demyelination effects of the inborn errors of metabolism that involve both the folate and C-1 pathways. In contrast to the Faya study mentioned above, the study by Bell (et al 1994) was fastidious in both its design and execution. It was a double blind randomised medication comparison (desipramine) trial with clearly defined entry and exit points. It chose to compare the relationship between plasma levels of SAMe and the clinical response that was found in patients who had a major depressive illness. The only significant criticism that one could reasonably level at this particular trial structure was that it had a small entry cohort of only 26 patients. Given the fact that each required a huge amount of input it is not really surprising that there were not many, but the fact of the matter is that it is difficult to get statistically significant results from such a small cohort. The results were really both impressive and significant. In terms of clinical response. In terms of clinical response the authors found that at the end of the 4 week tria l 62% of the SAMe treated patients had significantly improved. The definition of improvement was given as a 50% decrease on the Hamilton Depression Rating Scale (HAM-D). This compares with the 50% improvement found with the desipramine group. So in this respect, SAMe compared favourably with desipramine. The really significant finding from this trial, at least in the context of this dissertation, was the fact that regardless of which medication the patients were given (either SAMe or desipramine), the ones that did respond were found to have a significant increase in the blood levels of SAMe. This is very good evidence that there is a direct correlation between the degree of improvement of severely depressed patients and the blood levels of SAMe, irrespective of the treatment type. This strongly suggests that SAMe has a major role in the determination and control of mood. This is possibly one of the strongest pieces of evidence that we have found, in terms of hard demonstrable fa ct, that SAMe does have a place in the treatment of depressive states. This finding is expanded further by Bottiglieri (1994) (II) who writes another review of the current knowledge relating to SAMe. In this review he takes a slightly different, neurological perspective. He points to evidence which shows that although there is no consistent evidence to link SAMe with psychiatric illness, low levels of SAMe in the CSF have been found in patients with other neurological deficits such as Alzheimers Disease, subacute combined degeneration of the spinal cord (SACD) and some of the HIV associated neuropathies. Other studies have also been able to demonstrate the finding that SAMe levels are low in patients who have suffered depression. (Johnstone Stevens 1992). The same study also found that the enzyme MAT (which catalyses the reaction between methionine and ATP to produce SAMe) was found to be low when assays were done on the red blood cells of depressed patients. Further evide nce comes from the paper by Baldessarini (1987) in which the authors found that SAMe has low levels in dementia alcohol abuse and increasing age. This point may well be relevant insofar as it is well known that patients who are depressed are more likely to use alcohol as a means of mediating their symptoms. The fact is that this actually worsens their overall condition. An excess of alcohol interferes with the production of SAMe. The situation is compounded by the fact that SAMe is required in the liver to provide the methyl groups necessary for the methylisation and detoxification of alcohol. In short, alcohol reduces the levels of SAMe which are therefore not available to detoxify the alcohol. This can result in liver damage. The lowering of the SAMe levels increases the tendency to clinical depression and therefore the patient will often feel the need to drink more, and so the cycle continues.. (Reid Reynolds 1994). This is really a very well written, researched and complex p aper which we have, (for obvious reasons), extracted the relevant pieces of information that are strictly relevant to this dissertation. In the paper by Flynn (et al 1994) it has is reported that giving SAMe supplements to these patients not only appears to protect the liver against the toxic effects of alcohol, but it also can reduce alcohol-related depression. (Kegan et al 1990) Trials have also been done in the depressive states that can frequently