3 Types of Erroneous Use of Dashes

3 Types of Erroneous Use of Dashes 3 Types of Erroneous Use of Dashes 3 Types of Erroneous Use of Dashes By Mark Nichol Dashes, like semicolons, are basically commas with superpowers. However, while semicolons take the place of commas to set off independent clauses or separate a series of list items in which at least one item itself consists of a list, a single dash denotes an abrupt break in syntax, and a pair of dashes signal a parenthetical phrase that is more emphatic than one bracketed by commas (or parentheses). In the following examples, though, dashes are misused. Discussion after each sentence describes the problem, and a revision illustrates a solution. 1. Everybody thinks their job title should be capitalized- and why not- it’s about them. In this sentence, the writer has conflated the two functions of a dash. What follows capitalized is an emphatically delivered opinion about the previous assertion, and the first dash is correct, but then the writer seeks to repeat the effect by setting off â€Å"it’s about them.† However, the result is that â€Å"and why not† mistakenly appears to be a parenthetical phrase. For this reason, single dashes cannot be used consecutively, even at a greater remove, so the second emphatic phrase must be distinguished in another way: â€Å"Everybody thinks their job title should be capitalized- and why not? It’s about them.† 2. Changing channels on the radio while driving- even adjusting your vehicle’s climate controls are distracting activities. Here, the opposite error is committed. The writer apparently intended to sequester a parenthetical phrase from the main clause but neglected to provide a complementary second dash: â€Å"Changing channels on the radio while driving- and even adjusting your vehicle’s climate controls- are distracting activities.† 3. Combined with a focus on disruptive innovations like artificial intelligence, telehealth, and virtual care- an abundance of new data is becoming available to healthcare providers. Here, the flaw is that the dash is inserted in place of a comma to suggest a syntactical swerve, but the syntax itself does not take off in a new direction, and a quotidian comma is appropriate: â€Å"Combined with a focus on disruptive innovations like artificial intelligence, telehealth, and virtual care, an abundance of new data is becoming available to healthcare providers.† Want to improve your English in five minutes a day? Get a subscription and start receiving our writing tips and exercises daily! Keep learning! Browse the Punctuation category, check our popular posts, or choose a related post below:Cost-Effective vs. Cost-EfficientWhen to Form a Plural with an ApostropheHow often is "bimonthly"?

ALTERED HEALTH STATUS AND HEALTH PROMOTION IN MENTAL HEALTH NURSING Essay

ALTERED HEALTH STATUS AND HEALTH PROMOTION IN MENTAL HEALTH NURSING - Essay Example His unusual behaviours included the following. He entered without a licence and pointed a gun at a shop assistant. He stabbed a friend during an unprovoked argument. Also, he committed the offence of burglary, and his fingerprints were found at the scene of the crime. Mr. Abouja was imprisoned and then later transferred to a forensic ward due to mental illness. While in the forensic unit, Mr. Abouja suffered a cardiac arrest secondary to a bi-lateral massive pulmonary embolism. After having suffered a pulmonary embolism, Mr. Abouja should be assessed for further risk in the near future. â€Å"Confirmation of pulmonary embolism (PE) must be followed by risk stratification in order to obtain information on short-term prognosis and determine the need for more aggressive therapy such as thrombolysis or surgical interventional embolectomy† (Konstantinides, pp. 69). The medication Mr. Abouja has been placed on is Warfarin, also commonly known as rat poison. The levels of Warfarin ha ve to be carefully evaluated, to ensure that the patient is not poisoned himself. Basically, Warfarin is most likely going to be used for a lengthier amount of time in order to treat Mr. Abouja’s illness. â€Å"A vitamin K antagonist such as warfarin should be considered for long-term treatment† (Stein, 2007, pp. 129). There is a timetable for how long the Warfarin should be used. â€Å"Initial treatment [with Warfarin] is usually for a minimum of three to six months† (James, Ortel, & Tapson, 2007, pp. 42). However, the nurse should make sure â€Å"In healthy subjects, sildenafil alone or in combination with warfarin or aspirin did not affect bleeding time or prothrombin time. However, in a recent study, a transient prolongation of bleeding time 1 hour after administration of 100 mg of sildenafil was demonstrated† (Broderick, 2005, pp. 215). Therefore, bleeding complications are possible when taking Warfarin. Generally, Warfarin is used in these types of situations such as the one in which Mr. Abouja found himself in. â€Å"[Warfarin, also known as Coumadin, is] used to prevent the formation of blood clots in the heart and to prevent stroke in patients with conditions such as atrial fibrillation and atrial flutter†¦[usage] must be carefully monitored by a [regularly-administered] blood test†¦Ã¢â‚¬  (Cohen, 2010, pp. 196). Mr. Abouja was given Warfarin for the Pulmonary Embolism. He is being given 3 mg of Risperdal (Risperidone) on a daily basis, a commonly-used antipsychotic. Some of the side effects Mr. Abouja is suffering, among others, are muscle weakness and sexual dysfunction. Mr. Abouja’s mother had a history of heart disease or PE; his father refused to be in touch due to his offences. Mr. Abouja was born in Angola. 2. Identify appropriate assessment tool/framework and provide rationale for ?your choice of tool/framework. (200 words) The assessment measures which would be appropriate to use as a framework f or care would be: 1) a physical assessment; 2) a psychological assessment; and 3) a emotional assessment. The patient had a physical assessment completed upon him. This physical assessment is rationalised by the fact that he needs to have an intervention for any physical problems that may come up since he has just had a major health issue with the cardiac arrest. Interestingly enough, Mr. Abouja had no pain in his upper left arm, which is recognizant of having heart problems—namely, risk of cardiac arrest. The physical assessme

