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During and therefore sufficient blood supply to the brain luxury perfusion purchase viagra soft 50mg mastercard erectile dysfunction medication costs, oxygen supply exceeds the oxygen must be maintained consistently 50 mg viagra soft with amex vacuum pump for erectile dysfunction canada. A normal adult requirements of the tissue generic viagra soft 100 mg online impotence hypertension, as reflected by the appear- male’s brain containing approx buy generic viagra soft on-line erectile dysfunction treatment wikipedia. This is one of the brain’s oxygen consumption is almost entirely for the reasons why primary post-ischemic recovery may be oxidative metabolism of glucose, which in normal followed by delayed post-ischemic hypoxia and physiological conditions is the almost exclusive secondary metabolic failure . The magnitudes of these vide lactate to the neurons where lactate is further increases are linearly related to the frequency of oxidatively phosphorylated . Overall, 87% of the action potentials in the afferent pathways, and total energy consumed is required by signaling, increases in the projection zones occur regardless of mainly action potential propagation and postsynaptic whether the pathway is excitatory or inhibitory. Cerebral blood flow, oxygen utilization and energy metabolism in the brain are still not under- metabolic rates of glucose in man (approximate values). Chapter 1: Neuropathology and pathophysiology of stroke during and after ischemia of varying degree and Flow thresholds for preservation duration it was possible to construct a discriminant of function and morphological integrity curve representing the worst possible constellation of The different energy requirements for maintenance residual blood flow and duration of ischemia still of membrane function and for propagation of infor- permitting neuronal recovery (Figure 1. These mation (signals) lead to different thresholds of energy results broaden the concept of the ischemic penum- consumption and consequently blood flow required bra: the potential for recovery (or irreversible for preservation of neuronal function and morpho- damage) is determined not only by the level of logical integrity. The range of perfusion between residual flow but also by the duration of the flow those limits – a blood flow level below which neur- disturbance. Each level of decreased flow can, on onal function is impaired and a lower threshold average, be tolerated for a defined period; flow below which irreversible membrane failure and mor- between 17 and 20 ml/100 g/min can be tolerated for phological damage occur – was called the “ischemic prolonged but yet undefined periods. As a rule used penumbra” ; it is characterized by the potential in many experimental models, flow rates of 12 ml/100 for functional recovery without morphological g/min lasting for 2–3 hours lead to large infarcts, but damage, provided that local blood flow can be re- individual cells may become necrotic after shorter established at a sufficient level and within a certain periods and at higher levels of residual flow. It is characterized by the potential for disappeared at approximately 18 ml/100 g/min. The functional recovery without morphological large variability of the functional thresholds of damage. This explains the gradual development of Imaging of penumbra neurological deficits, which might additionally be Based on the threshold concept of brain ischemia, related to altered single-cell activity with grouped or the penumbra can be localized on quantitative flow regular discharges at flow levels above the threshold. Under experimental conditions opment of irreversible morphological damage is time- the most reliable way to localize the infarct core is the dependent. A biochemical marker of core plus penum- þ leakage of K out of cell bodies, indicating loss of bra is tissue acidosis or the inhibition of protein membrane function and leading to anoxic depolar- synthesis. The interaction of severity and duration of ische- of gene transcripts that are selectively expressed in mia in the development of irreversible cell damage the penumbra, such as the stress protein hsp70 was studied by simultaneous recordings of cortical or the documentation of the gradual disappearance neuronal activity and local blood flow. Based on of the penumbra with increasing ischemia time  13 recordings from a considerable number of neurons (Figure 1. Biochemical imaging of infarct core and penumbra after experimental middle cerebral artery occlusion. An alternative method is vation of vitality markers, such as flumazenil binding quantitative mapping of the apparent diffusion coef- to central benzodiazepine receptors . In the following, Finally, new developments in non-invasive the most important mediators of infarct progression molecular imaging are of increasing interest for will be discussed. These methods make use of contrast probes that trace gene transcription or of Brain infarcts grow in three phases: intracellular conjugates that reflect the metabolic acute phase, within a few minutes after the onset status and/or bind to stroke markers. The number of ischemia; terminal depolarization of cell of molecules that can be identified by these methods membranes; rapidly expands and greatly facilitates the regional subacute phase, within 4–6 hours; molecular analysis of stroke injury. Progression of ischemic injury With the advent of non-invasive imaging evidence has Peri-infarct spreading depression been provided that brain infarcts grow. This growth is A functional disturbance contributing to the growth not due to the progression of ischemia because the of the infarct core into the penumbra zone is activation of collateral blood supply and spontaneous the