accompany Alzheimers Disease. In this condition, SAMe blood levels can be very low to the point where they can be almost undetectable. (Smythe 1998) Morrison ( et al 1996) found that SAMe can produce small, but measurable, improvements in the depressive score ratings of some patients with Alzheimers Disease . In terms of efficacy, there is plenty of evidence to show that SAMe is superior to placebo, but few well constructed trials have sought to demonstrate that it is actually as good as, or perhaps superior to conventional medications. (Rudoref et al 1989) compared SAMe to a number of other antidepressants currently in use at the time. His results show that SAMe was at least equal to, and in some instances superior, to imipramine (a tricyclic antidepressant). This particular paper reports the results of a number of smaller separate trials, all of similar design. It has to be said that the entry cohort for each were actually very small and therefore proper statistical significance cannot really be applied to these reported findings. (Kegan et al 1990) found that patients who did not respond well to mainline antidepressants or alternatively had unacceptable side effects, could have a good response with SAMe. Again, the numbers involved were comparatively small. Conclusions and Discussion Throughout the dissertation we have been endeavouring to answer the question Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatmen t of depression? From the evidence that we have assembled it would appear that the answer is a qualified Yes. There is little doubt that examination of the evidence that we have for the neuroactivity of SAMe suggests that it is certainly a good candidate for influencing the neural pathways that control and regulate mood. From both a theoretical and a practical perspective we can see that it probably SHOULD work. As with most things in the field of pharmaceuticals, there is a huge gulf of difference between thinking that something should work, and the reality of it producing good, consistent and safe results in the patient. SAMe was discovered in 1952 as a chemical entity, but it was not until 1974 that it was first produced on a commercial scale for human therapeutic use. This represents the fact that initially, nobody saw its potential as a therapeutic agent. As its chemistry was better understood, it was appreciated that its function was central to many of the vital rate lim iting processes within the cell. The decision was taken to promote it as a therapeutic agent in several different therapeutic fields, and the hugely expensive mechanism of getting pharmacological approval was initiated. It is noted that it was originally investigated and approved in Italy, and this is the reason for the fact that the majority of the early work has Italian authorship. In 1974, initial approval was granted and large scale trials began. In this dissertation we have discussed the evidence that SAMe is effective in cases of depression. A considered overview of all of the available evidence would have to conclude that it does not appear to have any significant therapeutic advantage over any of the other currently available antidepressants in terms of efficacy. The majority of the studies that have compared SAMe with another agent have shown that both work better than a placebo with a few percentage points difference between them. Almost without exception, the studie s that have been reviewed are really quite small in terms of entry cohort and therefore are not suitable for major extrapolations in terms of efficacy comparisons. The two meta-analyses that we have presented are also flawed in this respect and although positive trends can be identified, the statistical validity is certainly not up to the standards that we would expect if they were published in a contemporary peer reviewed journal today. Where SAMe does appear to have a major clinical benefit over its competitors is in its side effect profile. It does appear to be extraordinarily safe and free from significant side effects. The only real contraindication that we have seen is when it is being considered in patients who have a history of mania or in the presence of bipolar disorder. Even then, it does appear to be a comparatively unusual event. Some studies have reported nausea. This is thought to be a centrally mediated effect as it has been shown to exert a protective effect on t he gut lining having been used, transiently, as an ulcer-healing agent. In terms