Dyadic partner Essay Example | Topics and Well Written Essays - 250 words

Dyadic partner - Essay Example When he is confused, he would also tug at his hair. He wears bright colored shirts like red, blue or green, when he is happy. But when he is excited about something and wants to share it with others, he sits upright and looks at other person’s eye. The body language of my partner is therefore vital means of communicating his mood. Whenever he comes in bright tee-shirt, I am much relaxed because I know that when he is happy, he works better with higher productive outcome! When I see him sitting upright on his chair, I know that he has some good news. But my worries are heightened when I see him tugging at his hair or find him looking away rather than talking to me. As I know that these behavior indicate his discomfort with the issue or his doubts which he is wary of sharing. At these times, I pick up the topic or issue that he is passionate about. When he gets involved and comfortable, I broach the subject of which he is wary about. This way, I am able to know his problem and resolve it so that he can focus on his

Cultures. African Culture Research Paper Example | Topics and Well Written Essays - 1000 words

Cultures. African Culture - Research Paper Example This persuasive essay looks at the African culture and its significance. The African continent consists of two main cultures, which are the Sub-Saharan Africa and North African cultures. These cultures have a number of ethnic, tribes, social groups. One of the main features of this way of life is the large number of cultural groups where some nations can have twenty or more ethnic groups, and the variety of their principles. The African culture is varied and diverse. Like other cultures in the world, it has been obstructed upon by both external and internal forces, which in turn affect it negatively and positively. Their art, music, literature, and African cultural customs of Africa have motivated interest and admiration all over the world (Barakat79). The African continent has a rich custom of arts and crafts. Their arts and crafts observe manifestation in an assortment of leather arts, woodcarvings, brass, and other metal works. These art and crafts consist of sculptures, woodwork paintings ceremonial, pottery, religious ornaments, and other dresses. According to Barakat, African art must be innovative and in being revolutionary, the artists ought to be collective, functional and committed to their works (80). Barakat continues to note that art is socially functional within the society (81). The African culture places a lot of emphasis on the appearance and jewelry, which has endured an important individual accompaniment. Most pieces of this jewelry are crafted using cowry shells and metallic materials (Namulundah 23). In the same way, the masks are crafted using elaborate objects and are significant part of the culture. During ceremonies, these masks are used as symbols of spirits and ancestors, deities and mythological characters (Namulundah 23). Certain themes are significant in the African arts and crafts, and these themes keep on recurring from one art to another. They include men carrying weapons, women carrying children, men posing as hunters with anim als on their shoulders. Pairs may symbolize ancestors, society founder, married people, or twins (Namulundah 23). The couple subject rarely displays intimacy of the married people. The mother carrying a child or children as argued by Namulundah shows strong aspiration of the African women to give birth to her own children (23). The theme is also an agent of woman mars and the communities as her children. On the other hand, the man carrying a weapon or animal subject represents principle and power (Namulundah 23). An alien or a stranger may be someone from other ethnic groups or somebody from a different nation, and accurate representation of the stranger signifies fairly better gap from the stranger (Namulundah, 23). Oral presentation is very important in African arts and crafts. African oral literature includes arts like origin fables, myths, history, folklore, lineage, folk therapies that are very common with the African continent. Initially this information was not recorded in wr itten materials, but instead passed from one generation to another through word of mouth. Storytelling and singing are very common and highly appreciated in this society. Just like other human culture, the African religion and folklore represents different aspects of social issues within the African community (Namulundah 21). Similarly, like all other civilization and cultures, myths have been presented in different parts of the African continent. Religion and culture share space and deeply rooted in the African cultures. For example, the Ethiopian culture consists of their African culture and informs dietary customs together with rites and rituals (Namulundah 21). The pygmy myth

The drug metabolism

The drug metabolism Introduction: If an exogenous microorganism enters the human body, this invokes the immune system to produce antibodies to come into contact with the foreign potentially pathogenic species and lead to its destruction. Although when drug molecules enter the human body this does not result in the synthesis of antibodies, due to their relatively small molecular weight. This is why the endogenous metabolism of drugs is vital in ensuring no or the minimum toxicity from a very broad spectrum of xenobiotics i.e. molecules/compounds which are found in a given organism, but are not synthesized naturally by it and or normally found within it. We can define drug metabolism as the enzymatically catalysed conversion of exogenous drug molecules into generally less active metabolites, which have a faster rate of clearance from the body. (While this is true for the majority of metabolites it is important to acknowledge that some metabolites actually are of higher toxicity than their