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That said impotence may be caused from quizlet discount sildalist, the correlation between biosimilar market shares and price reductions is weak erectile dysfunction after radiation treatment prostate cancer buy generic sildalist on line, suggesting the existence of barriers to effective competition erectile dysfunction band sildalist 120mg discount. Promoting biosimilar uptake is important for driving savings and ensuring the continued participation of players in the market impotence medical definition discount 120 mg sildalist amex, but it is the market entry of biosimilars that promotes price competition erectile dysfunction protocol pdf download free purchase sildalist 120 mg mastercard. The two graphs below show a) the market penetration of biosimilars as a proportion of all products within the same drug class eligible for biosimilar competition (vertical bars erectile dysfunction 32 sildalist 120mg generic, left axis) and b) the price evolution across all products within the class eligible for biosimilar competition (diamonds, right axis). The first graph shows the results for the class of drugs known as erythropoietins, used in the acute care setting to stimulate red blood cell production in a number of conditions, including chronic renal failure. Erythropoietins were among the first biosimilar products to be approved in Europe. In the Netherlands, limitations on the prescribing of reference products are often part of agreements reached between insurance companies and hospitals, though budget constraints within hospitals already provide incentives for the use of biosimilars. With the exception of Estonia, France, Latvia, and Poland, most countries do not permit unrestricted substitution of biologicals at the point of dispensing. In France, draft legislation permitting substitution of biosimilars was introduced in 2017 but is limited to initiating treatment in treatment-naive patients, or to ensuring continuity for patients previously dispensed a biosimilar (ibid. Encouraging rational use Efforts to minimise waste in expenditure on medicines can be undermined significantly by over-prescribing and inappropriate use. This section focuses on two specific groups of medicines that are frequently subject to over-prescription, and have particular implications for public health: antibiotics and hypnotics/anxiolytics (mainly benzodiazepines). In addition, overprescribing of antibiotics incurs a number of other direct and indirect costs, by medicalising conditions for which antibiotics are not useful, and by putting patients at risk of adverse effects (and the costs of treating them). Primary care accounts for 80-90% of all antibiotic prescriptions in Europe, with most prescribed for respiratory tract infections (van der Velden et al. However, rates of antibiotic prescribing differ significantly across Europe, despite little evidence of differences in the prevalence of infectious diseases (Llor and Bjerrum, 2014). Prescribing influences have been shown to be multifactorial and include cultural and socioeconomic elements, diagnostic uncertainty, the way health care is funded or reimbursed, the percentage of generic drugs in the market, economic incentives and pharmaceutical industry influences, attitudes and beliefs about the therapeutic value of antibiotics among patients, as well as differences in prescriber and patient expectations of consultations for respiratory tract infections (Llor and Bjerrum, 2014). Cyprus and Romania provide data on overall consumption (including the hospital sector). The European Commission has also published guidelines for the prudent use of antimicrobials in human health (European Commission, 2017). Levels of prescribing of hypnotics and anxiolytics, especially among the elderly, are another important public health issue. Apart from the associated mortality and morbidity, these impose substantial additional and potentially avoidable costs on health systems. Elderly patients with prescriptions for benzodiazepines or related drugs, number per 1 000 patients aged 65 and over, 2015 or nearest year Elderly patients with prescriptions for long-acting benzodiazepines or related drugs Elderly patients with long-term prescriptions for benzodiazepines or related drugs Per 1 000 persons aged 65 years and over 160 150 140 120 113 102 100 85 82 80 67 54 57 60 44 36 34 40 31 27 18 18 18 20 20 9 5 n. Among patients with these three conditions, it has been estimated that between 4 and 31% do not fill their first prescription; of those who fill their first prescription only 50 to 70% take their medications regularly. However the authors also found that while patient non-adherence contributes to wastage, a range of other factors are also implicated, some