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Non-compliance with treatment in schizophrenia Major problem Up to 50% of outpatients do not comply with prescribed treatment Some patients are cognitively compromised discount 50 mg viagra super active with visa, challenging the idea of informed consent Reasons given by patients for non-compliance: thinking more clearly (subjectively) when psychotic buy discount viagra super active online, side effects (acute dystonia and Parkinsonism common in first-episode cases) buy viagra super active on line amex, feeling better buy viagra super active 25mg free shipping, dissatisfaction with treatment, forgetfulness, lack of transport, financial reasons, failure to improve, employment, confusion over medication, and being out of town 1204 Syrup and depot preparations, and possibly atypical drugs,(Lieberman ea, 2003; Haddad, 2008) increase compliance Patients prescribed depots tend to have less insight than do those on atypical drugs (Mahadun & Marshall, 2008) Sophisticated testing suggests very few acute voluntarily admitted patients understand need for antipsychotic drugs (Paul & Oyebode, 1999) Patients outside hospital have only limited knowledge about their depot medications (Goldbeck ea, 1999) Adherence therapy may not be effective, at least in ordinary clinical settings (Gray ea, 2006) Beta-blockers in high dosage were suggested but have not become popular, results being contradictory. Classical (typical) neuroleptics are said to be less effective for negative symptoms (e. Antipsychotic medication should be continued for at least 6 months in acute cases. Megadosing with neuroleptics was fashionable but more time on more conservative doses may have the desired effect. Similarly, caution has replaced rapid neuroleptisation because of the potential risks of neurological and cardiac adverse effects; anyway, the efficacy of rapid escalation of doses in order to speed up response has not found support from research. Patients who smoke may need higher doses of antipsychotic drug than do non-smokers. Nicotine reduces Parkinsonian side effects, possibly because of nicotine- dependent activation of dopaminergic neurones. There is insufficient evidence to guide clinicians about when or in whom to stop maintenance drug therapy for schizophrenia. McEvoy ea (2006) found clozapine superior to other atypicals in chronic schizophrenic patients who did not respond to one atypical and the same group (Stroup ea, 2006) found that in chronic schizophrenic patients who just stopped taking an atypical that risperidone and olanzapine were more effective than quetiapine and ziprasidone. Use of medication only when symptoms emerge is associated with an increased risk of relapse and admission to hospital. Electroconvulsive therapy is still a useful treatment for some cases of schizophrenia. The meta-analysis of Crossley ea (2010) found that typical and atypical drugs were of similar efficacy but the side-effect profile was different. However, psychoanalytic theory may provide useful insights into the meaning of psychotic behaviour and thinking that, when used judiciously, may be helpful. Cognitive behaviour therapy: In the setting of a non-confrontational, trusting relationship, patients are asked to review symptoms and associated reasoning, to monitor them, to change the focus of attention and to relax, and to modify behaviour. Redevelopment of skills can be aided by industrial and occupational therapy, social therapies, living-skills courses, day care programmes, rehabilitation schemes, community care schemes, and sheltered accommodation that provides support and supervision. Employment at some level, often below their previous level, is essential, be this open or sheltered. Even with optimal rehabilitation, many patients will require continuing attention and care. Schizophrenic patients may improve in an area specifically chosen for treatment, such as one aspect of memory, without benefit generalising to other aspects of the same function. However, one meta-analysis of cognitive remediation and social skills training in schizophrenia found them to have no benefit (Pilling ea, 2002b) and another meta-analysis (McGurk ea, 2007) found moderate improvement in cognitive performance with cognitive remediation. Krabbendam and Jolles (2002) conclude that the jury is still out on cognitive remediation whereas Szöke ea (2008) suggest that practice produces better results than cognitive remediation. Dickinson ea (2010) found that measures of cognitive function improved with computer-assisted cognitive remediation but that such improvement was not reflected in broader neuropsychological or functional outcome measures. Others have suggested that when the high dropout rate from family interventions is taken into account (intention to treat analysis) there is a significant reduction in benefit in terms of relapse prevention. Still others have commented on the lack of effect of behavioural interventions on intrafamilial communications. Priority families for intervention include those with a treatment-compliant schizophrenic relative living with them but who relapses frequently, those in whom disagreements erupt into violence, families who resort to the police, and those making heavy demands on staff. Family intervention strategies (Kane and McGlashan, 1995)  Psychoeducation – didactic information about the illness; information about vulnerability to relapse/ role of stress; understand need for treatment to control symptoms*  Stress management – enhanced communication (listening skills, clarifying wants/needs, providing positive/negative feedback), problem solving (managing daily problems and discrete but significant stressors, general problem solving skills)  Crisis intervention – recognising prodromal signs/symptoms, plans to deal with threatened compliance, active intervention during prodrome or relapse during treatment, and more structured psychosocial programmes *Burns (1999) stated that that psychoeducation adds little where general services are well developed. Prevention of schizophrenia There are good reasons why primary prevention is currently impossible. Early precursors of schizophrenia in childhood are too non-specific and many children who later develop schizophrenia are perfectly normal as children. Olanzapine reduces the positive symptoms of prodromal psychotic states but induces weight gain. Delusions As for hallucinations, delusions of influence might simply derive from a real difficulty in attributing ones own actions to the self. A schizophrenic patient may believe that he is the president of his country whilst residing in gaol for petty theft: this profound lack of awareness of a fundamental 1221 contradiction is called double orientation. Psychoanalysts have interpreted delusions as providing a defence against low self-esteem, although it is difficult to see how a delusion of persecution could fulfil this 1222 role (unless persecution is equated with self-importance ). McGilchrist and Cutting (1995) found that male schizophrenics located abnormal phenomena principally on the left with depressives locating them on the opposite side, results that might relate to localisation of brain dysfunction in psychosis. The schizophrenic patients typically had delusions of a ‘peculiar’ sensation, or, more specifically, of rotation and paraesthesiae. Depressives more often had delusions of blockage, pressure, weight, fullness, liquidity, pain or