precursors.) This occurs throu ghout nearly every organ (excluding ectodermal tissue) in the human body, but specifically the gastro-intestinal tract, lungs, kidneys and most importantly (and abundantly) the liver. While drug metabolism is essential in preventing a specific toxicity being produced from the accumulation of a drug(s), there are drawbacks that need to be addressed; a given drug may be a xenobiotic, but it is taken (or administered) in order to produce some degree of a therapeutic effect for its specifically targeted disease/pathology. Thus drug metabolism can inhibit the therapeutic benefit of a given molecule that ideally needs to be retained in a particular tissue of the body for a set period of time, to bring about a therapeutic effect. This is mainly due to the fact that a large number of drug molecules do mimic the structure of endogenous molecules close enough for the corresponding specific enzymes to target them as well as nonspecific enzymes which only identify certain molecular groups as opposed to the entire pharmacophore of a given drug. This unexpected drug metabolism could result in an undesired decrease in the bioavailability of a drug which would lead to increased d oses or dosage frequencies; this would cause a decrease in patient compliance which in the current medicinal environment is vital. Absorption and clearance: In the case of drug absorption into the desired tissues of the body generally a lipophilic character is required. This is because regardless of the site of drug uptake, it must pass through the cell membranes of targeted cells. These cell membranes are lipophilic in nature as they consist of a phospholipid bilayer. The inside of this bilayer is made up of hydrocarbon tails which are straight chain hydrocarbons which interact with each other via Van der Waal interactions and London forces. Thus drug molecules are designed to have sufficient lipophilic character that they can form these interactions with the lipid bilayers and pass into cells. Unfortunately this means that they are of limited hydrophilicity and either do not go into dissolution in an aqueous environment at all or do so at a very slow rate. As previously mentioned as this is unacceptable due to the accumulation of a given drug that would occur and produce toxicity, the drug must undergo a series of transformations that serve to increase the hydrophilic nature of the drug molecules. This predominately occurs in liver cells (hepatocytes) in processes known as phase I and phase II metabolism. Phase I and Phase II: Phase I metabolism is constituted of oxidative, reductive and hydrolytic reactions. These serve to produce primary metabolites that are susceptible to other reactions, which consist of the following conjugations; glucuronic acid, sulphate, amino acid, glutathione, water, acetyl, fatty acid and methyl. These occur via the corresponding conjugating agents and are known as phase II reactions. They aim to produce secondary metabolites that are far more hydrophilic nature than their precursor drug counterparts. This is with the addition of e.g. amine, carboxylic acid, hydroxyl groups as well as others, simply to increase the number of very electronegative atoms (with lone pairs of electrons) in a given species. Thus these metabolites can from a greater number of hydrogen bonds with the aqueous medium of the nephronal filtrate of the kidneys and be excreted at a faster rate via the passing of urine. The main constituent of phase I transformations are oxidative reactions, as they activate the selected species in generally one of two ways; hydroxylation and epoxidation. We can define oxidation as the gain of oxygen in a molecule or more precisely the loss of at least one electron from a species reacting with molecular oxygen. This is true for the two general mechanisms mentioned above as adding either a hydroxyl group or an epoxide ring to a molecule increases the number of oxygen atoms that the molecule contains. Firstly this increases the ability of the newly formed metabolite to act as a nucleophile due to the lone pair of electrons available for covalent bond formation (from the oxygen atom added to the molecule). Secondly it increases the chances of attack by an electrophilic species, because of the high electron density of the lone pair of electrons on the oxygen atom. Oxidation Properties and mechanisms of the Cytochrome P450 isoenzyme superfamily: The majority of these oxidative metabolic reactions are carried out by a superfamily of enzymes known as cytochrome P450, this can be displayed as: RH + O2 +NAD(P)H + H+ ? ROH + H2O + NAD(P)+ [1] The P450 enzymes catalyse the biodegradation of other exogenous species that are not drugs such as; organic solvents, ethanol (or consumed alcohol), anaesthetics, pesticides and carcinogens [1]; While endogenous molecules such as organic acids, steroids and prostaglandins are also biodegraded [1]. These enzymes are intracellular hemoproteins that function as external monooxygenases (mixed function oxidases) enzymes that serve to incorporate a single atom of molecular oxygen into a lipophilic xenobiotic substrate (i.e. a drug molecule), with the concomitant reduction of the other atom to water [1]. While internal monooxygenases take two reductive equivalents from the substrate in order to reduce one atom of molecular oxygen to water, this is normally done with an external reductant for external monooxygenases [1]. In eukaryotic cells the P450 enzymes consist of around half a thousand amino acid that compose their quaternary structure, these hemoproteins are membrane bound and have a heme prosthetic group at their centres. It is thought that the reason the enzymes can be bound to the cell membranes is the N-terminus of the enzymes tertiary structure has numerous hydrophobic amino acids (i.e. ones which contain aromatic/cyclic groups and have few very electronegative atoms such as oxygen and sulphur) that can interact with the lipid bilayer of the cells. Most hemoproteins in mammalian cells have nitrogen atom from the histidine residues imidazole group to form a ligand with the iron-heme prosthetic group. While for