of specific types of depression, we have presented evidence that SAMe appears to work in certain types of depressive states more predictably than in others. It seems to be at its most useful therapeutically, in states of primarily endogenous depression. To a lesser degree it has an effect in those depressive states which can be associated with the degenerative dementias. There seems to be little direct evidence that it has a significant effect in the reactive forms of depression. From what we know about the neuropharmcology of SAMe, this would appear to be both logical and, to an extent, predictable. As far as the endogenous depressions are concerned, it is thought that they are primarily caused by various metabolic disturbances within the neuronal pathways of the brain. We know that, on a simplistic level that this is where SAMe has its prime effects. We know that it has various trophic effects on the neuroexcitatory pathways and it does therefore not require a huge leap of faith to see that it could work in these situations. Reactive depression is not thought to be a straightforward chemical abnormality in the brain, but it a reaction to external events, and therefore is more likely to be mediated by inhibitory triggers coming from the higher intellectual centres in the brain possibly working through the hippocampus. Again, it does not require a huge insight to appreciate that SAMe might be less effective in those circumstances. Many of the degenerative dementias are thought to be due to (in part) a failure of the methylating processes in the neural tissues. These are generally associated with neuronal destruction, so significant improvement in cognitive function simply would not be expected. From the evidence that we have seen, it appears that SAMe is capable of exerting a minor degree of positive change in mood states in some cases of dementia, but it is clearly not the degree of response that we have seen in the more straightforward endogenous depressive states. In summary, SAMe does appear to offer a serious alternative to orthodox medications in the field of depressive illness. As with all therapeutic agents, the science of pharmacology is knowing about the nature of the drugs, the art of using them is to make correct judgements about the type of patient who is likely to respond to them. References Altar, C. A. (1999) Neurotrophins and depression. Trends in Pharmacological Sciences, 20, 59-61. Bazin, N., Perruchet, P., De Bonis, M., et al (1994) The dissociation of explicit and implicit memory in depressed patients. Psychological Medicine, 24, 239-245. Baldessarini, R.J. (1987) Neuropharmacology of S-adenosyl-L-methionine Ann J Med 83(Suppl 5A): 95-103 Bell KM, Potkin SG, Carreon D, Plon L 1994 S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Supp l 1994;154:15-8 Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H 1992 Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res 1992 Dec;44(3):257-62 Bigger et al 1990 Neuroendocrine effects of SAMe, a novel putative antidepressant J Psychiatr Res, 1990, 24:2. Bottiglieri T, Hyland K, Reynolds 1994 (I) The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 1994 Aug;48(2):137-52 Bottiglieri T, Hyland K 1994 (II) S-adenosylmethionine levels in psychiatric and neurological disorders: a review. Acta Neurol Scand Suppl 1994;154:19-26 Breggin, P.R. 1994 Talking Back to Prozac NYC: St. Martins Press, 1994. Bressa, G.M. (1994) S-adenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies Acta Neurol Scand: Suppl 154: 7-14 Carney MW, Edeh J, Bottiglieri T, Reynolds EM, Toone BK 1986 Affective illness and S-adenosyl methionine: a p reliminary report. Clin Neuropharmacol 1986;9(4):379-85 Carney, M.W. et al (1987) S-adenosylmethionine and affective disorder Ann J Med 83(Suppl 5A) 104-06. Caruso, I. Pietrogrande, V. (1987) ..Comparing [SAMe], naproxen and placebo in the treatment of degenerative joint disease Ann J Med 83 (Suppl 5A): 66-71. Cohen BM, Stramentinoli G et al. 1989 Effects of the novel antidepressant SAMe on alpha-I and beta adrenoceptors in rat brain. Eur J Pharmacol, 1989, 170(3):210-207. Cooper, J.R., Bloom, F.E. Roth, R.H. 1999 The Biochemical Basis of Neuropharmacology NYC, Oxford: Oxford Univ. Press, 1999 Czyrak A, Rogoz Z, Skuza G, Zajaczkowski W, 1992 Antidepressant activity of S-adenosyl-L-methionine in mice and rats. 