weakness. Hallucinations Perhaps half of psychiatric patients who have auditory vocal hallucinations experience welcome as well as unwelcome voices, and up to half of them wish to keep them. Hallucinations are often said to be experienced as originating in the outside world or within one’s own body, but not, 1223 according to time-honoured dogma, within the mind as through imagination. Third person auditory hallucinations heard in clear consciousness are not unique to schizophrenia, being found also in alcoholic hallucinosis. It is suggested that people that feel marginalised or subordinate in society may hear voices of people they believe to be their superiors. It has been known for many years that direct stimulation of superior temporal gyrus structures can provoke complex hallucinations. Altered preconscious planning of discourse has been suggested as a cause of auditory hallucinations in schizophrenia. Defective feedback so that self-generated subvocal speech is not recognised as such constitutes another such hypothesis. Imagining sentences spoken in another person’s voice necessitates monitoring of inner speech. Patients activated left anterior insula and right middle temporal gyrus and deactivated anterior cingulate and parahippocampal gyri. In another study, when hallucinators imagined speech they differed from other groups by their reduction in activity of the parietal operculum. Others have found an inability of patients with a wide range of psychoses who had auditory hallucinations or passivity phenomena to distinguish between self-stimulation and external stimulation (tap own palm v experimenter doing so). Fu ea (2001) got healthy volunteers and schizophrenic patients to read adjectives aloud, their voice then been audible in a distorted or undistorted manner. Controls hearing their own distorted voice activated hippocampus, cingulate and cerebellum. Acutely psychotic patients failed to engage these areas of the brain and tended to attribute their own distorted voice to other people. Remitted patients showed activation patterns intermediate between the controls and the acute psychotics. Unilateral auditory hallucinations have been reported in association with a contralateral left superior temporal gyrus lesion and ipsilateral conductive deafness; the hallucinations stopped on wearing a hearing aid. Probably, auditory hallucinations involve a number of cortical and subcortical areas. Visual hallucinations are probably much more common in chronic schizophrenia than we generally think. According to Dubovsky and Thomas (1992) visual and auditory hallucinations are equally common in 1224 psychotic depression. Visual hallucinations are common in Lewy body dementia and have been reported in a minority of dissociative (hysterical) cases. Hallucinations as conversion symptoms (‘pseudohallucinations’) have a long history and may differ in a number of ways from those seen in the psychoses, e. The vision is usually transparent and colourless and imitates the patient’s movements. Most cases do not progress or incapacitate, the person being able to remain emotionally detached from the experience. Autoscopic hallucinations are rare in the functional psychoses, including schizophrenia. Heautoscopy, an extension of autoscopy, refers to the projection of sensation as well as visual aspects of the self – the patient is able to see and feel his double outside the self. This is different from two phenomena that may occur together in some organic disorders: a feeling of presence (feeling that an invisible other being is close by) and from out of body experience (feeling that one is separated from one’s body). Synaesthesiae (stimulation of one sensory modality is experienced as an hallucination in another modality, e. Splitting of perception, a rare experience found in schizophrenia or organic disorders, involves a failure to make the normal link between two or more perceptions, as when a patient watching a movie experiences 1225 the visual and sound elements to arise from unconnected sources.

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Thirty cases of schizophrenia arose between ages 16 to 43 years best 50 mg viagra super active, giving a cumulative risk of 0 viagra super active 25 mg overnight delivery. The latter reached milestones purchase viagra super active with visa, especially walking buy cheap viagra super active 50 mg line, later, had more speech problems, low educational test 1112 scores , solitary play preferences, less social confidence, and more social anxiety. Health visitors rated their mothers as having below average mothering skills and understanding of their children. Reports of less syntactically complex speech in premorbid children are contradictory, positive reports perhaps detecting state characteristics. In a 45-year follow-up study in Denmark (Sørensen ea, 2010) people who developed psychiatric diagnoses other than schizophrenia reached most developmental milestones earlier than did those with a diagnosis of schizophrenia but later than did controls (people who were never admitted to a psychiatric department) and the two patient groups differed significantly for the age at which they could walk unsupported. This finding is supported by a Finnish report of a failure to progress in education despite early academic normalcy. A study of draftees in Israel (Davidson ea, 1999) found that adolescents who later received a diagnosis of schizophrenia had poor social and intellectual functioning, as well as low organisational ability. They attributed this phenomenon to the prodromal effects of psychotic illness rather than to problems encountered in utero or around the time of birth. It is likely that young people at high genetic risk for schizophrenia perform poorly on all tests of intellectual function and memory. Cannon ea (2001) found that suspiciousness, sensitivity, and peer relationship problems among attendees at a child psychiatric department to be predictive of schizophrenia in adulthood. A follow-up of the 1966 birth cohort from Northern Finland to age 34 (Isohanni ea, 2006) found that impaired performance (e. Combining high-risk status with cognitive disturbance may prove useful in predicting transition to psychosis. The Bonn Scale for the Assessment of Basic Symptoms has been used to detect prodromal schizophrenia. In one study (Werry ea, 1991) only 61% of childhood onset cases of schizophrenia retained this diagnosed on follow up, the others being rediagnosed as bipolar disorder, schizoaffective disorder, or other psychoses. Insidious onset, poor premorbid functioning, and absence of prominent affective symptoms were found to predict diagnostic continuity as schizophrenia. Hollis (2003b) reported that premorbid social impairment was more common in early-onset schizophrenia than in other early-onset psychoses; overall, impaired premorbid development, enuresis and incontinence during psychosis were specifically associated with the negative psychotic symptom dimension. Childhood-onset schizophrenia is associated with the same eye-tracking dysfunction as that reported in adult schizophrenia. Owever, Bakalar ea (2009) followed up 49 right-handed childhood onset cases of schizophrenia (mean baseline age 14. Less than one in a hundred people with schizophrenia had this diagnosis as children. Commoner causes of psychosis in childhood are major depressive disorder, bipolar affective disorder, and severe cases of dissociation, as may be found in posttraumatic