P450 enzymes this ligand is formed between the prosthetic group and the thiol group of a cysteine residue which is located near the C-terminus of the protein. This ligand activates the porphyrin ring (four conjugated pyrrole rings) to nucleophilic substitution by an oxygen atom. This is because the thiol group has an electron inductive effect due to its high electronegativity and so makes the carbon atom it is directly bonded to very electropositive and thus of greater electrophilicity/susceptibility of nucleophilic attack by the lone pair of electrons from the oxygen atom, so allowing oxidation to take place. The general process of the catalytic oxidative cycle of the cytochrome P450 enzyme superfamily: The substrate binds to a specific P450 enzyme and is followed by the first electron of the coenzyme NADPH via the electron transport chain. This is then followed by the binding of an oxygen atom that accepts the second electron from the coenzyme to produce a ferric peroxy anion [1]. The anion forms a ferric hydroperoxy complex via protonation, which in turn is heterolytically cleaved to form a Fe(V)=O species [1]. The newly formed highly electrophilic iron-oxo intermediate then attacks the substrate to form a hydroxylated metabolite. This product disassociates to allow another substrate to bind and the oxidation cycle to continue [1]. Schematic organisation of different cytochrome P450 systems. Upper row, left: bacterial system, right: mitochondrial system. Lower row, left: microsomal system, right: self-sufficient CYP102 (P450-BM3).[1] Aromatic hydroxylation: This leads on to the first major constituent of oxidative reactions; aromatic hydroxylation. This is simply the addition of at least one hydroxyl group to a given substrate although depending on the chemical environment that the product is formed in (e.g. pH) the hydrogen atom may be lost from the hydroxyl group. Aromatic compounds are first metabolized to the corresponding arene oxides; this is by electrophilic addition of the aromatic ring (of the previously mentioned iron-oxo intermediate) to produce either a carbocation species. This carbocation would be formed via the movement of an electron to the Fe(IV) species, giving a Fe(III) species bound to a the mentioned carbocation; or by formation of a radical which serves as a tetrahedral intermediate. The produced arene oxides then take on further transformations, which involve removal of the epoxide group that was added and introduction of a hydroxyl group and potentially another nucleophilic substitute. The simplest transformation is simply intramolecular rearrangement to for a para-arenol. Also hydration can take place in the presence of water and using the enzyme epoxide hydrolase. This causes opening of the epoxide ring and formation of a trans-3,4 arenediol. These primary metabolites can also undergo attack by large macromolecules which serve as nucleophiles. This is because the oxygen in the epoxide ring serves to make both the meta and para carbon positions electropositive and electrophilic in nature. Although any nucleophilic substitution that does go on to occur is at the para position, due to greater resonance stability of the formed secondary metabolite. Another example of aromatic hydroxylation would be the metabolism of isoliquiritigenin. It is a chalcone found in licorice roots and other plants [3] which has shown potent antitumor, phytoestrogenic activity and antioxidant properties. [3] Schematics for its metabolism can be shown below. [3] The metabolism of aromatic compounds that get hydroxylated can be slowed by using para-substituted aromatic compounds with either chlorine or a fluorine atom in the para position. While electron withdrawing groups deactivate the ring towards electrophilic substitution and activate it towards nucleophilic substitution; electron donating groups activate the ring towards electrophilic substitution and deactivate it towards nucleophilic substitution. While most ring deactivators go in the meta position, halogens direct ortho-para, i.e. the same as ring activators. This is because the halogens, especially fluorine and chlorine are very electronegative and thus have an electron inductive effect and decrease the electron density of the ring. This inductivity is far greater than the resonance stability that the halogen can give the ring thus deactivating it. Thus the addition of these halogen atoms decreases the nucleophilic nature of the ring and decreases the rate of metabolism. This can b e shown with the metabolism of the drug Diclofenac (shown below [4]) which is an anti-inflammatory drug as it is has a half-life of around one hour. While its derivative fenclofenac which has a para-substituted chlorine atom has a half-life twenty times longer. Alkene epoxidation: Epoxidation of alkenes occurs readily, because they are more volatile than the ? bonds of aromatic compounds, this simply involves the addition of an epoxide ring to a molecule in order for it to then undergo further transformations. For example the drug Coumarin has been used clinically at high dosages in humans in the treatment of high-protein lymphedemas (Jamal and Casley-Smith, 1989) and as an antineoplastic agent in the treatment of renal cell carcinoma (Marshall et al., 1994) and malignant melanoma (Marshall et al., 1989). [5] It and its 3/7-hydroxy isomers undergo epoxidation and then either glutathione conjugation or non-enzymatic intramolecular rearrangement [5] to secondary metabolites. This is shown schematically below. [5] It is also vitally important that environmental carcinogens are broken down via drug metabolism, in particular by the P450 enzymes. For example acrylonitrile (AN2) is widely used in the production of acrylic and modacrylic fibres, plastics, rubbers, resins, and as a chemical intermediate in the synthesis of many other industrial products (IARC,1999). Early epidemiological studies have suggested that AN may increase the incidence of lung, colon, and stomach cancers among exposed workers (Thiess and Fleig, 1978; Blair et al., 1998).