of which are unavoidable, such as treatment changes due to lack of efficacy or the emergence of adverse effects. Those that can be addressed included inappropriate repeat prescribing and dispensing processes, which, independently of any patient action, may cause excessive volumes of medicines to be supplied (Trueman et al. A study examining waste samples in Vienna in 2015-16 found significant quantities of prescription medicines discarded in household garbage. Alternatively, payers could determine reimbursement amounts that correspond to the actual dose administered. Policies aimed at tackling poor adherence and unnecessary waste of medicines by patients are aimed at encouraging improved communication between clinicians and patients and enhancing patient understanding of the importance of completing prescribed courses of treatment. Conclusions Progress in reducing wasteful spending in health is not only a barometer of quality improvement; it is both an ethical and financial imperative in the pursuit of resilient and equitable health care systems. While the estimate that as much as one-fifth of health spending could be eliminated is sobering, the many avenues for saving money and streamlining services, without undermining access or quality of care, are cause for optimism. For hospitals, reducing or eliminating unnecessary investigations and procedures, many of which expose patients to unnecessary risks without the prospect of clinical benefit, is an obvious target for direct intervention. However minimising avoidable admissions, particularly for ambulatory care-sensitive conditions, reducing unnecessary length of stay, and improving discharge processes require broader perspectives. Enhanced primary care services, expanded postacute care facilities, post-discharge care coordination, and in-home care services all require health system reforms that cannot be initiated by hospitals alone. For pharmaceuticals, creating and supporting competitive markets and promoting the uptake of generics and biosimilars can generate substantial savings. That said, reducing waste does not necessarily mean spending less; it may equally be achieved by gaining better value for money from existing expenditure. Using health technology assessment to inform selection, pricing and procurement of new medicines facilitates an understanding of the true opportunity costs of therapies and helps avoid the displacement of high value interventions with ones of lesser value. Prescribers and patients need to understand the value offered by generics and biosimilars, and be adequately reassured as to their equivalence and safety. Both need to appreciate the risks of overprescribing antibiotics and the circumstances in which they are of low or no benefit. In hospitals, patients and providers need to recognise that not only will certain investigations and procedures provide no benefit, they may even be harmful. Financial incentives for patients and providers must also be calibrated to reinforce appropriate behaviours. Above all, the development and promulgation of guidelines and protocols that provide both a basis for discussion and engagement and support for rational clinical decision-making, are critical to the waste-reducing armamentarium. This analysis captures only five of thirty conditions for which hospitalisations may be avoidable through better primary care, and is therefore conservative. That said, not all hospitalisations related to these five conditions would be avoidable. Analyses which group women according to obstetric criteria (for instance number of foetuses, presentation of foetus, previous C-section) provide finer analyses of the drivers behind these trends and differences in C-sections rates (Betran et al. A campaign, established in 2012 by the American Board of Internal Medicine and since emulated in a growing number of countries, has sought to promote a dialogue around appropriate care. Day surgery is defined as the release of a patient who was admitted to a hospital for a planned surgical procedure and discharged the same day. Inguinal hernia repair is a procedure to repair a defect in the abdominal wall that allows abdominal contents to slip into a narrow tube called the inguinal canal and is commonly performed laparoscopically (using minimally invasive keyhole surgery, allowing patients to return home more quickly). Cholecystectomy is the removal of the gallbladder, also commonly performed laparoscopically. Delayed discharges from hospital are defined here as cases in which a hospital patient remains in hospital, despite being clinically ready to be discharged. A generic medicine is defined as a pharmaceutical product with the same qualitative and quantitative composition in active substances, and the same pharmaceutical