stress disorder. There may be suspiciousness, paranoid thinking, unresisted obsessionality, illusions (including somatosensory), depersonalisation/derealisation, and 1119 occasional transient quasi-psychotic episodes with little or no external provocation. Nevertheless it is often viewed as part of a ‘schizophrenic spectrum’, along with (very variably) schizophrenia, schizoaffective disorder, paranoid personality disorder (Hans ea, 2004), other non- affective psychoses, and psychotic affective illness. Features of this disorder can be found in relatives of patients with disorders other than schizophrenia or schizotypal (personality) disorder, especially in association with affective disorder, although schizotypal symptoms appear to be particularly common in the relatives of schizophrenic patients. Neuroimaging studies using schizotypal patients suffer from various methodological shortcomings (e. The 1121 onset if often insidious , the person becoming more withdrawn and introverted, avoiding friends, losing drive, dropping out of activities, and developing an interest in subjects like psychoanalysis, occultism or 1117 Once labelled as having ‘latent’ or ‘borderline’ schizophrenia (as were schizoid personalities). A related concept is that of schizotaxia,(Meehl, 1962) an old idea that has been modified over the years. Genetically vulnerable individuals are exposed to early adversity, such as birth anoxia, leading to abnormal development of certain brain structures. In childhood, the presentation of this liability to schizophrenia presents as ‘schizotaxia’ as shown by various degrees of cognitive, neurobiological and social deficits. It has been suggested that 20-50% of first-degree relatives of schizophrenics are schizotaxic. Most cases remain schizotaxic but some will develop schizotypal disorder or schizophrenia. There is some evidence for improved function in people with schizotaxia who are given low-dose risperidone. Genetically vulnerable individuals are exposed to early adversity, such as birth anoxia, leading to abnormal development of certain brain structures. In childhood, the presentation of this liability to schizophrenia presents as ‘schizotaxia’ as shown by various degrees of cognitive, neurobiological and social deficits. Heschl’s gyrus and other superior temporal areas (including primary and secondary auditory cortices) may be involved in auditory hallucinations in schizophrenia. Any sensory modality may be affected by hallucinations, but most commonly these are auditory. The time-honoured differentiation between true and pseudo-hallucinations can be very difficult to make in practice. There may be perplexity (ideas of reference, persecution or 1123 grandiosity may be fleeting), depression or elation , flattening or blunting of affect, anger, or incongruous emotional display (e. Behaviour may be characterised by withdrawal, bizarre activity, or catatonia (vide infra). Full-blown catatonia is more likely to be seen today in people coming from the Third World or in people from isolated localities. However, catatonia has many causes other than schizophrenia and more subtle manifestations should be actively sought. There may be a ‘defect state’ with lack of vivacity and enthusiasm, emotional unresponsiveness, apathy, poverty of speech, inability to form more than fleeting interpersonal ties, anhedonia, loss of employment or marriage, and impaired effectiveness in social roles, including parental responsibilities. Most cases will have recurrent episodes with positive symptoms, often without any prodrome. The interviewer finds it difficult to get straightforward answers to simple questions. Unlike the dysphasic, the schizophrenic has no idea that he is difficult to understand. Less words than normal are employed, words, phrases and even syllables are repeated. An excess of thought disorder has been found in relatives of schizophrenics and interpreted as being due to shared genes rather than rearing. Others have found profound deficits of prepulse inhibition of the acoustic startle response in early- but not late-onset schizophrenia, while others found evidence for defective prepulse inhibition, probably genetically transmitted, in schizophrenia spectrum disorders, including schizotypal personality disorder (Hazlett ea, 2003) and the relatives of patients with schizophrenia. The authors felt that their findings supported continuity between early and later-onset cases. Onset can be acute with disturbed behaviour, or insidious with gradual development of odd ideas and conduct. Course is variable and specifiable (by 5-character categories) as continuous, episodic with progressive/stable defect, episodic remittent, incomplete/complete remission, other, and observation less than a year. Symptoms must be present for at least one month (except for simple schizophrenia where at least one year is required). The one-month criterion only applies to certain symptoms: thought echo, delusions of control, commenting hallucinatory voices, culturally inappropriate and completely impossible persistent delusions, persistent hallucinations in any modality, breaks/interpolations in train of thought, catatonic behaviour, and negative symptoms such as blunt affect or self-absorption. It does not include a retrospective recognition of a prodrome: loss of interest, social withdrawal, poor hygiene, anxiety, mild depression, preoccupation, etc. Avoid a diagnosis of schizophrenia in the presence of overt brain disease or during drug intoxication/withdrawal. Similar conditions developing in the presence of epilepsy or other brain disease are coded under F06. The disturbance has lasted at least 6 months, including at least 1 month of active-phase symptoms: 2 or more delusions, hallucinations, disorganised speech, grossly disorganised or catatonic 1128 behaviour, negative symptoms. The subtypes are: paranoid (preoccupation with 1 or more delusions 1129 or frequent auditory hallucinations), disorganised (disorganised speech and behaviour, flat or inappropriate affect), catatonic (motor immobility, excess motor activity, extreme negativism, peculiarities of voluntary movement, echolalia, echopraxia), undifferentiated (not meeting criteria for foregoing subtypes – commonest type in clinical practice), and residual (no prominent symptoms or signs, but has attenuated features, e. A mood episode plus active phase schizophrenic symptoms occur together and are preceded or followed by at least 2 weeks of delusions or hallucinations without prominent mood symptoms. At least 1 month of non-bizarre delusions without other active phase schizophrenic symptoms. Seven subtypes, depending on the prominent delusional theme: erotomanic, grandiose (megalomania, delusions of personal greatness), jealous (infidelity of sexual partner), persecutory (persecution of self or of others emotionally close to self), somatic (false belief one has physical defect or general medical condition; monosymptomatic hypochondriacal psychosis: 1130 parasitophobia, insects in skin, dysmorphophobia or body dysmorphic disorder, body odours , and non-functioning body parts), mixtures of foregoing, and unspecified because delusions do not fit into any specified category. Kendler ea (1994) found simple schizophrenia to be rare, debilitating, similar to ‘typical’ schizophrenia in presentation and course except for the absence of positive symptoms, and, from a family perspective, it appeared to be related to ‘typical’ schizophrenia.