[6] As a result P450 epoxidation is vital for preventing carcinogenic action of AN. While the metabolic basis of the acute toxicity of AN has not been fully elucidated, it is generally attributed to its metabolism to CEO (cyanoethylene oxide) and cyanide, and glutathione depletion. The primary target of acute toxicity of AN is the central nervous system due, at least partially, to the liberation of cyanide (Ahmed and Patel, 1981; Benz et al., 1997). [6] The below diagram illustrates how AN is metabolised by the P450 enzymes, specifically the CYP2E1 isoform.[6] Alcohol and aldehyde metabolism: Alcohols and aldehydes can be metabolized by cytochrome P450 enzymes to aldehydes and carboxylic acids respectively, but the majority of these transformations are catalysed by alcohol dehydrogenase and aldehyde dehydrogenase. These enzymes are predominantly in the liver and require the coenzyme NAD+ or NADP+. General equations for these reactions are shown below. [Alcohol Dehydrogenase]Ez + RCH2OH + NAD + RCHO + NADH + H+ [Aldehyde Dehydrogenase]Ez + RCHO + NAD+ + H2O RCOOH + NADH + H+ Reduction: Cytochrome P450 enzymes are used along with reductases to metabolise drugs that have a carbon atom that is able to be reduced such as a carbonyl or an unsaturated carbon, a nitro group or a compound with an azo group. In addition upon reaction usually a specific stereoisomer is formed. The structure of the rest of the compounds often attribute to which stereoisomer is formed. Some stereoisomers can prove to be toxic. Carbonyl compounds: Carbonyl compounds are reduced by cytochrome P450 into alcohols and are NADP or NADPH dependent. The enzymes involved in the reduction of carbonyls are classified based upon their gene sequence, 3-D structure and cofactor dependence into superfamilies of; medium-chain dehydrogenases/reductases, aldo-keto reductases, short-chain dehydrogenases/reductases which include carbonyl reductases. The majority of these enzymes are present in the cytosol however there are some that are found in the microsomes and mitochondria. Short-chain dehydrogenases/reductases (SDRs) and aldo-keto reductases (AKR) are the most common enzymes used in drug metabolism. These enzymes also exhibit high specificity for the drugs that they reduce. Saturated ketones reduced to alcohols whilst in an unsaturated ketone both the ketone group and the double bonds are both reduced. Steroidal drugs undergo oxidoreduction of the hydroxy/keto group at C17[7]. This makes the compound more water soluble and hence easier to be excreted. Some metabolising enzymes behave differently and undergo different types of reactions when in different cells. An example is carbonyl reductases within tumour cells and normal cells. These have become a target of new drugs such as oracin in the treatment of breast cancer [9]. The enzymes within the cancer cells metabolise oracin and doxorubin more effectively than in normal cells hence reducing the efficacy of the cytostatic effect of the drugs. Some carbonyl compounds however do not undergo reduction via the cytochrome P450 pathway but are rather reduced by other pathways including the aldo-keto reductases (AKR). An example is a drug containing a 1,3-diketone derivative S-1360 which upon reduction produces a key metabolite HP1 which constitutes a major clearance pathway[9]. Nitrogen compounds: The reduction of nitrogen containing compounds are reduced to amines in order to aid excretion as amines are more water soluble than their nitro groups. Azo compounds on the other hand may be metabolised within the body to produce the active drug as opposed to the precursor which may be formulated to get pass the first pass effect or the hydrophilic barrier in order to enter their target cells. The azo group provides 2 compounds with amine groups which can be further metabolised like any other amine. Both of these functional groups are both reduced by cytochrome P450 enzymes and are NADPH dependent. Hydrolysis: This is part of the Phase I metabolism pathway. The metabolites produced are all susceptible to Phase II conjugation and thus being excreted after the conjugation. The functional groups of the drugs that are metabolised by hydrolysis include esters and amides, which produce carboxylic acids, alcohols and amines. Esters are hydrolysed quicker than amides in vivo. Unlike oxidation and reduction the reactions are typically not carried out by the cytochrome P450 system. The most significant enzymes involved in the hydrolysis of the esters and amides are carboxylesterases and arylesterases, cholinesterases and serine endopeptidases. The active site of the enzymes involved may be stereospecific as to which enantiomer of the drug is metabolised and in addition which enantiomer of the drug is generated. Some of these products are toxic and dangerous to the body. Amino acid reactions Several phase I reactions produce a carboxylic acid metabolite. Xenobiotic carboxylic acids can be metabolised before elimination by amino acid conjugation. Glycine; the most common conjugating amino acid forms ionic conjugates that are water soluble with aromatic, arylaliphatic and heterocyclic carboxylic acids. In these reactions, first the xenobiotic carboxylic acid is activated by ATP to form the AMP ester by the enzyme acyl synthetase. Then the AMP ester is converted to a Coenzyme-A thioester. Next, an amide or peptide bond is formed between the thioester and the amino group of glycine. The latter reaction is mediated by the enzyme acyl transferase. These reactions are shown in figure 1. The amino acid conjugate produced is ionic and therefore water soluble, hence it is easily eliminated in the urine and bile. (1) Glutathione conjugation Glutathione is a protective compound in the body that removes potentially toxic electrophilic compounds and xenobiotics. Drugs are metabolised by phase I reactions to form strong elecrophiles that can react with glutathione to form conjugates that are not toxic. This phase II reaction differs from others since electrophiles are subject to conjugations rather than nucleophiles. The nucleophilic thiol group on the glutathione compound (figure 2) attacks elecrophiles (electrophilic carbons with leaving groups). Compounds that can be conjugated to