generation of peri-infarct spreading depression- thrombolysis tend to improve blood flow over time. These depolarizations are Infarct progression can be differentiated into three initiated at the border of the infarct core and spread phases. During the acute phase tissue injury is the over the entire ipsilateral hemisphere. During spread- direct consequence of the ischemia-induced energy ing depression the metabolic rate of the tissue mark- failure and the resulting terminal depolarization of edly increases in response to the greatly enhanced cell membranes. At flow values below the threshold energy demands of the activated ion-exchange of energy metabolism this injury is established within pumps. In the healthy brain the associated increase a few minutes after the onset of ischemia. During the of glucose and oxygen demands is coupled to a paral- subsequent subacute phase, the infarct core expands lel increase of blood flow but in the peri-infarct into the peri-infarct penumbra until, after 4–6 hours, penumbra this flow response is suppressed or even core and penumbra merge. As a result, a misrelationship arises expansion are peri-infarct spreading depressions and between the increased metabolic workload and the low a multitude of cell biological disturbances, collectively oxygen supply, leading to transient episodes of hypoxia referred to as molecular cell injury. Finally, a delayed and the stepwise increase in lactate during the passage phase of injury evolves which may last for several of each depolarization. During this phase secondary The pathogenic importance of peri-infarct depo- phenomena such as vasogenic edema, inflammation larizations for the progression of ischemic injury is and possibly programmed cell death may contribute supported by the linear relationship between to a further progression of injury. The largest increment of infarct volume occurs Correlation analysis of this relationship suggests that during the subacute phase in which the infarct core during the initial 3 hours of vascular occlusion each expands into the penumbra. Using multiparametric depolarization increases the infarct volume by more imaging techniques for the differentiation between than 20%. This is probably one of the reasons that core and penumbra, evidence could be provided that glutamate antagonists reduce the volume of brain 1 hour after occlusion of the middle cerebral artery infarcts because these drugs are potent inhibitors of 15 the penumbra is still approximately of the same size spreading depression. Section 1: Etiology, pathophysiology and imaging Peri-infarct spreading depressions are depolariza- pathogenic importance in different ischemia models. Therefore, the relative contribution of the following injury mechanisms differs in different types Molecular mechanisms of injury of ischemia. As the severity of acidosis correlates with the “molecular” does not anticipate any particular injury severity of ischemic injury, it has been postulated that pathway (Figure 1. Schematic representation of molecular injury pathways leading to mitochondrial failure and the endoplasmic reticulum 16 stress response. Injury pathways can be blocked at numerous sites, providing multiple approaches for the amelioration of both necrotic and apoptotic tissue injury. The changes in suggests that acidosis may induce calcium toxicity, intracellular calcium activity are highly pathogenic: and that this effect is the actual mechanism of acido- prolonged elevation of cytosolic calcium causes mito- toxicity . The activation of ionotropic glutamate secondary disturbances, notably inhibition of protein receptors results in the inflow of calcium from the synthesis. Calcium-dependent pathological events are extracellular into the intracellular compartment, therefore complex and contribute to a multitude of leading to mitochondrial calcium overload and the secondary molecular injury pathways. However, following quences of free radical reactions are the release pharmacological inhibition of ionotropic glutamate of biologically active free fatty acids such as arachi- receptors, an apoptotic injury mechanism evolves donic acid, the induction of endoplasmic reticulum that may prevail under certain pathophysiological stress, the induction of mitochondrial disturbances conditions. The latter may induce ischemic cell injury has been debated, but this does apoptosis and thus enhance molecular injury not invalidate the beneficial effect of glutamate pathways related to mitochondrial dysfunction. An The therapeutic benefit of free radical scavengers, explanation for this discrepancy is the above- however, is limited, as recently documented by the described pathogenic role of peri-infarct depolariza- therapeutic failure of the free-radical-trapping agent tions in infarct expansion. During ischemia anoxic depolarization in com- flow and the alleviation of hypoxic injury, whereas bination with the activation of ionotropic glutamate in neurons it contributes to glutamate excitotoxicity and acid-sensing ion channels causes a sharp rise of and – by formation of peroxynitrate – to free-radical- cytosolic calcium . However, zinc may also exhibit neuro- ally will cause disruption of the outer mitochondrial protective properties, indicating that cells may possess membrane and the release of pro-apoptotic mito- a specific zinc set-point by which too little or too chondrial proteins (see below). It is initiated A large number of biochemical substrates, molecules and mechanisms are involved in the by the ischemia-induced release of calcium stores progression of ischemic damage. This again leads to selective inhib- tigated in the search for possible pharmacological ition of polypeptidepol chain initiation, disaggregation targets (for review see Rothwell and Luheshi ).