form as the reference product, and to which bioequivalence has been demonstrated. Department of Health (2016), Discharging older patients from hospital: Report by the Comptroller and Auditor General, National Audit Office, London. Law (2014), Guidance for the use and reduction of misuse of benzodiazepines and other hypnotics and anxiolytics in general practice, Helsedirektoratet (2018), Norwegian Health Directorate, Number of patients ready for discharge, statistikk. Infarmed (2018), Press release: the La Valletta Technical Committee met for the fourth time in Lisbon, This appears to have been driven by a slowdown in the rate of reduction of deaths from circulatory diseases and periodical increases in mortality rates among elderly people due partly to bad flu seasons in some years. Large inequalities in life expectancy persist not only by gender (women still live nearly 5fi years more than men on average), but also by socioeconomic status. Communicable diseases, such as measles, hepatitis B and many others, pose major threats to the health of European citizens, although vaccination can efficiently prevent these diseases. But in most countries where vaccination coverage is high, very few cases of measles were reported. The current gender gap better the recent slowdown in life expectancy gains in is particularly large in Latvia and Lithuania where many European countries (Raleigh, 2018). These gender gaps are partly due to greater exposure to risk Definition and comparability factors among men, particularly greater tobacco Life expectancy at birth measures the average consumption, excessive alcohol consumption and less number of years that a person can expect to live healthy diet, resulting in higher death rates from heart based on current mortality rates (age-specific diseases, various types of cancer and other diseases. However, since 2011, the are falling, actual life spans will on average be gains in life expectancy have slowed down markedly, higher than life expectancy calculated with particularly in some Western European countries, with current death rates. Public Health Action) (2018), European Mortality the marked reduction in 2015 was due at least Bulletin, Life expectancy at birth, by gender, 2016 Total Women Men Years 90 85 80 75 70 65 60 1. This section focuses the results for the period 2012-16 show a gap of mainly on inequalities by education level since this is 8 years in life expectancy at age 35 between men in the socioeconomic indicator with the most widely the top income quartile and those in the bottom available data. In the Slovak Republic, Hungary, Poland, the Czech Republic and Latvia, 30-year-old men with a low Definition and comparability level of education can expect to live more than 10 years Life expectancy measures the average number less than those with a high level of education. The highest education level educated men and women for two age groups (25-64 refers to people who have completed a tertiary and 65-89 years) across 10 European countries. Data on life expectancy by education gap is particularly large among men in both education level have been extracted from the age groups. This gap is due Not all countries have information on education to much higher mortality rates from all the main as part of their deaths statistics. In these two countries, An important gap in mortality rates by education level the large share of the deceased population with also exists among older men and women, driven missing information about their education level mainly by higher death rates from circulatory diseases can affect the accuracy of the data. Smoking remains a very important risk factor for both circulatory diseases and different types of cancer (notably lung cancer). Gap in life expectancy at age 30 between people with the lowest and highest level of education, 2016 (or nearest year) Women Men 6. Mortality rates by education level and causes, 10 European countries, 2011 (or nearest year) Circulatory External Cancer Other Women Men 600 Deaths per 10 000 population 600 Deaths per 10 000 population 500 500 400 400 300 300 200 200 100 100 0 0 25-64 65-89 25-64 65-89 25-64 65-89 25-64 65-89 Low education High education Low education High education Note: Countries covered are Belgium, the Czech Republic, Denmark, Finland, Hungary, Latvia, Norway, Poland, Slovenia and the United Kingdom (England). In these two countries, women can annually by Eurostat based on life table data and expect to live more than 85% of their life expectancy age-specific prevalence data on long-term free of disability, and this share reaches around 90% for activity limitations. The comparability of the data on healthy life As people get older, the share of the remaining years is limited by the fact that the indicator