give thioether conjugates of glutathione: Epoxides Haloalkanes Nitroalkanes Alkenes Aromatic halo- and nitro- compounds Glutathione-S-transferases (GST) are enzymes which catalyse the reactions above. There are thirteen different human GST subunits which have been identified and they belong to five different classes. They are located in the cytosol of the liver, kidney and gut. The enzyme GST is thought to increase the ionisation of the thiol group of glutathione, leading to an increase in its nucleophilicity towards electrophiles. (1)(2) Once formed, GSH conjugates may be excreted directly or more often they are further metabolised to N-acetylcysteine conjugates which can then be excreted via phase III metabolism. Phase III Metabolism further modification and excretion Before being excreted in the urine, most xenobiotics are made less toxic and more water soluble as polarity increases by metabolising enzymes in phase II reactions. In phase III metabolism water soluble compounds are excreted in the urine. However, some drug compounds are not metabolised and therefore are not excreted. These non-metabolised compounds are readily reabsorbed from the urine through the renal tubular membranes and into the plasma to be recirculated. (3) Some xenobiotic conjugates from phase II reactions are further metabolised during phase III metabolism reactions. Glutathione-S conjugates may be metabolised further by hydrolysis of the glutathione conjugate (GSR) at the y-glutamyl bond of the glutamate residues by y -glutamyl transferase (y -GT) followed by hydrolysis of glycine residues resulting in a cysteine conjugate containing a free amino group of the cysteine residue. This then undergoes N-acetylation to form mercapturic acid. The final products; mercapturic acids are S-derivatives of N-acetylcysteine synthesised from glutathione (figure 4). (1)(2) First-pass Metabolism The metabolism of many drugs is dependent on the route of administation therefore orally administered drugs are subject to first pass metabolism and consequently their bioavailablity is reduced. This occurs as a result of the orally administered drugs entering the systemic circulation via the hepatic portal vein, so the drug is exposed to the intestinal wall and the liver, which is thought to be the main site of first-pass metabolism of orally administered drugs. Other possible sites are the gastrointestinal tract, blood, vascular endothelium and lungs. First-pass Metabolism in the Liver During first-pass metabolism, the cytochrome P450 enzymes family represent the most significant of the hepatic enzymes. It has been estimated that the endoplasmic reticulum of the liver contains approximately 25 000 nmol of cytochrome P450. Although there are several human P450 subfamilies and multiple individual isozymes within subfamilies, only five P450 enzymes are shown to be significant for the process of first-pass metabolism: CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 Cytochrome P450 drug substrates are commonly highly extracted during first-pass metabolism. Examples of these drugs are; morphine, verapamil, propranolol, midazolam, lidocaine. Drugs that are highly extracted such as lidocaine have a low bioavailability when taken orally therefore they are not administered orally. CYP3A4 is the most commonly active isozyme against P450 drug substrates. This is possibly due to the enzymes abundance and broad substrate specificity. Highly extracted substrates for conjugative, reductive or non-P450 oxidative enzymes are less common. These include labetalol, morphine, terbutaline, isoproterenol and pentoxifylline. The gut is also an important organ involved in pre-systemic metabolism. Metabolism here for drugs with high first-pass metabolism leads to a reduced bioavailability. Some metabolizing enzymes such as CYP3A4 is found at a higher level in enterocytes than in the liver. Recent findings state that gut wall metabolism is the major cause of low bioavailability of certain drugs. Intestinal First-pass Metabolism Various drug metabolizing enzymes found in the liver are also found within the epithelium of the gastrointestinal tract. These include cytochromes P450, glucuronosyl transferases, sulfotransferases, N-acetyl transferase, glutathione S-transferases, esterases, epoxide hydrolase and alcohol dehydrogenase. The small intestine contains high amounts of three cytochrome P450 enzymes; CYP3A, CYP2D6 and CYP2C. Unlike the liver which has a relatively uniform distribution of P450enzymes, the distribution of P450 enzymes is not uniform along the small intestine and villi. Proximal mucosal P450 content is normally higher than distal mucosa P450 content. Therefore it has been established that protein level and catalytic activity of drug-metabolizing enzymes in the small intestine are generally lower than those in the liver. This has been demonstrated by comparison of cytochrome P450 enzymes in the liver and the small intestine. The extent of first-pass metabolism can result from interindividual variability: Genetic variation Induction or inhibition of metabolic enzymes Food increases liver blood flow. This can increase the bioavailablity of some drugs by increasing the amount of drug presented to the liver to an amount that is above the threshold for complete hepatic extraction Drugs that increase liver blood flow (similar effects to food) and drugs that reduce liver blood flow Non- linear first pass kinetics, i.e. dose Liver disease increases the bioavailability of some drugs with extensive first-pass metabolism (4) To avoid first pass metabolism a drug can be administered sublingual and buccal routes. These routes lead to drugs being absorbed by the oral mucosa. During sublingual administration the drug is put under the tongue where it dissolves in salivary secretions. An example of a sublingual drug is nitroglycerine. During buccal administration the drug is positioned between the teeth and the mucous membrane of the cheek. Both of these routes avoid destruction by the GI fluids and first pass effect of the liver. Drugs may also be administered via other routes to avoid first-pass metabolism, for