- 3-methyl crotonyl-coa carboxylase deficiency
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- Coffin Siris syndrome
- Neuronal intestinal pseudoobstruction
- Shy Drager syndrome
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Can selective termination ever be justiWed buy 100 mg viagra soft impotence from prostate removal, or is allowing ‘targeting’ of a particular fetus on grounds of sex generic 50mg viagra soft free shipping erectile dysfunction book, for example purchase viagra soft master card impotence grounds for divorce states, simply wrong whether that sex is male or female? In a series of illuminating case examples purchase viagra soft 50 mg overnight delivery erectile dysfunction mental treatment, Mahowald teases out the ethical issues around selective termination, concluding that it may sometimes be justiWed but that practitioners need to be alert to possible abuses in justice which it may raise. Traditional arguments for secrecy are beginning to give way to counter-arguments for openness, but will donors still be forthcoming if their identities can be traced? Evidence from Sweden (the Wrst country to introduce non-anonymous donation) indicates that after an initial dip in the number of donors, earlier levels of donation are regained, but with a diVerent sort of donor, with more altruistic motivations. Finally, the validity of the arguments both for and against anonymity are considered, and the implications of changes in the practice of secrecy for donor insemination are outlined. Elina Hemminki (Chapter 12), a Finnish epidemiologist and health tech- nology assessment expert, approaches antenatal screening from an evidence- based medicine viewpoint. Her contribution is particularly valuable because, as an ‘outsider’ to medical ethics, she is able to pick up inconsistencies in how the reproductive ethics literature treats diVerent interventions which actually raise many of the same questions. Whereas Tong and Mahowald primarily consider the individual woman or couple, Hemminki concentrates on popu- lations, and on the ethical questions raised by mass screening. Is it right, for example, to impose on those undergoing screening an unavoidable risk of false positives and false negatives – which will never be altogether eliminated, no matter how precise the screening process? Through the organization of screening pro- grammes and concomitant research, medicine and health care have been given the authority to deWne which diseases and characteristics qualify for these beliefs’. Directing our attention to the wider societal impact of screen- ing, outside the dyadic doctor–patient relationship, Hemminki argues that medicine has been given something of a poisoned chalice. What appeared at Wrst to be a straightforward part of the goals of medicine, the reduction of disease in populations through genetic screening, is neither straightforward nor necessarily part of the goals of medicine. Similarly, the development of stem cell technologies may appear at Wrst to be an unmitigated blessing in terms of disease reduction, but the manner in which stem cell lines are being established gives profound cause for fears about abuse and exploitation. Most commentators have concentrated on the moral status of the embryo, and those who have concluded in favour of developing stem cell banks or lines have done so on the basis that the embryo used is not harmed because it will in any case be destroyed (e. In contrast, Dickenson concentrates on the risks of exploita- tion of pregnant women, and conversely on the arguments in favour of their possessing a property right in stem cells derived from their embryos or fetuses, in addition to the procedural right to give or withhold consent to the further use of those tissues. These rights can be viewed in a Lockean fashion, as derived from the labour which women put into the processes of superovulation and egg extraction (embryonic stem cells) or early pregnancy and abortion (embry- onic germ cells). Uniting philosophical and jurisprudential argumentation, Dickenson argues that it is legally fallacious and politically dangerous to assume that biotech- nology companies should necessarily own the products derived from women’s labour in reproduction. Many of these issues centre around responsibility for bringing infected children into the world, or orphaning children, particularly in the Third World context. Dickenson which sets utilitarian arguments in favour of reducing the incidence in the general population against the individual woman’s ‘right to know’ – and perhaps to take prophylactic measures. She argues that arguments for ano- nymized testing are dominated by the ‘old ethics’ of medical paternalism, but that whereas paternalism is