If we take seriously the feminist challenge to modern bioethics when we deal with patients from diVerent cultural backgrounds order 25 mg viagra super active amex, we can Wnd a proper Multicultural issues in maternal–fetal medicine 59 way to promote the health and well-being of women and children without ignoring diVerence proven 25 mg viagra super active, social ties and local cultures purchase 50 mg viagra super active fast delivery. In order to promote health as well as justice cheap 50 mg viagra super active with mastercard, we need to take into account the local context and the particular physical, social and cultural circumstances of the particular patient. This means that the delivery of health services to individuals has to start by focusing on their characteristi- cs and powers of their communities, instead of promoting standardized benchmarks. Sensitivity to diVerences between individuals and social collectives, and a focus on the positive features of particular cultural systems, help us to turn communities into progressive rather than regressive forces in the improve- ment of maternal and fetal health. Strong communal and family values, diVerent cultural beliefs and social practices should not be condemned, rather they should be objectively considered as an integral part of develop- ment. No culture is inherently unreasonably resistant to development and change towards better living conditions as long as enough sensitivity and respect is shown towards its particular, local characteristics. To summarize, this chapter aims to show that it is not impossible to Wnd a shared set of values that can be universally promoted in diVerent types of cultures, without requiring cultural assimilation. While individuals may disregard their communities, there is no logically valid or morally legitimate reason why they should not work for the good of these communities – as long as we treat the individual members as equally valuable. A recent breakthrough in research has shown that mother-to-child transmission (vertical transmission) can be reduced with the use of anti-viral drugs (Connor et al. This exceedingly bleak outlook is relieved in part by the discovery that the following measures can reduce vertical transmission: ∑ Avoidance of breast-feeding decreases transmission after birth by about 14 per cent (Dunn et al. In fact, provided that the resources are available, vertical transmission rates can now be reduced to less than two per cent (Tudor-Williams and Lyall, 1999). Neverthe- less, pregnant women in these countries can at least be conWdent that their oVspring can escape infection, and, that if they accept treatment, they themselves may beneWt from earlier diagnosis (de Cock and Johnson, 1998). Studies in the early 1990s in Kenya and other African countries have shown that the epidemic has had little impact on attitudes and subsequent child- bearing (Ryder et al. In addition, some countries, such as Uganda and Senegal, have managed to reduce transmission by vigorous public health education programmes (Anonymous, 2000b). Pregnant women are considered an ‘epi- demiological useful’ group because they represent a stable sub-group of the heterosexually active population at ‘normal risk’. I shall now consider the potential implications of a positive result, the nature of the relationship between the health professional and the pregnant woman, and the process of consent, as these are all relevant to a discussion about the ethics of anonymized and named testing. The implications of a positive result A pregnant woman is likely to experience considerable distress on discovery of her positive status (Manuel, 1999), particularly as she may feel more vulnerable and dependent on others, and she has the added responsibility of motherhood ahead of her. Once born, however, the interests of the child are paramount, and parental views may be overridden if they are seen to conXict with the child’s welfare. Babies can still gain protection from infection if given antiviral treatment within 48 hours of birth, even if the mother has refused to take medication or have a Caesarean section (Wade et al. It is beyond the scope of this discussion to consider the poignant dilemma for parents of whether or not to disclose to their child his or her incurable infection and uncertain life expectancy, or to explore the burden of imposing life-long unpleasant treatment on a child, and of protect- ing him or her from stigma. It is evident from the case above, however, that women may Wnd that breast-feeding causes disapprobation, and may even result in their infants being considered ‘at risk’. Abstention from breast-feeding creates particular diYculties in countries and cultures where breast-feeding is the norm, and bottle-feeding stigmatizes a woman (Graham and Newell, 1999). The relationship between the health professional and the patient As I have discussed elsewhere (de Zulueta, 2000a), the relationship between a health professional and a patient can be characterized as a Wduciary one. The health professional is therefore entrusted to put the patient’s interests Wrst, and to hold certain things (such as conWdential information) ‘in trust’. As Brazier succinctly expresses this: ‘It is trite to describe the health profes- sional’s relationship with his or her patient as a relationship of trust, yet the description encapsulates the very heart of the relationship’ (Brazier and Lobjoit, 1999: p. The health professional has a duty to promote the well-being of both the mother and the unborn child, but should only provide care that the mother agrees to. Failure to seek the patient’s consent is not only a moral failure, but, in English law, also leaves the doctor liable to the tort or crime of battery or to the tort of negligence. The information required is such that the patient understands in broad terms the nature and purpose of the procedure, and the principal risks, beneWts and alternatives (Chatterton v Gerson, 1981). Consent is a process, not an event, and involves a continuing dialogue between the health care professional and the patient, such that there is genuine shared decision-making. I submit that in the case of anonymized testing, and in the case of ‘routine’ voluntary named testing, consent is often vitiated by a lack of understanding and information, and sometimes by coercion. This may be justiWed in countries where the resources are not available to oVer counselling or treatment, and where the data may be used to galvanize the developed world into providing aid. These Wgures, it is argued, can then be used to provide the justiWcation for allocating more resources to the treatment and prevention of the disease, particularly in areas of high prevalence. But I would counter-argue that it is unprofessional and unethical to encourage individuals to relinquish beneWts that may aVect third parties (human fetuses), even if these are not ‘legal persons’. Finally, it could be argued that if an informed mother agrees to anony- mized testing, she does not intend to deprive the fetus of beneWt, as she does not know if she harbours the virus. This argument is also used to justify the health professional’s behaviour – no harm is intended, and there is no responsibility to act upon the result since it is unobtainable. A woman attending an antenatal clinic carries the reasonable expecta- tion that all tests and procedures are done either directly to beneWt her or her unborn child (de Zulueta, 2000a). The case for abuse of trust is even stronger than with anonymized testing of pregnant women, as the mothers are even more likely to assume that all tests are for the baby’s beneWt. Since the baby relies entirely on others to protect his interests, it is arguably even more