example; rectal, inhalation, transdermal, intravenous. (5) Prodrugs Many drugs require metabolic activation in order to exert their pharmacological action; these are described as pro-drugs. There are two types; type I and type II which has subtypes A and B dependent on the site of activation. Type I prodrugs are converted intracellularly at the target cells (A) or at tissues that usually metabolise compounds (B). An example of a type IA prodrug is Zidovudine and type IB prodrug is captopril. Metabolic activation of type I prodrugs is usually linked to phase I metabolic enzymes. Type II prodrugs are converted extracellularly in GI fluids (A) or in the systemic circulation (B). An example of a type IIA prodrug is sulfasalazine and type IIB prodrug is fosphenytoin. Type II prodrugs are very popular as they are involved in overcoming bioavailability problems, which are commonly experienced with many drugs, by improving permeability and reducing the first pass effect. (6) Type I Prodrugs are used to target a drug to its specific site of action; an example of this is the drug used in Parkinsons disease levodopa; the inactive form of the drug which is metabolised in the neurone by the enzyme dopa decarboxylase to the active form; dopamine. Dopamine does not cross the blood-brain barrier so it is given as the levodopa precursor which is lipophilic so it can cross the barrier and then metabolized in vivo to dopamine. (7) Another example of the use of prodrugs is the pharmacological activation of a type II prodrug Azathioprine to mercaptopurine which is a chemotherapeutic agent used in the treatment of leukaemia. When mercaptopurine is administered, its clinical usefulness is restricted because of its rapid biotransformation by xanthine oxidase to an inactive metabolite 6-thiouric acid. Therefore larger doses have to be given as it has a low bioavailability, this leads to toxicity. By administering mercaptopurine as its cysteine conjugate, the limitations can be overcome. This ionic form of the pro-drug conjugate is selectively taken up by the renal organic anion transport system. The kidney B-lyase enzyme system then cleaves the prodrug conjugate to give the active mercaptopurine in the kidney (figure 5). (8)(9) To conclude, prodrugs can be metabolised in different ways to form the active drug. They can be used to target specific sites, improve absorption and improve oral delivery of poorly water-soluble drugs. They can also be used to avoid first pass metabolism in drugs with high first pass extraction and reduce toxicity. (6) Factors affecting metabolism There are several factors that can affect drug metabolism. Age, sex, inducers and inhibitors are some of which can effect drug metabolism which are mentioned below. How does age affect drug metabolism: There are many physiological changes that occur with ageing. The changes have the potential to affect both drug disposition and metabolism. Drug metabolism is mainly functioned by the liver, its size, blood perfusion and synthetic capacity for proteins which all determine the rate of hepatic drug elimination[5]. Paediatric population Phase one and phase two metabolic pathways may not be active at birth due to maturational changes. The paediatric population and elderly population have differences in their capacity to metabolise a drug which can therefore produce a lower or higher plasma concentration of active substances compared with adults depending on the enzyme system used. There are examples of metabolites produced by therapeutic agents in children that are not usually seen in adults. The metabolites produced maybe the reason for some of the efficacy and or toxicity visible with drug administration in children. An example is: caffeine production in a neonate receiving Theophylline. Other therapeutic agents which show changes in metabolite production in children are; Valproic acid, paracetamol, Chloramphenicol, Cimetidine Salicylamide. In most cases the differences that occur between children and adults are in the ratios of the metabolites relative to the parent drug rather than in new metabolites individual to the paediatric population with some exceptions. The paediatric population shows the same set of enzymes as the adult population. (1) In general age related changes in drug metabolism have been shown to occur due to a consequence of diminished enzyme activities within the elderly human liver due to the size of the liver decreasing and hepatic blood flow decreasing. With age the liver blood flow is generally reduced by about 20-30% and there is a decrease in liver size by about (17-36%). Currently there is no clear pattern; however there are two general trends that influence the rate of metabolism. One trend is that drugs that are undergoing hepatic microsomal oxidation are more likely to be metabolised slowly in the elderly and those which are conjugated are not likely to be influence by the age factor. Secondly, drugs that have high hepatic clearance, extraction ratios example-Chlormethiazole, and Labetalol and undergo extensive first pass metabolism whilst oral absorption may show a large increase in bioavailability in the elderly. Elderly population In general in the elderly population hepatic blood flow decreases up to 40% and there can be a considerable reduction in the amount of drug reaching the liver per unit. Studies have shown that the effect of ageing on liver enzymes with particular drug

Characters, Setting, Themes, and Symbols of Heart of Darkness Essay