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Psychiatry Res 1995 Apr 28;56(3):295-7 Fava M, Rosenbaum JF, MacLaughlin R, Falk WE, Pollack MH, Cohen LS, Jones L, Pill L (II) 1990 Neuroendocrine effects of S-adenosyl-L-methionine, a novel putative anti depressant. J Psychiatr Res 1990;24(2):177-84 Flynn 1994 SAMe in the treatment of major depression complicating chronic alcoholism Curr Ther Res Clin Exp 1994,55:1. Gold PW, Goodwin FK, Chrousos GP, 1988. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress N. Eng. J. Med. 319:413-420. Gould, E., Tanapat, P., McEwen, B., et al (1998) Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proceedings of the National Academy of Sciences of the USA, 95, 3168-3171. Harmer, S. A. Hill, M. J. Taylor, P. J. Cowen, and G. M. 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Am J Psychiatry 1990 May;147(5):591-5 Kegan B et al. 1990 Oral SAMe in depression: a randomized, double blind, placebo-controlled trial. Am J Psychiatr 1990, 147:591-595. Kendler KS, 1998. Major depression and the environment: a psychiatric genetic perspective Pharmacopsychiatry 31(1):5-9 LeDoux, J. (1996) The Emotional Brain. New York: Simon and Schuster. 1996 Levine, E. S., Crozier, R. A., Black, I. B., et al (1998) Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proceedings of the National Academy of Sciences of the USA, 95, 10235-10239 Lopez, J. F., Chalmers, D., Little, K. Y.,Watson, S. J., 1998. Regulation of 5HT1a receptor, glucocorticoid and mineralocorticoid receptor in rat and human hippocampus: Implications for the neurobiology of depression. Biol Psychiatry 43: 547-573 Lopez, J. F., Liberzon, I., Vazquez, D. M., Young, E. A.,Watson, S. J., 1999 (I) Serotonin 1a receptor mRNA regulation in the hippocampus after acute stress. Biological Psychiatry 45: 943-947. Lopez, J. F., Akil, H.,Watson, S. J., 1999 (II) Neural circuits mediating stress and anxiety. Biological Psychiatry 1999 Janicak PG, Lipinski J et al. 1989 Parenteral SAMe in depression. lit erature review and preliminary data. Psychopharmacol Bull 1989,25(2):238-242. Mathews, C. van Holde, K. 1990 Biochemistry, pp. 708-15. Redwood City CA: Benjamin/Cummings Pub., 1990. Melzter H, 1989. Serotonergic dysfunction in depression. Br J Psychiatry 155:25-31. Morrison et al, (1996) Brain [SAMe] levels are severely decreased in Alzheimers disease Neurochem 67, 1328-31. Murphy BEP, 1991. Steroids and Depression. J Steroid Biochem 38:537-559 Nemeroff, C. B., 1998. The neurobiology of depression. Sci Am 278: 42-49 Peinell and Smith 2003 Treatment Complementary Health Practice Review, April 1, 2003; 8(2): 99 115. Post RM. 1992. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149:999-1010 Reid Stewart 2001 How antidepressants work New perspectives on the pathophysiology of depressive disorder The British Journal of Psychiatry (2001) 178: 299-303 Reid Reynolds 1994 SAMe in the treatment of major depression complicating chronic alcoholism Curr Ther Res Clin Exp 1994,55:1. Reynolds et al, (1984) Methylation and mood Lancet II, 196-98. Robertson, J. Monte, T. 1997 Natural Prozac San Francisco: Harper, 1997. Rosenbaum JF, Fava M, Falk WE, Pollack MH, Cohen LS, Cohen BM, Zubenko GS 1990 The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatr Scand 1990 May;81(5):432-6 Rudoref MV, Potter WZ. 1989 Antidepressants: A comparative review. Drugs 1989, 7(5):713-738. Saarelainen, P. Hendolin, G. Lucas, E. Koponen, M. Sairanen, E. MacDonald, K. Agerman, A. Haapasalo, H. Nawa, R. Aloyz, P. Ernfors, and E. Castren 2003 Activation of the TrkB Neurotrophin Receptor Is Induced by Antidepressant Drugs and Is Required for Antidepressant-Induced Behavioral Effects J. Neurosci., January 1, 2003; 23(1): 349 357. Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P, Le Graz ie C 1993 Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychother Psychosom 1993;59(1):34-40 Shah, P. J., Ebmeier, K. P., Glabus, M. F., et al (1998) Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study. British Journal of Psychiatry, 172, 527-532 Siuciak, J. A., Lewis, D. R., Wiegand, S. J., et al (1997) Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacology, Biochemistry and Behavior, 56, 131-137 Skolnick, P. (1999) Antidepressants for the new millennium. European Journal of Pharmacology, 375, 31-40. Smith, M. 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A., Du, F., et al (1999) Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience, 89, 157-166 Zuess J 2003 An Integrative Approach to Depression: Part 1Etiology Co mplementary Health Practice Review, January 1, 2003; 8(1): 9 24.