unethical to use the baby ‘merely as a means, rather than as an end in himself’, to paraphrase Kant. In order to make an informed choice, the woman needs to understand the nature of the test itself, as well as the advantages and disadvantages of not receiving the result should it be positive. They cite a case when a doctor was found in breach of duty for failing to inform a woman of the potential consequences of not agreeing to a cervical smear. In addition, the leaXet issued by the Department of Health, in circulation after 1994, does not refer to treatments available for reducing vertical transmission. In any case, the notion of passive consent, that is to say that consent is implied unless there is a verbal refusal, is ethically unsound and ‘a concept quite alien in English law’ (Brazier and Lobjoit, 1999: p. In clinics that pro- vide universal testing (see later), the women should have received the relevant information from a pre-test discussion with the midwife, and the 70 P. In one study only Wve per cent fully understood the nature of the testing, and a signiWcant proportion believed that they would be informed should the result be positive (Chrystie et al. The principle of autonomy is frequently infringed by the process of anonymized testing, and, as Brazier says, ‘Consent truly is a myth’ (Brazier and Lobjoit, 1999: p. The ethics of named testing The Department of Health’s Unlinked Anonymous Surveys Steering Group in 1989 rejected mass voluntary testing as an alternative to anonymized testing. As argued above, the beneWts of named testing, and the arguments in favour of truth-telling are further strengthened, particularly as third parties are placed at risk by non-disclosure. The majority of industrialized countries adopted a universal testing policy (whereby all women were oVered the test), and developed their own guide- lines. Women at high risk in ‘low-prevalence areas’ may well miss out; this resource allocation dilemma is one well known to all screening programmes, and diYcult to resolve. This merits further discussion, but suYce to say that if resources are available, there is a strong argument for recommending a universal policy for all pregnant women (Hudson et al. The American Medical Association recently voted in favour of mandatory testing of pregnant women, although mandatory testing is a legal requirement in only a few states such as Texas and New York (Phillips et al. The reasons for this include the following: ∑ ‘high status coercion’ by professionals (see below); ∑ imposed targets, placing health professionals under duress to maximize uptake; ∑ multiple tests, creating confusion; ∑ lack of time and resources to allow a discussion suYciently detailed for women to understand the nature and purpose of the test. A health professional occupies a position of authority, and if he or she recommends a test, many women would feel that it is not within their rights to refuse. The strongest factor inXuencing uptake, excluding the direct oVer of a test, has generally been the individual midwife interviewing the woman (Jones et al. These Wndings reinforce the hypothesis that consent is driven by the health professional’s agenda, and that routine testing may not always be fully voluntary. Women most at risk (aside from intravenous drug users) are from high-prevalence areas, particularly from sub-Saharan Africa, and their Wrst language is not English or any other Western language. Schott and Henley (1996) quote studies that show that women who speak little or no English are given fewer choices and less information, and that health professionals tend to be paternalistic and insensitive towards them, concluding that: ‘They cannot give genuinely informed consent’ (Schott and Henley, 1996: p. The individual is seen as an integral part of the family or community and a woman has to consult her spouse, or other members of the family, and even elders, before consenting to medical or surgical procedures (Schott and Henley, 1996; NuYeld Council on Bioethics, 1999; de Zulueta, 2001). There are no clear guidelines for how long pre-test discussion should take, but it seems unlikely that all the issues referred to can be discussed in such a short time span. They point out the conXicts for the health professionals in providing an ‘ideal’ pre-test counselling practice with ‘the time and cost constraints of busy practices and managed care plans’. Some tests, for example, for Down’s syndrome, are done with the implicit understanding that if they prove positive, the mother is expected to have an abortion.

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Long distance lorry drivers are often overweight and suffer from obstructive sleep apnoea buy viagra super active 100 mg amex. The condition resembles hypertension in that there is a continuum from normality to severe 421 abnormality order viagra super active 50 mg mastercard. The main complications are nocturnal arrhythmias buy cheap viagra super active on line, hypertension purchase viagra super active amex, and, again rarely, polycythaemia and cor pulmonale. Patients with sleep apnoea may represent problems for anaesthetists, especially after nasal surgery when packs are used. Other approaches include sleeping in lateral or face up position, avoiding respiratory depressants (alcohol - probably causes hypotonia; hypnotics), correcting any anatomical abnormality of the upper respiratory 424 tract , losing weight (Johansson ea, 2009), muscle tone improvers such as theophylline or protryptyline or respiratory stimulants like acetazolamide, and, rarely, bypass of obstruction with tracheostomy. Garrigue ea (2002) point out that many patients with sleep apnoea have nocturnal bradycardia, paroxysmal tachyarrhythmias, or both. They found that those patients who received atrial overdrive pacing at a rate of 15 beats/min above baseline rate had a significant decrease in the number of episodes of central or obstructive sleep apnoea without reducing total sleep time. A score > 9 on a 0-24 scale is abnormal (sometimes confusingly expressed as 5 +/- 4). In acromegaly there an increased serum somatomedin-C level and failure of serum growth hormone levels to be suppressed to < 1 ng/ml after an oral glucose load. He will vividly remember what he was dreaming about, which often reflects some daytime event or preoccupation. Nightmares may accompany nocturnal hypoglycaemia, the partner noticing that the patient is sweaty and restless during sleep and the patient complaining of hangover and headache next morning. Rehearsal of a repetitive nightmare may cause it stop if it is given an imaginary happy ending, so-called elimination of the threat through mastery. Somnambulism may occur in patients with bipolar affective disorder on a combination of lithium and an antipsychotic agent. Madden ea, 2009) Children with either terrors or somnambulism are 432 433 very difficult to waken , are confused and do not remember what happened. In sleepwalking, the subject, who has a blank stare, sits up and makes repetitive movements or, less commonly, walks or goes to the toilet and urinates; standing the child during stage 4 may induce walking. In a night terror, the child appears to wake in great fear but is, in fact, asleep; there may be dramatic screaming, agitation, sweating and tachycardia. They affect 3% of children between 1 and 14 years of age, are uncommon in adults, and occur only in predisposed people who usually have a family history of sleep problems. Stairs, fires and other potentially dangerous items should be made secure 434 for somnambulists. The child should not be roused from a terror as this will prolong the attack and leave the child confused. One report of success with paroxetine was contaminated