Characters, Setting, Themes, and Symbols of Heart of Darkness      Ã‚   Deep within the chest of every man, woman, and child beats the heart of darkness. On the surface, mankind has achieved a sophisticated level of civilization. Joseph Conrad forces the reader to peel away the pristine layer of sweetness and see the unaltered truth. Heart of Darkness reveals the true nature that lurks behind every smile, handshake, and conversation. Conrad's portrayal of the characters, setting, symbols, and ironies allow the reader to reflect on the true nature of man.    Each of the main characters in Heart of Darkness plays a significant role in the overall theme of the novel. The central character is a thirty two year old sailor, Charlie Marlow. He is a dynamic character who essentially controls the development of the theme. Through Marlow's experiences and revelations, the author illustrates how forces of light and darkness serve to weave the human soul together; thus, essentially how good and evil are reflected in an individual. Marlow's journey leads him in an urgent search for Kurtz, the one man who can... ...art lies the raw evil of untamed lifestyle" (Heart of Darkness: A systematic evaluation).    Works Cited "The Congo" Created December 07, 1997 (Accessed 12 February 2002). Conrad, Joseph. Heart of Darkness. New York: Penguin Books, 1983. "The Fear" Created December 07, 1997 (Accessed 12 February 2002). "Heart of Darkness: A systematic evaluation of the darkness inherent in men's souls" "The Perfect Native" Created December 07, 1997 (Accessed 12 February 2002). "The Setting" Created December 07, 1997 (Accessed 12 February 2002). Characters, Setting, Themes, and Symbols of Heart of Darkness Essay Characters, Setting, Themes, and Symbols of Heart of Darkness      Ã‚   Deep within the chest of every man, woman, and child beats the heart of darkness. On the surface, mankind has achieved a sophisticated level of civilization. Joseph Conrad forces the reader to peel away the pristine layer of sweetness and see the unaltered truth. Heart of Darkness reveals the true nature that lurks behind every smile, handshake, and conversation. Conrad's portrayal of the characters, setting, symbols, and ironies allow the reader to reflect on the true nature of man.    Each of the main characters in Heart of Darkness plays a significant role in the overall theme of the novel. The central character is a thirty two year old sailor, Charlie Marlow. He is a dynamic character who essentially controls the development of the theme. Through Marlow's experiences and revelations, the author illustrates how forces of light and darkness serve to weave the human soul together; thus, essentially how good and evil are reflected in an individual. Marlow's journey leads him in an urgent search for Kurtz, the one man who can... ...art lies the raw evil of untamed lifestyle" (Heart of Darkness: A systematic evaluation).    Works Cited "The Congo" Created December 07, 1997 (Accessed 12 February 2002). Conrad, Joseph. Heart of Darkness. New York: Penguin Books, 1983. "The Fear" Created December 07, 1997 (Accessed 12 February 2002). "Heart of Darkness: A systematic evaluation of the darkness inherent in men's souls" "The Perfect Native" Created December 07, 1997 (Accessed 12 February 2002). "The Setting" Created December 07, 1997 (Accessed 12 February 2002).

Examine computer Forensics and Privacy Essay

Although the Fourth Amendment of the Constitution protects us from illegal searches and seizures, it left somewhat of a grey area when it came to electronic communications. With all the technological advances almost every person uses some kind of device to communicate electronically that goes out to the Internet. When using these devices to communicate information can be intercepted and even altered in some ways. Because of these advances in technology Congress has implemented laws to protect people from having information stolen or accessed illegally by individuals or even in some cases Law Enforcement. In the advent of Computer Forensics, certain guidelines must be met before obtaining any information either by intercepting the transmission, securing the device or acquiring the information by means of remotely connecting into the device. Several laws have been implemented to protect a person’s rights with regards to accessing their electronically stored data. The Wire Tap Act is one of these laws. This law prohibits any interception of a communication between two private parties without an order issued by a court. Any violation of this Act will result in criminal or civil liability, and a violation by governmental officials in a case could result in a suppression of that evidence. Both the Stored Wired and Electronic Communications Act, and the Pen Registers and Trap and Trace Devices Statute identify the need for protecting the privacy of individuals with regards to computers and the data within them. Initially this act was regarding phone numbers that an individual called, but since the implementation of the Patriot Act, I.P addresses can now be accessed along with emails ,communication ports, and what Web sites are being accessed from either your computer or cell phone. Investigators must obtain legal access to computers before obtaining any data from them. The case of Jamie Staley provided an example of how such an intrusion of computer privacy can in fact take place. This case involved the defendant Jamie Staley intercepting emails from members of her husband’s family with  information pertaining to a bitter divorce and child custody battle. Through computer forensic analysis it was determined that in fact Jamie had intercepted and in some cases altered electronic transmissions made by her ex husband’s grandparents and their attorney. This was clearly a violation of the Attorney Client privilege and also the Wire Tap Act, which clearly stated that electronic data being transmitted cannot be intercepted by a third party. An argument can also be made that the Stored Wired and Communications Act regarding accessing stored data had also been violated. When gathering evidence the individual who is responsible for the process has an obligation to obtain the data as accurately and responsibly as possible. Data must be collected both legally and proficiently, in order to protect the rights of the individuals being investigated. Both policies and procedures must be followed to protect the integrity, and reliability of the evidence being collected. Sources: 1. Stored Communications Act : http://en.wikipedia.org/wiki/Stored_Communications_Act 2. â€Å"Pen Registers† and â€Å"Trap and Trace Devices https://ssd.eff.org/wire/govt/pen-registers 3. Computer Security and Forensics Law Checklist: By Josh Wepman http://www.ehow.com/list_6746948_computer-security-forensics-law-checklist.html