is years of life that they can expect to live free of disability derived from self-reported data which can be falls. Life expectancy and healthy life years at birth, by gender, 2016 (or nearest year) Healthy life years Life expectancy with activity limitation Women Men 86. Life expectancy and healthy life years at 65, by gender, 2016 (or nearest year) Healthy life years Life expectancy with activity limitation Women Men 23. The concentrated mainly among people aged 75 and over, most important causes of violent deaths are road traffic and was attributed mainly to higher mortality from accidents and other accidental deaths, and suicides. Once the among people aged over 65 is circulatory diseases, the population structure is adjusted by age, the agemain cause for people under 65 is cancer, particularly standardised mortality rate was about 50% higher among women (Eurostat, 2018). The main reason for this much include heart attack and other diseases, and stroke are higher mortality rate in Bulgaria and Romania is higher the most common causes of death from circulatory mortality rates from circulatory diseases. Mortality rates accounting for 22% of all deaths among women and are based on the number of deaths registered in a 29% of all deaths among men. This group of diseases accounted for 8% of all death among women and 9% among men. Main causes of mortality by country, 2015 Circulatory system Cancer Respiratory system External causes Other Age-standardised rates per 100 000 population 1800 1600 1400 1200 1000 800 600 400 200 0 1. Note: External causes of death include accidents, suicides, homicides and other causes. They are the lowest in France, over 55% of all deaths from circulatory diseases, and Luxembourg and Spain (Figure 3.

Catalepsy should not be confused with the term cataplexy erectile dysfunction in diabetes ppt purchase discount sildalist, a syndrome in which muscle tone is transiently lost impotence australia discount sildalist 120mg free shipping. Cross Reference Cataplexy; Catatonia Cataplexy Cataplexy is a sudden loss of limb tone which may lead to falls (drop attacks) without loss of consciousness biking causes erectile dysfunction order sildalist 120 mg online, usually lasting less than 1 min erectile dysfunction low libido buy generic sildalist on line. Attacks may be precipitated by strong emotion (laughter erectile dysfunction statistics by age generic sildalist 120 mg without prescription, anger erectile dysfunction in young age sildalist 120mg for sale, embarrassment, surprise). Sagging of the jaw and face may occur, as may twitching around the face or eyelids. During an attack there is electrical silence in antigravity muscles, which are consequently hypotonic, and transient arefiexia. Rarely status cataplecticus may develop, particularly after withdrawal of tricyclic antidepressant medication. Therapeutic options for cataplexy include tricyclic antidepressants such as protriptyline, imipramine, and clomipramine; serotonin-reuptake inhibitors such as fiuoxetine; and noradrenaline and serotonin-reuptake inhibitors such as venlafaxine. Although sufferers are unaware of the condition, it does alarm relatives and bed partners. There are no associated neurological abnormalities and no identified neurological or otorhinolaryngological cause. After recovery patients are often able to recall events which occurred during the catatonic state (cf. Kraepelin classified catatonia as a subtype of schizophrenia but most catatonic patients in fact suffer a mood or affective disorder. Sphincters may also be involved, resulting in incontinence, or, in the case of large central disc herniation at L4/L5 or L5/S1, acute urinary retention. Cauda equina syndrome secondary to lumbar disc herniation: a meta-analysis of surgical outcomes. Cross References Bulbocavernosus refiex; Foot drop; Incontinence; Radiculopathy; Urinary retention Central Scotoma, Centrocaecal Scotoma these visual field defects are typical of retinal or optic nerve pathology. Cross References Analgesia; Main succulente Charles Bonnet Syndrome Described by the Swiss naturalist and philosopher Charles Bonnet in 1760, this syndrome consists of well-formed (complex), elaborated, and often stereotyped visual hallucinations, of variable frequency and duration, in a partially sighted (usually elderly) individual who has insight into their unreality. Predisposing visual disorders include cataract, macular degeneration, and glaucoma. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Storage of sphingolipids or other substances in ganglion cells in the perimacular region gives rise to the appearance. There may also be athetoid movements (slow, sinuous, writhing), jointly referred to as choreoathetosis. There may be concurrent abnormal muscle tone, 80 Chorea, Choreoathetosis C either hypotonia or rigidity. One model of basal ganglia function suggests that reduced basal ganglia output to the thalamus disinhibits thalamic relay nuclei leading to increased excitability in thalamocortical pathways which passes to descending motor pathways resulting in involuntary movements. Hypernatraemia or hyponatraemia, hypomagnesaemia, hypocalcaemia; hyperosmolality; Hyperglycaemia or hypoglycaemia; Non-Wilsonian acquired hepatocerebral degeneration; Nutritional. Where treatment is necessary, antidopaminergic agents such as dopaminereceptor antagonists. Luria claimed it was associated with deep-seated temporal and temporodiencephalic lesions, possibly right-sided lesions in particular. The pathophysiology of this mechanosensitivity of nerve fibres is uncertain, but is probably related to increased discharges in central pathways. Cross References Rigidity; Spasticity Claudication Claudication (literally limping, Latin claudicatio) refers to intermittent symptoms of pain secondary to ischaemia. Claudication of the jaw, tongue, and limbs (especially upper) may be a feature of giant cell (temporal) arteritis. Claw Foot Claw foot, or pied en griffe, is an abnormal posture of the foot, occurring when weakness and atrophy of the intrinsic foot muscles allows the long fiexors and extensors to act unopposed, producing shortening of the foot, heightening of the arch, fiexion of the distal phalanges and dorsifiexion of the proximal phalanges (cf. A few beats of clonus are within normal limits but sustained clonus is pathological. Clonus refiects hyperactivity of muscle stretch refiexes and may result from self-re-excitation. Patients with disease of the corticospinal tracts may describe clonus as a rhythmic jerking of the foot, for example, when using the foot pedals of a car. Cluster Breathing Damage at the pontomedullary junction may result in a breathing pattern characterized by a cluster of breaths following one another in an irregular sequence. Cross Reference Coma Coactivation Sign this sign is said to be characteristic of psychogenic tremors, namely, increased tremor amplitude with loading (cf. They may also occur occasionally in other oculomotor brainstem disorders such as Miller Fisher syndrome, but are not seen in normals. Myasthenia gravis: a review of the disease and a description of lid twitch as a characteristic sign. Such collapsing weakness has also been recorded following acute brain lesions such as stroke. There may be accompanying paralysis of vertical gaze (especially upgaze) and light-near pupillary dissociation. It represents a greater degree of impairment of consciousness than stupor or obtundation, all three forming part of a continuum, rather than discrete stages, ranging from alert to comatose. Cross References Abulia; Akinetic mutism; Caloric testing; Catatonia; Decerebrate rigidity; Decorticate rigidity; Locked-in syndrome; Obtundation; Oculocephalic response; Roving eye movements; Stupor; Vegetative states; Vestibulo-ocular refiexes Compulsive Grasping Hand this name has been given to involuntary left-hand grasping related to all right-hand movements in a patient with a callosal haemorrhage. The description does seem to differ from that of behaviours labelled as forced groping and the alien grasp refiex. Reading comprehension is good or normal and is better than reading aloud which is impaired by paraphasic errors. Conduction aphasia was traditionally explained as due to a disconnection between sensory (Wernicke) and motor (Broca) areas for language, involving the arcuate fasciculus in the supramarginal gyrus. Cross References Aphasia; Conduction aphasia; Optic aphasia; Parapraxia, Parapraxis; Speech apraxia 90 Congenital Nystagmus C Confabulation the old definition of confabulation as the falsification of episodic memory occurring in clear consciousness, often in association with amnesia (in other words, paramnesias related as true events), has proven increasingly deficient, not least because most amnesic patients, suffering from medial temporal lobe/hippocampal lesions, do not confabulate, and poor memory alone cannot explain confabulation. Anterior limbic structures are thought culpable, and the pathogenesis includes a wide variety of diseases, which may include associated phenomena such as amnesia, disorientation, false recognition syndromes including the Capgras delusion, and anosognosia. Moreover, as there is a lack of correlation of meaning when this term is used by different health professionals, it is regarded by some as an unhelpful term. This may be due to a variety of factors, including prolonged muscle spasticity with or without muscle fibrosis. This often occurs in the context of limb immobilization or inactivity, for example, in a