by early co-prescription of clonazepam (Lillywhite ea, 1994) but paroxetine does seem to be effective and often more quickly than any antidepressant action could account for. Note that pergolide (and carbergoline) are ergot derivatives and may cause serosal reactions (e. Pockets of high prevalence of night terrors and somnambulism have been discovered, e. Shift work, alcohol, neuroleptic drugs, stimulants, and antihistamines may induce somnambulistic episodes. Night terrors are benign and usually resolve within a few years, but can be very distressing. Lask (1988) suggested that parents note the timing of night terror episodes on 5 successive nights, and the presence of any signs of autonomic arousal (e. The child is then roused for 10-15 minutes prior to an episode (use autonomic arousal as timer if it is difficult to time the onset of the terror). This regime is continued until the terrors stop; in many cases the terrors stopped within one week; if there is a recurrence, then the treatment is continued for another week. Some children with terrors have medical problems (reflux, periodic limb movements, sleep-related breathing difficulties) that need attention. Sleepwalking with onset after childhood may be associated with stress, personality problems,(Sours ea, 1963; Calogeras, 1982) or medication. Sleep deprivation, migraine, head trauma, stroke, encephalitis, and hyperthyroidism can also precipitate somnambulism. Nocturnal sleep fragmentation and even insomnia are other aspects of the syndrome. Extremely short (seconds) micro-sleep periods may occur that are not noticeable to either patient or onlooker. Sudden cessation of antidepressants should be avoided because of the potential danger of 442 precipitating episodic or continuous cataplexy. It can be spontaneous or evoked (by the emotional response to cataplexy itself or by stopping antidepressant treatment for cataplexy). However, schizophrenia-like disorders do appear to be more common in narcoleptics than in the general population,(Davison, 1983) and narcoleptic patients with hallucinations may be misdiagnosed as having schizophrenia. Most cases of narcolepsy appear to be sporadic,(Linkowski, 2002) although such cases may have an underlying genetic susceptibility. Doberman pinchers) suffer from familial narcolepsy; narcoleptic phenomena also occurs in mice. Canine narcolepsy (autosomal recessive with full 449 450 penetrance ) is associated with mutations in the orexins/hypocretins receptor-2 gene. The same neurones that produce orexins/hypocretins in mice are activated by modafinil. Short episodes of sleep are repeated frequently and, with time, such naps may become less restorative and nocturnal sleep may become disturbed. During an ordinary night’s sleep the narcoleptic is prone to myoclonus, broken sleep, and pulse and breathing abnormalities. Patients may have disturbing dreams and may complain of sensing a ‘presence’ in the room. Narcoleptics have problems at work, in marriage, in industry, and in traffic throughout life. Knock-out, knock-in, and traditional transgenic mice are genetically engineered mice with genetic material removed from a particular locus, inserted into a particular locus, and randomly inserted (not into a particular locus) respectively. Modafinil induces cytochrome P-450 isoenzymes so that at least 50 μg of 455 ethinyloestradiol needs to be given in anovulants to prevent contraceptive failure. Adverse effects of modafinil include anxiety, agitation, aggression, central stimulation, headache, insomnia, anorexia, abdominal pain, nausea, gastric discomfort, dry mouth, palpitation, tachycardia, and tremor. Occasionally a pruritic skin rash appears, and very rarely one may encounter buccofacial dyskinesia. Psychotic symptoms attributable to amphetamines may abate when the dose is lowered or the medication is 456 changed to modafinil. Eighty percent of patients presenting with restless legs syndrome also have periodic limb movement disorder. A person awakened by hypnic jerking may experience siderealism (feeling as if falling in space). A similar picture may be 459 cause by nocturnal or fragmentary myoclonus and hyperekplexia syndrome (startle disease ). He remains confused and disorientated, so-called sleep drunkenness, and complains of prolonged and deep nocturnal sleep. Menstrual-related hypersomnia involves excessive daytime sleepiness for some days prior to menstruation. Painful legs, moving toes: Continuous unilateral pedal sinusoidal flexion-extension with ipsilateral leg pain whilst awake, with continuation during sleep at a reduced intensity, usually associated with peripheral nerve lesions such as in the lumbar roots. Delayed sleep phase syndrome: This circadian rhythm disorder may affect up to 10% of insomniacs attending sleep disorders clinics. The patient cannot get to sleep until after everyone else and, if allowed, sleeps on that much later. Bright light exposure in the morning and light restriction in the evening may help. Where sleep phase is advanced (advanced sleep phase syndrome) treatment is by evening exposure to 460 bright light. The irregular sleep-wake type of circadian rhythm sleep disorder was described in physically sick people who spent years in bed and were socially isolated. However, it is more likely to be seen in association with intellectual disability, brain damage, and dementia. There is an absence of any pattern to sleeping and waking, patients sleeping for a few hours at irregular intervals. The therapist ‘blames’ the mood disturbance and not the patient for the latter’s dysfunction and suggests that (as well as psychosocial stress) predisposed people may be made more vulnerable to mood disorders by disruptions in circadian rhythm.

IgA provides an antigenic barrier by binding bacteria and other antigens discount viagra super active online amex, although this barrier function is specific for particular antigens and requires previous exposure for development of the response discount viagra super active 100mg. Pancreatic secretions are secreted into the lumen of the acinus and accumulate in intralobular ducts that drain to the main pancreatic duct purchase 50mg viagra super active free shipping, then directly into the duodenum buy viagra super active 100mg on-line. Control of the exocrine function of the pancreas is via the hormones gastrin, cholecystokinin and secretin. Pancreatic secretions from ductal cells contain bicarbonate ions that neutralise the acidic chyme from the stomach and are important in protecting the pancreas from recurrent acute and chronic pancreatitis by quickly sweeping zymogens out of it. To remain viable, all cells of the body are required to maintain a low intracellular concen- tration of sodium. The sodium–potassium pump is a highly conserved integral membrane protein, expressed in virtually all animal cells. The transport of sodium creates both an electrical and a chemical gradient across the plasma membrane. In turn this provides: • a cell’s resting membrane potential, the gradient of which is the basis for excitability in nerve and muscle cells • export of sodium from the cell, providing the driving force for several facilitated transporters, which import glucose, amino acids and other nutrients into the cell • translocation of sodium from one side of an epithelium to the other, creating an osmotic gradient that drives absorption of water. A beta glycoprotein subunit appears critical in facilitating plasma membrane localisation and activation of the alpha subunit. There are 8–10 transmembrane domains; alpha and beta subunits exist in several isoforms. Different isoforms of the alpha subunit have different affinities for such glycosides. Binding of these widely-used drugs to sodium