Tuesday, June 9, 2020
How to Choose Research Essay Topics For Middle SchoolThe world of online college and online classes is ever growing and finding a good college or university to apply to for your middle school career can be difficult. However, when it comes to writing essays and engaging in research, there are hundreds of sites that will help you find the ideal middle school curriculum to meet your educational needs. Some of these courses and organizations offer free tools and resources for research and essay writing.A good place to start to find out what other different middle schools have to offer, would be the site CollegeBoard. Once you have signed up for an account, you can input your information for a personalized list of institutions to choose from. There are a number of middle schools on the list that offers research and study skills instruction and career development curriculum that are designed for students in grades six through eight.Another way to search for middle school research paper to pics would be on sites like Grammarly and Google. The site Wordtracker also offers a selection of comparative essay topics based on school grade levels. However, many of these sites will require that you provide a log in with a student ID. Using these tools can prove to be a great tool in helping you find the perfect middle school topics to write about.Other sites that will help you locate different middle schools that offer specific programs in a particular subject area include Open School. They list colleges and universities that are affiliated with a specific field of study so that you can compare schools in the same field. This site also provides information on how much research and essay writing time is typically required to complete a certain course.Before choosing a college or university to attend, you will want to find out what a high school has to offer. One way to find this out is to visit a middle school for yourself. Doing so may provide you with helpful advice that will aid you in deciding which school or college to choose.It's a good idea to find out if the school you're considering can provide the same kind of guidance and support that you get from similar subjects at home. That way, if you do decide to enroll, you'll be able to learn at your own pace. Middle school students are often encouraged to read more and take more advanced courses because they are so focused on learning and mastering their academic subjects.Your parents are the best guide in choosing a college or university for your high school. Your parents might know the quality of education at a college or university offers, but they don't always have a first-hand view of the school. Take advantage of that fact and ask them what type of academic support they got from their college or university.Middle school students, as well as adults, should take advantage of the informational tools available online to help them choose essay topics for their schoolwork. There are a number of web-bas ed applications that can help in determining the right topics for college or university courses. If you are looking for information on essays, research papers, or just general research topics, it's now easier than ever to find the resources you need.
Wednesday, May 27, 2020
<h1>Essay Sample Companies - How to Improve Your Grades</h1><p>The notoriety of article tests has been expanding in the recent years. All in all, what is the noteworthiness of paying attention to paper tests? There are numerous understudies who are keen on taking article tests and improving their evaluations. In the event that you are additionally going to take this course to improve your evaluations, you have to consider these focuses first.</p><p></p><p>First of all, taking exposition tests isn't equivalent to getting an immediate suggestion from a specialist in the field. You can't simply turn up at any school or college and take the principal article test that is introduced to you. The serious issue with this methodology is that the article tests don't have a genuine application. It might be that you get it from a companion who took one and has been beneficial for one year, however as far as possible is very short.</p><p></ p><p>Essay tests can give you pieces of information with regards to how to compose a powerful paper and they can likewise give you guides to concentrate from. Moreover, you should take a gander at the occasions the essayist utilizes the word 'I' and the quantity of different words that are utilized by the writer. The primary thought is that you will get a vibe of the style of composing when contrasted with the paper samples.</p><p></p><p>B2 Cefre has been the pioneer in helping understudies increment their evaluation midpoints and they are the best article test supplier. The projects that they offer are amazingly significant. These projects permit you to investigate exposition tests for use in your own paper and they give you thoughts for expanding your evaluation average.</p><p></p><p>Another point to consider is that the educators may give out article tests, yet they are not no different. For instance, some may require an ar ticle and others will give an example. Things being what they are, what is the most ideal approach to getting an excellent paper test? The best way to do this is to visit the sites of the different article tests that are available.</p><p></p><p>At the day's end, B2 Cefre offers something other than paper tests. You will likewise discover around thirty distinct subjects that you can apply to improve your evaluations. This permits you to choose the subject that is generally material to your course.</p><p></p><p>Then, you can peruse the articles and afterward pick the one that fits best with the standards that you have set for yourself. The subsequent stage is to apply the information that you have picked up from the article tests. The projects that B2 Cefre offers are brilliant and you will find that there is a ton to pick up from taking them.</p><p></p><p>Of course, you should recollect that article tests are not a similar thing as proposal letters from teachers. The advantage is that they will inform you as to whether the teacher has lived up to your desires and they will assist you with improving your grades.</p>