fiexed posture. Cross Reference Tic Copropraxia Copropraxia is a complex motor tic comprising obscene gesturing, sometimes seen in Tourette syndrome. Cross References Coprolalia; Tic Corectopia Corectopia is pupillary displacement, which may be seen with midbrain lesions, including transtentorial herniation and top-of-the-basilar syndrome, peripheral oculomotor nerve palsies, and focal pathology in the iris. As well as observing whether the patient blinks, the examiner should also ask whether the stimulus was felt: a difference in corneal sensitivity may be the earliest abnormality in this refiex. The fibres subserving 93 C Corneomandibular Refiex the corneal refiex seem to be the most sensitive to trigeminal nerve compression or distortion: an intact corneal refiex with a complaint of facial numbness leads to suspicion of a non-organic cause. Although this may occur in the context of psychiatric disease, especially depression and schizophrenia, it may also occur in association with organic brain abnormalities, specifically lesions of the non-dominant temporoparietal cortex, or migraine. Cross References Capgras syndrome; Delusion; Disconnection syndromes Coup de Poignard Coup de poignard, or dagger thrust, refers to a sudden precordial pain, as may occur in myocardial infarction or aortic dissection, also described with spinal subarachnoid haemorrhage. Subarachnoid haemorrhage presenting as acute chest pain: a variant of le coup de poignard. This lesion may be associated with hemifacial atrophy and epilepsy, and neuroimaging may 95 C Cover Tests show hemiatrophy and intracranial calcification. Whether these changes refiect infiammation or a neurocutaneous syndrome is not known. It should be performed in the nine cardinal positions of gaze to determine the direction that elicits maximal deviation. Cross References Heterophoria; Heterotropia Cramp Cramps are defined as involuntary contractions of a number of muscle units which results in a hardening of the muscle with pain due to a local lactic acidosis. Cramps are not uncommon in normal individuals but in a minority of cases they are associated with an underlying neurological or metabolic disorder. Cross References Fasciculation; Myokymia; Neuromyotonia; Spasm; Stiffness Cremasteric Refiex the cremasteric refiex is a superficial or cutaneous refiex consisting of contraction of the cremaster muscle causing elevation of the testicle, following stimulation of the skin of the upper inner aspect of the thigh from above downwards. It may also be absent in elderly men or with local pathology such as hydrocele, varicocele, orchitis, or epididymitis. It may be peripheral in origin (retinal disease; opacities within cornea, lens, vitreous); or central (lesions anywhere from optic nerve to occipitotemporal region). Cross Reference Photophobia Decerebrate Rigidity Decerebrate rigidity is a posture observed in comatose patients in which there is extension and pronation of the upper extremities, extension of the legs, and plantar fiexion of the feet (= extensor posturing), which is taken to be an exaggeration of the normal standing position. Decerebrate rigidity indicates a deeper level of coma than decorticate rigidity; the transition from the latter to the former is associated with a worsening of prognosis. Recurrent hallucinations or vivid dream-like imagery may also enter the differential diagnosis. Deja vu has also been reported to occur in several psychiatric disorders, such as anxiety, depression, and schizophrenia. Cross References Aura; Hallucination; Jamais vu Delirium Delirium, also sometimes known as acute confusional state, acute organic reaction, acute brain syndrome, or toxic-metabolic encephalopathy, is a neurobehavioural syndrome of which the cardinal feature is a deficit of attention, the ability to focus on specific stimuli. Diagnostic criteria also require a concurrent 102 Delirium D alteration in level of awareness, which may range from lethargy to hypervigilance, although delirium is not primarily a disorder of arousal or alertness (cf.

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Such large genomes are measured in megabase pairs (Mb) erectile dysfunction jacksonville doctor quality 120 mg sildalist, or millions of base pairs erectile dysfunction topical treatment buy 120mg sildalist visa. The human genome is large erectile dysfunction vacuum pump price cheap sildalist 120 mg fast delivery, but it is by no means the largest among animals or higher plants erectile dysfunction in diabetes pdf purchase sildalist 120mg overnight delivery. At 3000 Mb erectile dysfunction causes prostate discount sildalist 120mg with mastercard, the human genome is only 67 percent the size of that in corn and only 4 percent the size of that in the salamander Amphiuma (Table 6 does kaiser cover erectile dysfunction drugs cheap 120 mg sildalist. Among higher animals and plants, a large genome size does not imply a large number of genes. Considering the number and size of proteins produced in human cells, it appears that no more than about 4 percent of the human genome actually codes for proteins. Therefore, in higher animals and plants, the actual number of genes is much less than the theoretical maximum. A remarkable feature of the genetic apparatus of eukaryotes is that the enormous amount of genetic material contained in the nucleus of each cell is precisely divided in each cell division. An analogy may be helpful in appreciating the prodigious feat of packaging that such chromosome condensation represents. Although the genomes of prokaryotes and viruses are much smaller than those of eukaryotes, they also are very compact. The individual polynucleotide strands of a relaxed circle form the usual right-handed (positive) helical structure with ten nucleotide pairs per turn of the helix. When the ends were rejoined again, the result would be a circular helix that is "underwound. In solution, parts B and C would be in equilibrium [Electron micrograph courtesy of K. This twisting is called supercoiling, and a molecule with this sense of twisting is negatively supercoiled. The two responses to underwinding are not independent, and underwinding is usually accommodated by a combination of the two processes: An underwound molecule contains some bubbles of unpaired bases and some supercoiling, with the supercoiling predominating. Although supercoiling occasionally plays a role in the expression of some genes, the overall biological function of supercoiling is unknown. Depending on conditions, topoisomerase I enzymes can either increase or decrease the amount of supercoiling. These enzymes work by producing a doublestranded gap in one molecule through which another double-stranded molecule is passed. The molecular structure of the enzyme includes two sets of "jaws" set approximately at right angles (Figure 6. The term chromosome is a misnomer for this structure, because it is not a true "chromosome" in the sense of a eukaryotic chromosome. The degree of condensation of the isolated nucleoid (that is, its physical dimensions) is affected by a variety of factors, and some controversy exists about the state of the nucleoid within the cell. The enzyme illustraed here, from the yeast Saccharomyces cerevisiae, has two sets of "jaws. The loops must be isolated from one another in such a way that rotation in one loop is not transmitted to other loops. These long molecules usually fracture during isolation, but some fragments that are recovered are still very long. However, conventional electrophoresis can separate only molecules smaller than about 20 kb. All molecules larger than about 20 kb have the same electrophoretic mobility under these conditions and so form a single band in the gel. The most common modifications alter the geometry of the electric field at periodic intervals during the course of the electrophoretic separation. Some electrophoretic apparatuses alternate the electric field between two sets of electrodes oriented at right angles or among three sets of electrodes forming a hexagon. Some of the proteins present in chromatin determine chromosome structure and the changes in structure that occur during the division cycle of the cell. Other chromatin proteins appear to play important roles in regulating chromosome functions. The histone molecules from different organisms are remarkably similar, with the exception of H1. In fact, the amino acid sequences of H3 molecules from widely different species are almost identical. For example, the sequences of H3 of cow chromatin and pea chromatin differ by only 4 of 135 amino acids. The H4 proteins of all organisms also are quite similar; cow and pea H4 differ by only 2 of 102 amino acids. There are few other proteins whose amino acid sequences vary so little from one species to the next. When the variation between organisms is very small, we say that the sequence is highly conserved. The extraordinary conservation in histone composition through hundreds of millions Page 230 of years of evolutionary divergence is consistent with the important role of these proteins in the structural organization of eukaryotic chromosomes. In the electron microscope, chromatin resembles a regularly beaded thread (Figure 6. Histone H1 also appears to play a role in bridging between the beads, but it is not shown in Figure 6. The size of the linker ranges from 20 to 100 nucleotide pairs for different species and even in different cell types in the same organism (200 145 = 55 nucleotide pairs is usually considered an average size). The structure of