pumps specifically inhibits their activity. Inhibition of sodium pump activity in cardiac myocytes results in an increase in intracellular sodium concentration; in turn this leads to an increase in intracellular calcium concentration by sodium–calcium exchange, which appears to be the proximal mechanism for enhancing cardiac contractility. The major hormonal controls over pump activity can be summarised as follows: • Thyroid hormones appear to stimulate subunit gene transcription. Within minutes of elevated insulin secretion, pumps containing alpha-1 and 2 isoforms have increased affinity for sodium and increased turnover rate. In skeletal muscle, insulin may also recruit pumps stored in the cytoplasm or activate latent pumps already present in the membrane. Some molecules, water for instance, are transported by both routes, but the tight junctions are impermeable to large organic molecules from the diet (e. Such molecules are transported exclusively by the transcellular route, by absorptive enterocytes equipped with specific transporter molecules that facilitate their entry into and out of the cells. Within the intestine, there is a proximal-to-distal gradient in osmotic permeability. The observed differences in permeability to water across the epithelium are due almost entirely to differences in conductivity across the paracellular path; tight junctions vary considerably in ‘tightness’ along the length of the gut. In the case of secretion, two distinct processes establish an osmotic gradient that pulls water into the lumen of the intestine: • Increases in lumen osmotic pressure resulting from influx and digestion of foodstuffs. The chyme that passes into the intestine from the stomach typically is not hyperosmotic, but as its macromolecular components are digested, the osmolarity of that solution increases (e. Chloride ions enter the crypt epithelial cell by co-transport with sodium and potassium; sodium is pumped back out via sodium pumps and potassium is exported via a number of channels on the basolateral surface. Accumulation of negatively charged chloride anions in the crypt creates an electric potential that attracts sodium ions, pulled into the lumen apparently across tight junctions; the net result is secretion of NaCl. Secretion of NaCl into the crypt creates an osmotic gradient across the tight junction and water is drawn into the lumen by the paracellular route. It is one of the most common clinical signs of gastrointestinal disease, but can also reflect primary disorders outside of the digestive system. There are numerous causes of diarrhoea, but in almost all cases this disorder is a manifestation of one of the following four basic mechanisms: • Osmotic diarrhoea. Occurs if osmotically active solutes are retained in the intestinal lumen; water will not be absorbed and diarrhoea will result. For example, a failure to digest lactose (lactose intolerance) means that lactose remains in the intestinal lumen and osmotically ‘holds’ water. This change results in prolonged opening of the chloride channels, leading to uncontrolled secretion of water. Secretory diarrhoea can also result from laxatives, hormones secreted by certain types of tumour (e. Examples of pathogens frequently associated with infectious diarrhoea include bacteria, Salmonella, E. The immune response to inflammatory conditions in the bowel contributes substantively to development of diarrhoea. In order for nutrients and water to be effi- ciently absorbed, the intestinal contents must be adequately exposed to the mucosal epithelium and retained long enough to allow absorption. Disorders in motility that accelerate transit time can decrease absorption, resulting in diarrhoea. Alterations in intestinal motility (usually increased propulsion) are observed in many types of diarrhoea. What is not usually clear, and is very difficult to demonstrate, is whether primary alterations in motility are the cause of diarrhoea or simply an effect. It has saved millions of children from diarrhoea, still a leading cause of death, particularly in the developing world. The transport of glucose must be accompanied by Na+ (symport) and is the basis of rehydration therapy (see Section 4. Symporters transport substances in the same direction; antiporters transport substances in opposite directions. The junctions have a dual function: preventing solutes from crossing the epithelium between cells and allowing a concentration gradient of glucose to be maintained across the cell sheet; and acting as diffusion barriers within the plasma membrane, which help confine the various carrier proteins to their respective membrane domains. Protein digestion begins in the stomach, where proenzyme pepsinogen is autocatalytically converted to pepsin A. Most proteolysis takes place in the duodenum via enzymes secreted by the pancreas, including trypsinogen, chymotrypsinogen and pro-carboxypeptidase A. These serine and zinc proteases are produced in the form of their respective proenzymes; they are both endopeptidase and exopeptidase, and their combined action leads to the production of amino acids, dipeptides and tripeptides. Endopeptidases are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i. Enterokinase, a brush-border enzyme, activates trypsinogen into trypsin, which in turn con- verts a number of precursor pancreatic proteases into their active forms. The mechanism by which amino acids are absorbed is conceptually identical to that of monosaccharides. The lumen plasma membrane of the absorptive cell bears a number of dif- ferent Na+ amino acid symporters. Na+-independent transporters on the basolateral membrane export amino acids to the extracellular space. There is virtually no absorption of peptides longer than four amino acids, but there is absorption of di- and tripeptides in the small intestine. Such transporters are of proven pharmaceutical utility for enhancing oral absorption. This ability, which is rapidly lost, is of immense importance because it allows the newborn animal to acquire passive immunity by absorbing immunoglobulins in colostral milk. Hartnup disorder is an autosomal recessive impairment of neutral amino acid transport affecting the kidney tubules and small intestine. It is believed that the defect is in a specific system responsible for neutral amino acid transport across the brush-border membrane of renal and intestinal epithelium, but the defect has not yet been characterised. It is likely caused by a combination of factors (protein deficiency, energy and micronutrient deficiency). The absence of lysine in low-grade cereal proteins (used as a dietary mainstay in many underdeveloped countries) can lead to kwashiorkor. Bile acids and pancreatic lipase, mixed with chyme, act in the lumen to emulsify and digest triacylglycerols into their monoacylglycerols and free fatty acids. Bile, stored in the gall bladder and released into the duodenum, contains the bile salts, sodium glycocholate and sodium taurocholate. Such amphipathic molecules have a ‘detergent effect’ on lipids, intercalating and breaking them down to smaller aggregates, and eventually to micelles (4–8 nm diameter), thereby enabling the action of pancreatic lipase. The drug orlistat (Xenical), which is promoted for the treatment of obesity, acts by inhibiting pancreatic lipase, thereby reducing the digestion and absorption of fat in the small intestine. Fatty acids and monoacylglycerols enter the enterocyte by diffusion and are transported into the endoplasmic reticulum, where they are used to re-synthesise triacylglycerol. Beginning in the endoplasmic reticulum and continuing in the Golgi, triacylglycerol is packaged with cholesterol, lipoproteins and other lipids into particles called chylomicrons.