usually justiWed on the basis of the relationship of trust between the doctor and patient, that Wduciary relationship actually rules out anonymized testing. How can we balance the respect due to the pregnant woman’s autonomy – particularly when she is not sick – with concern for the welfare of the woman and the fetus? Disability and enhancement Issues surrounding disability and enhancement are touched on by several of the authors already summarized, but they come to the fore in the chapters by Neil McIntosh, Priscilla Alderson, Christine Overall, and Rebecca Bennett and John Harris. Neil McIntosh (Chapter 21), a consultant paediatrician in Scotland, oVers a practising clinician’s slant on disability, in the context of ethical issues in withdrawing life-sustaining treatment. He writes, ‘Life-sustaining treatment implies that treatment is being given in order to maintain or create the best possible outcome for the child’s future life. At the end of his chapter, McIntosh oVers a useful typology of uncertainty concerning the probability of severe disability and its eVect on clinical decision-making, but what about the utility question? This sceptical view emerges strongly among the people with disability interviewed by the English sociologist and children’s rights advocate Priscilla Alderson (Chapter 13). Many of the conditions dealt with by McIntosh are more immediately life-threatening than those in the adults interviewed by Alderson; after all, these people have reached adulthood. Where does the ethically aware clinician draw the line between hopeless prolongation of an ‘abnormal’ life and sensitivity to the disability-rights view? In terms of the abortion debate, Alderson appears to favour a movement away from antenatal testing for common disabilities and a return to uncondi- tional acceptance of handicapped children as ‘a gift of God’. If, as Dickenson argues, women’s labour in pregnancy and childbirth gives them the Lockean right to control the circumstances in which they will perform that labour – and indeed whether they will perform that labour at all – there is no basis for imposing on pregnant women the duty to endure childbirth in the full knowledge that a severely handicapped child is likely to be the outcome. Alderson does, however, acknowledge the advantages of prenatal testing and termination when there is no other means of avoiding intolerable suVering on the part of the child and family. She was actually a member of the working party of the Royal College of Paediatrics on withdrawal and withholding of treatment from severely ill neonates and children, which handed down guidelines that accept the ‘unbearable’ situation, one in which repeated intervention is more than can be borne, as a legitimate reason for withhol- ding treatment. Overall’s scepticism about the philosophical validity of the Wrst claim, that existence itself is a beneWt, creates a productive tension with the work of Rebecca Bennett and John Harris. It is logically incoherent to claim that a being now in existence is ‘better oV’ being born, Overall writes, because if that person had not been born, there would be no entity with which we can compare it. It may well be that it does not make sense to talk of someone being made better or worse oV by being brought into existence, but it does appear to make sense to talk about lives that are worth living and those that are so blighted by suVering that they may be considered ‘‘unworthwhile’’. Harris asserts that harm is done, on a utilitarian calculus, because more ‘handicapped’ children have been born, although no speciWc child has been harmed by being brought to existence, because it is impossible to compare existence with non-existence. In the Journal of Medical Ethics article (Harris, 2000) from which Chapter 20 is drawn, Harris asks whether a deaf couple who choose to implant a deaf fetus over a hearing fetus are to be pitied if, by mistake, the ‘normal’ fetus is implanted instead. Difference: gender and culture For the past 20 years feminist theory has been preoccupied with the notion of diVerence, dating perhaps from Carol Gilligan’s In a DiVerent Voice (1982, 1993 – 2nd edn. Gilligan advanced the hypothesis that a diVerent ethical ‘voice’ needed to be heard, one less concerned with the autonomy of the atomistic individual and more willing to recognize embeddedness in rela- tionship. Although that voice was not only to be found in women, assess- Introduction 13 ments of moral maturity in conventional psychological developmental test- ing tended to reward the autonomy model, and to Wnd that model more frequently in boys and men. French psychoanalytic feminist theorists such as He´le`ne Cixous and Luce Irigaray provided an alternative emphasis on