<h1>How to Tell a Story and Be More Effective at Making Others Feel Interesting</h1><p>If you need to attempt to live from your own understanding, the correct technique is to attempt to tell others how it is having a comparative encounter. The other path is to open up about your background and offer with others how that impacted your dynamic procedure or made the various things that you were thinking at that point. So as to effectively do this, you have to record everything that transpired around then with the goal that you can think about a decent story to use.</p><p></p><p>To depict your experience, you ought to return to when you were more youthful. Be progressively explicit. You can recount to your story utilizing distinctive pictures, vivid expressions, and the sky is the limit from there. While portraying the second that you had the most achievement, make certain to compose what made you succeed and not simply anything else.</p>&l t;p></p><p>The significant thing to recall is that an encounter shouldn't be about victories. An effective experience can be commonplace. Regardless of whether the encounters are not about progress, they will in any case impact you. What you realize in life isn't something you discover at school or school. It is something that you get en route while investigating the numerous encounters that are accessible to you.</p><p></p><p>For model, suppose that you needed to find out about the significant business matters at a specific time. You returned to take a gander at a similar business for some time and saw that you comprehended the business enough to have a smart thought of how it was doing. In the event that you recorded what you did and why you settled on that choice, you can begin to make a positive tale about your life experience.</p><p></p><p>If you need to depict your experience, you ought to return to when you were m ore youthful. Be increasingly explicit. You can recount to your story utilizing striking pictures, vivid expressions, and that's only the tip of the iceberg. While depicting the second that you had the most achievement, make certain to compose what made you succeed and not simply anything else.</p><p></p><p>A story that everybody should know the beginnings and parts of the bargains great beginning. You can think back to when you required cash for a basic need and make sense of how you went over the cash. At the point when you think back to when you were a small child, you can choose the best snapshots of your life that you think made you the best individual that you are today. Keep all the subtleties and record it, yet ensure that you include humor and a feeling of marvel to it to make it believable.</p><p></p><p>Another great methodology is to record all the subtleties and data about an incredible story you read about. The key is to m ake it an individual encounter that has a great deal of riddle and interest to it. That is actually how your encounters will ponder you.</p><p></p><p>In rundown, an extraordinary method to help other people to all the more likely comprehend their own life is to give them a pleasant story. They will at that point recall the things that you did in your life and consider them simultaneously, making an extraordinary memory to impart to others.</p>
Tuesday, May 26, 2020
Modern Day Human Sex Trafficking With the advances in technology society now mainly uses cellphones and the internet as means of communication; traffickers see this as an opportunity, by using technology as a tool to reach victims from all around the world, as well as buyers. However, as traffickers are adapting to the online market for trafficking, technology is also creating ways in which we can identify traffickers and victims. Sex trafficking has been around for centuries, however in this day and age it is Ã¢â¬Å"the second fastest growing criminal industry; sex trafficking Ã¢â¬Å"accounted for 83% of all reported human trafficking incidentsÃ¢â¬ . Sex trafficking is a global problem; traffickers are utilizing the advances in technology to their advantage. They are taking advantage of the loopholes in technology that can leave their marks untraceable which enables them to conduct business discreetly. What people do not realize is that sex trafficking is a major problem in the states as well. Large n umbers of victims come in from areas such as Ukraine, Russia, and various parts of Africa. This wide variety of locations of victims furthers the difficulties faced in trying to stop it due to victimÃ¢â¬â¢s unfamiliarity with the system. To start, sex trafficking is illegal in all states, except in Nevada where prostitution is legal in counties with a population of 700,000 or greater, 10 out of 17 counties in Nevada have licensed brothels. Prostitution is legally definedShow MoreRelatedSlavery : A African American Slave1518 Words Ã |Ã 7 Pageseconomic, and racial factors that influence slavery, even in modern time. Of