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Karyotyping: chromosomes can only be viewed with clarity during cell division; phytohaemagglutinin is used to stimulate cell division in vitro order genuine viagra super active, then colchicine is used to arrest cell division in metaphase; hypotonic saline is then used to swell the cell so as to separate the chromosomes from one another; stains generic 100mg viagra super active fast delivery, such as Giemsa purchase discount viagra super active on-line, demonstrate the banding properties (light and dark bands that are characteristic of each 885 chromosome ); a photograph is taken discount viagra super active, from which the chromosomes are cut and arranged in homologous pairs. The term karyotype analysis simply refers to the visualisation of chromosome number and gross structure. Linkage analysis: tests if observed co-occurrence of a disorder and a marker for a genetic locus within a given pedigree are compatible with that locus contributing to disease susceptibility. One can attempt to trace a gene from a protein or a protein from a gene, or look at candidate genes. However, for loci closely situated to one another, recombination is rare, and associations tend to persist for many generations. Mosaicism (in Down’s syndrome): occurs when non-disjunction takes place during any cell division after fertilisation; there are normal and trisomic cells in the same person; the effects on cognitive development are very variable. Liability must pass a certain threshold: population incidence represents the threshold for the general population. Familial incidence is the threshold for relatives of patients with multifactorial disorder. Notation for gene locations: this is a shorthand way of describing the position of a gene in the genome. Xq27-28 means that the gene is on the X chromosome, on the long arm (p, short arm, from French for 885 Each band is assigned a number. The astute observer will have noticed that the example given is that of the fragile site in the fragile X syndrome. A + or – sign before a symbol refer to the addition or absence of whole chromosomes (e. Pairwise concordance: the proportion of pairs of twins concordant for a particular trait. To be more exact: number of twin pairs in which both twins are affected by a condition divided by the total number of twins. Partial trisomy: a translocation occurs where a part of a chromosome becomes attached to a different one. If parents are phenotypically normal carriers of translocations are at risk for having a partial trisomy for the first mentioned chromosome, i. In other words, the proportion of heterozygotes who express (see expressivity) the gene in any degree (some authors see penetrance as an all or none phenomenon, and expressivity as a more variable phenomenon); penetrance is a product of the modifying influence of other genes and the environment; some cases of tuberous sclerosis, for example, have only sparse facial papules because of low penetrance. Pericentric inversion: swapping of chromosomal material from one arm of a single chromosome with the other arm of the same chromosome. When people have 1 copy of a certain allele and share the same phenotype as do people with 2 copies of the same allele the allele is dominant for that trait. A recessive allele would need to occur twice in the same person (2 copies) to be expressed in the phenotype. Co-dominance refers to the situation where the person has 1 copy of the allele and a phenotype that is somewhere between (intermediate) those with 0 and 2 copies of the allele. Philadelphia chromosome: acquired chromosomal abnormality involving a deleted chromosome 22, its long arm being translocated to another autosome, usually chromosome 9; associated with chronic myeloid leukaemia. Pleiotropism (pleiotropic genes): a gene with more than one effect on the phenotype; several genes may contribute to one disorder, and a single gene may contribute to several disorders; many psychiatric disorders may be polygenic, the summation of a number of genes, each of small effect. Polygenes (polygenic): a character that is determined by more than one gene; many genes of small effect acting in concert to produce a phenotype, e. These have demonstrated downregulation of key oligodendrocyte and myelination genes (incl. Polymorphic markers: markers recognising fragments of variable size; at least 2 alleles should be present in the population to be useful. Positional cloning: a set of techniques by means of which disease genes are identified through their position in the genome rather than through their function. Presumed obligate carriers: non-affected relatives the gene or genes for a disorder, such as the mother of a patient with schizophrenia who, although not psychotic herself, has a parent or sibling with schizophrenia. Proband: a sampled individual with a condition or trait; propositus if male, proposita if female. Probandwise concordance: the proportion of co-twins concordant for a trait when ascertained through affected probands; or, number of affected co-twins of an affected proband divided by the total number of twins. If 2 heterozygous parents produce children, there is a 1 in 4 chance of a child being affected: ¼ will be normal, ½ will be carriers or healthy heterozygotes, and ¼ will be affected. In practice, consanguineous matings lead to a slight increase in perinatal mortality rate, congenital abnormalities and learning disorder. The risk is greatly increased if there is a history of recessive disorder in the family. Examples of autosomal recessive disorders include oculocutaneous albinism (ocular albinism is X-linked), congenital goitrous cretinism, Crigler-Najjar syndrome, cystic fibrosis, Friedrich’s ataxia, galactosaemia, Gaucher’s disease, glycogen storage disease, Hurler’s syndrome, Niemann-Pick disease, phenylketonuria, Tay-Sachs disease, and Wilson’s disease. Reciprocal translocation: mutual swopping of part of chromosome between autosomes or between autosomes and sex chromosomes – when this occurs in germ cells the result may be partial trisomies and monosomies; however, the balanced genetic rearrangement may continue on and not be manifest phenotypically unless a gene is disrupted. Recurrence risk: the risk of a relative developing the same condition as an affected probands. Recurrence risk ratio (λ1): ratio of risk of a disorder in a first-degree relative of an affected person/prevalence in general population. When the base rate of a disorder is low a high relative risk is still compatible with a low absolute risk. Ring chromosomes: rare deletion of the 2 ends of a chromosome, the broken ends (telomeres) fusing to form a ring; usually loses some chromosomal material; commonly associated with intellectual disability. This is mainly used for conditions where one gene accounts for much of the variance, which does not include most of the major psychiatric disorders. Sex-linked conditions: There are no proven examples of Y-linked single gene disorders in man. All known sex-linked conditions are due to genes on the X-chromosome, and these traits may be dominant or recessive. The affected male cannot transmit an X-linked trait to his sons, but all his daughters are affected. X-linked recessive traits manifest only in homozygous females, but they always manifest in males, there being nothing on the Y-chromosome to modify the trait. The family tree will be modified by the ability or inability of affected males to reproduce. If, in females, in most cells, the normal X-chromosome is inactivated, the result is a ‘manifesting heterozygote’. X-linked recessive traits include Christmas disease, haemophilia, Hunter’s syndrome, Lesch-Nyhan syndrome, and nephrogenic diabetes insipidus. Telomeric defects are known to be involved in some inherited disorders, including certain congenital aplastic anaemias. Because of the protective presence of telomerase, a germ cell replicates with no telomeric shortening. Translocation: part of one chromosome becomes attached to a different chromosome (or a different part of the original chromosome, or assumes a different orientation such as inversion), e. In 1991, a new type of genetic mutation was discovered, a dynamic or expansion mutation, in which the number of triplets in a repeat increases and the length becomes unstable. Nearly 20 diseases, including Huntington’s disease, 2 forms of fragile X syndrome, and myotonic dystrophy, have been linked to trinucleotide repeat expansions. Such repeats are unstable and lead to inheritance patterns at odds with traditional Mendelian genetics. Prediction of Huntington’s disease may never be 100% accurate due to some cases having a borderline number of repeats, i. Trisomy 8 usually results in (usually male) foetal loss, but survival, when it happens, is associated with moderate intellectual 891 disability. Trisomy 892 18 (Edward’s syndrome ) is nearly always lethal in infancy with less than 10% surviving for the first year. Unifactorial (unigenetic) disorders: these are single gene disorders, (the autosomal dominant and recessive disorders and X-linked recessive disorders) the opposite of multifactorial characteristics (Q. Because of high inter-individual variability microsatellites are commonly used as markers for linkage analysis.

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