diVer- ence, grounded in Lacanian psychoanalysis and based on a revision of the ‘mirror’ stage to accommodate female experience. Postmodernism, also, contributed an accent on diVerence, to the extent that the very notion of ‘woman’ is undermined – diVerences within the category are as important as those between men and women to postmodernist feminists (Butler, 1987). Other feminists, however, doubt that without a uniWed notion of ‘woman’ there can properly be any such thing as feminism or feminist politics (Dick- enson, 1997). Sceptics about the notion of ‘diVerence’ warn that ‘an aYrm- ation of the strengths of female ‘‘diVerence’’ which is unaware of [female suppression] may be doomed to repeat some of the sadder subplots in the history of Western thought’ (Lloyd, 1993: p. Kristeva, 1984), ShenWeld notes that ‘Kristeva argues that we cannot respect and accept strangers if we have not accepted our own portion of strangeness, in other words, the stranger within ourselves. The implication for cloning is that the parent(s) seeking reproductive cloning cannot accept that strangeness, car- ried in the matrix of the gestating mother. Another psychoanalytical question concerns the child thus con- ceived, rather than the parent: how will the child cope with building his or her sexual identity? The cloning debate has been treated very largely in conventional bioethical terms, as a matter of the domain of rightful choice of the rational consumer of medical care. Foregrounding diVerence and the construction of the subject, ShenWeld suggests instead that rationality is less important than identity and subjectivity. Writing from the viewpoint of public policy rather than psychoanalytical theory, the Finnish political scientist and development scholar Sirkku Hell- sten asks the diYcult question, ‘Where does legitimate cultural diVerence in obstetric and gynaecological practice end, and discrimination against women begin? Dickenson argument from within the liberal, contractarian tradition, and adding a feminist concern with diVerence, Hellsten concludes that we are not so bound.
These are compounds that bind bile acids; the drop in hepatic reabsorption of bile acids releases a feedback inhibition generic viagra soft 100mg without a prescription erectile dysfunction treatment photos, resulting in a greater amount of cholesterol being converted to bile acids to maintain a steady level in the circulation order generic viagra soft line erectile dysfunction treatment singapore. Focus on: atherosclerosis ‘Arteriosclerosis’ is a general term describing any hardening or loss of elasticity of medium or large arteries discount 50 mg viagra soft amex erectile dysfunction over the counter medications, and refers to the formation of an atheromatous plaque cheap viagra soft 50mg visa impotence drugs. Lipoprotein-associated phospholipase A2 is an emerging cardiovascular risk marker. Monocytes enter the artery wall from the bloodstream, with platelets adhering to the area of insult. This membrane protein mediates leukocyte-endothelial cell adhesion and signal transduction, and may play a role in the development of atherosclerosis and rheumatoid arthritis. There is also smooth- muscle proliferation and migration from tunica media to intima, responding to cytokines secreted by damaged endothelial cells. They are thought to participate in the removal of many foreign substances and waste materials in the body. It is characterised by a remodelling of arteries involving the concomitant accumulation of fatty substances called plaques. As the plaques grow, artery wall thickening occurs without any narrowing of the artery lumen; stenosis, the narrowing of the artery opening, is a late event, which may or may not occur, and is likely the result of repeated plaque rupture and healing responses. Most commonly a plaque will rupture, forming a thrombus, which can rapidly slow or stop blood ﬂow, leading to death of the tissues fed by the artery: an infarction. There is some evidence that atherosclerosis may be caused by an infection of the vascular smooth-muscle cells. Chickens, for example, develop atherosclerosis when infected with the Marek’s disease herpesvirus. Herpesvirus infection of arterial smooth-muscle cells has been shown to cause cholesteryl ester accumulation, which is associated with atherosclerosis. Various anatomical, physiological and behavioural risk factors for atherosclerosis are known. Many of these are recognised within the ‘metabolic syndrome’, a combination of disorders that increases the risk of developing cardiovascular disease and diabetes. Rosuvastatin is a statin shown to demonstrate regression of atherosclerotic plaque within the coronary arteries. The antioxidant effects of the statins may