course, we know that slavery in the 1800Ã¢â¬â¢s was extremely racial in that only blacks were enslaved. However, looking at the statistics as we talk about slavery, it has become widely apparent to me that slavery is largely associated with specific races as well as economic status. In todayÃ¢â¬â¢s world there are also other types of slavery, such as child t rafficking, forced labor/debt bondage, criminal exploitation, ect. And eachRead MoreSex Trafficking : A Common Issue For A Long Time1394 Words Ã |Ã 6 Pages Sex trafficking can happen everywhere. People do not even realize when it is happening. Someone could be living their life, just as they normally do, and decided to go to the mall. Sometimes they may not even know that a little kid is going to be kidnapped, and later raped. This is what sex trafficking is. Sex trafficking is commonly defined as when violence, drugs, lies, or any other form of coercion is used to force another person to have sex against their will. (Sex Trafficking in the U.S, 1)Read MoreThe Slavery Of The United States1603 Words Ã |Ã 7 PagesIntroduction The history of enslaving humans for the benefit of labor, sex, and financial gain runs deep and parallel to the existence of civilization. While a small portion of the history of slavery reflects a more humane and less brutal treatment of those in servitude, such as the Babylonian slaves of 18th century BC who were permitted to own land; contrastingly, most slavery practices historically have been established in a foundation of violence and control, such as the slaves of ancient GreeceRead MorePersuasive Essay On Human Trafficking851 Words Ã |Ã 4 Pagesbetter lives resort to human trafficking as a result. It is a worldwide issue that can be defined as the trading of humans, most commonly by force, sexual slavery, or commercial. It is one of the top leading crimes in the world today that puts not only women, but also men in danger. Human trafficking is a worldwide issue that has been going on for decades, and all the issues of the trafficking would make one wonder, how can it be st opped? Human trafficking has become the modern-day slavery, it can beRead MoreHuman Trafficking Outline Speech919 Words Ã |Ã 4 Pageswith me as soon as possible. Would you still accept the job? B. (thematic statement): Today I will be talking about human trafficking and how this horrible thing started. C. (establish significance): Human trafficking is a modern Ã¢â¬â day form of slavery of the 21st century. According to www.humantraffickinged.com an estimated of 27 million people are in modern day slavery across the world. Anywhere between 700,000 to 2 million people are trafficked across international borders each yearRead MoreThe Issue of Human Trafficking1512 Words Ã |Ã 7 Pagesfamilies each day. ThatÃ¢â¬â¢s 2,880 eighty children who should be playing outside and enjoying childhood. Instead they are torn from everything they know and forced into slavery, sometimes to never come out. Slavery was not fully abolished in 1865. Over 27 million men, women, and children are enslaved at this very moment (Ã¢â¬Å"The Cost of CoercionÃ¢â¬ ). That number is close to the population of Florida and Georgia combined who would be enslaved today. What most people today call Ã¢â¬Å"modern-day slaveryÃ¢â¬ is theRead MoreHuman Trafficking Is A Global Phenomenon1054 Words Ã |Ã 5 P agespresent day most people think of it as something that has passed, something that happened a long time ago. It was a tragic historical event that involved the capture and exportation and exploitation of human beings who were forced into labor with no freedom of movement or choice. However, the reality of the situation is that slavery still exists today, and on an even greater scale than it did many years ago. That form of slavery is human trafficking. It is commonly referred to as modern-day slaveryÃ¢â¬ Read MoreSex Trafficking : An Important Social Issue That Affects Vulnerable People1482 Words Ã |Ã 6 PagesLastName 1 Firstname Lastname Professor Maritato Introduction to Speech - Comm V01 Sex Trafficking General Purpose: To inform Specific Purpose: By the end of my speech, the audience should be able to explain what sex trafficking is and how it takes place domestically and abroad. Central Idea: Sex trafficking is an important social issue that affects vulnerable people. Introduction: When K. was 14 years old, she fell in love with her horseback riding instructor. She dreamed that they would be in loveRead MoreSex And Sex Trafficking1310 Words Ã |Ã 6 PagesThe Effects Poverty has on Sex Trafficking Suffering from poverty makes life unbearable at times and is hard to escape from. Most individuals that live in poverty are vulnerable and have little hope to improve their lives. Being vulnerable and having no hope for life can often leads to desperation. Sex trafficking and become a means of survival for these individuals. Low income is a major cause for sex trafficking. Sex trafficking can become a reason for a single mother to feed her children or canRead MoreHuman Trafficking in the United States Essays927 Words Ã |Ã 4 PagesStates. Over a century has went by since this day, and yet somewhere behind the mask of freedom that our country holds with such pride lingers a hidden trade. This is the trade of modern day slavery that remains prevalent in our country. Despite the freedoms we are granted as a citizen of the United States,- human trafficking is an enormous issue that is often overlooked. In fact very little light is shown on this topic, but the awful reality is there. Ev ery day women, children, and even men are kidnapped