be partly responsible for their therapeutic success. Two main liver lobes are each made up of thousands of lobules; lobules connect to small ducts that connect to larger ducts, forming the hepatic duct. The hepatic duct transports bile, produced by the hepatocytes, to the gallbladder and duodenum. The liver regulates, synthesises, stores and secretes many important proteins and nutrients, and puriﬁes, transforms and clears toxic or unnecessary compounds from the blood. Hepatocytes are optimised for function through their contact with sinusoids (leading to and from blood vessels) and bile ducts. A special feature of the liver is its ability to regenerate, maintaining function even in the face of moderate damage. In utero, energy is provided by glucose, with liver metabolism being directed to glucose degradation; activity of the rate-limiting enzymes of glycolysis, hexokinase and phospho- fructokinase is high. With the onset of post-natal life, and an intake of a fat-rich and carbohydrate-poor diet, infants develop the ability to synthesise glucose de novo from non-carbohydrate precursors (gluconeogenesis). In the inherited condition of Wilson’s disease, the secretion of copper into bile is abnormal, resulting in a low blood level of the copper-binding protein ceruloplasmin. Glycogen is mainly stored in the liver and muscle cells, but the kidneys and intestines also store some limited amounts of glycogen (Table 6. The inability to degrade glycogen may cause cells to become pathologically engorged, lead- ing to a functional loss of glycogen as an energy source and a blood glucose buffer. For example, the enzyme glucose-6-phosphatase is localised on the cisternal (inner) surface of the endoplasmic reticulum, and glucose-6-phosphate must be transported (translocated) across the endoplasmic reticulum to gain access to the enzyme. Mutation of either the phosphatase or the translocase will lead to symptoms characteristic of von Gierke’s disease. Hepatocytes secrete bile into canaliculi, then into bile ducts, where it is modiﬁed by addition of a bicarbonate-rich secretion from ductal epithelial cells. Further modiﬁcation occurs in the gall bladder, where it is concentrated up to ﬁvefold, through absorption of water and electrolytes. Only relatively small quantities of bile acids are lost from the body; approximately 95% of bile acids delivered to the duodenum are absorbed back into blood within the ileum. Venous blood from the ileum goes straight into the portal vein, and hence through the sinusoids of the liver (enterohepatic circulation). Hepatocytes extract bile acids very efﬁciently from sinusoidal blood; they are re-secreted into canaliculi. The net result of enterohepatic recirculation is that each bile salt molecule may be reused up to 20 times, and often 2 or 3 times during a single digestive phase (Figure 6. Liver disease, and damage to the canalicular system, can result in escape of bile acids into the systemic circulation. Assay of systemic levels of bile acids is used clinically as a sensitive indicator of hepatic disease. Bile acids are steroids, characterised by a carbon skeleton with four fused rings, generally arranged in a 6-6-6-5 fashion. Within the intestines, bacteria convert primary bile acids to secondary bile acids, for example deoxycholate (from cholate) and lithocholate (from chenodeoxycholate). Both primary and secondary bile acids are re-absorbed by the intestines and delivered back to the liver via the portal circulation. They facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents; emulsiﬁcation increases the surface area of fat, making it available for digestion by lipases. They facilitate the intestinal absorption of fat-soluble vitamins (vitamin A, retinol; vitamin D, cholecalciferol; vitamin E, tocopherol; and vitamin K). Their synthesis and subsequent excretion in the faeces represents the only signiﬁcant mech- anism for the elimination of excess cholesterol. In humans, roughly 500 mg of cholesterol is converted to bile acids and eliminated in bile every day. Bile acids and phospholipids solubilise cholesterol in the bile, thereby preventing the pre- cipitation of cholesterol in the gall bladder. When chyme from an ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate secretion of the enteric hormones cholecystokinin and secretin. Its effect on the biliary system is similar to that on the pancreas; it simulates biliary duct cells to secrete bicarbonate and water, expanding the volume of bile and increasing the ﬂow rate into the intestine. The processes of gall bladder ﬁlling and emptying can be visualised using an imaging technique called scintography. This procedure is utilised as a diagnostic aid in certain types of hepatobiliary disease.