chromatin varies with the concentration of salts, and the 110 A fiber is present only when the salt concentration is quite low. If Hl were present, it would bind to the octamer surface and to the linkers, causing the linkers to cross. The dimensions indicate known sizes of intermediates, but the detailed structures are hypothetical. Page 233 the salt concentration is further increased to that present in living cells, then a second level of compaction occurs: the organization of the 110 A nucleosome fiber into a shorter, thicker fiber with an average diameter ranging from 300 to 350 A, called the 30 nm fiber (Figure 6. In forming this structure, the 110 A fiber apparently coils in a somewhat irregular left-handed superhelix or solenoidal supercoil with six nucleosomes per turn (Figure 6. It is believed that most intracellular chromatin has the solenoidal supercoiled configuration. The final level of organization is that in which the 30 nm fiber condenses into a chromatid of the compact metaphase chromosome (Figure 6. Electron microscopic studies of chromosome condensation in mitosis and meiosis suggest that the scaffold extends along the chromatid and that the 30 nm fiber becomes arranged into a helix of loops radiating from the scaffold. Details are not known about the additional folding that is required of the fiber in each loop to produce the fully condensed metaphase chromosome. Without chromosome condensation, the chromosomes would become so entangled Figure 6. Each of these chromosomes has a length and cross-sectional diameter many times greater than those of the corresponding chromosome at mitotic metaphase in ordinary somatic cells, as well as a constant and distinctive pattern of transverse banding (Figure 6. Polytene chromosomes are atypical chromosomes and are formed in "terminal" cells; that is, the larval cells containing them do not divide and are eliminated in the formation of the pupa. Although they do not contribute to the tissues in the adult fly, the polytene tissues of larvae have been especially valuable in the genetics of Drosophila, as will become apparent in Chapter 7. Because the two largest chromosomes in Drosophila (chromosomes numbered 2 and 3) have centrally located centromeres, the chromosomes appear in the configuration shown in Figure 6. In a male, the Y chromosome, which consists almost entirely of heterochromatin, is incorporated in the chromocenter. The darkly staining transverse bands in polytene chromosomes have about a tenfold range in width. These bands result from the side-by-side alignment of tightly folded regions of the individual chromatin strands that are often visible in mitotic and meiotic prophase chromosomes as chromomeres. This linear array of bands, which has a pattern that is constant and characteristic for each species, provides a finely detailed cytological map of the chromosomes. The banding pattern is such that observers with sufficient training and experience can identify short regions in any of the chromosomes (Figure 6. Because of their large size and finely detailed morphology, polytene chromosomes are exceedingly useful for a process called in situ nucleic acid hybridization. The somatic chromosomes of Drosophila, drawn to scale with respect to the polytene fourth chromosome, are shownat the upper right as they appear in mitotic prophase. The chromocenter is the central region in which the centromeric regions of all chromosomes are united. However, in eukaryotes, some components of the genome can be detected because their base composition is quite different from the average of the rest of the genome. Information about the size of repeated sequences and the number of copies of a particular sequence can be obtained through studies of the rate of renaturation. Thus if each solution is separately denatured and renatured, the molecules of T7 will renature more rapidly than those of T4. If the two solutions are instead mixed, the T7 and T4 will renature independently of one another (because they are not homologous), and a curve such as that in Figure 6. Note that the curve consists of two steps, one for the more rapidly renaturing T7 molecules and the other for the T4 molecules. If such molecules are fragmented into many components of equal size, then the molar concentration of each component will be the same as that of the unbroken Figure 6. The times required for half-completion of renaturation, t1/2, are obtained by drawing the red horizontal lines, which divide each curve equally in the vertical direction, and then extending the red vertical lines to the time axis. In contrast, if a molecule with an overall sequence that includes both a unique component and several copies of different repeated sequences is fragmented, fragments containing the more numerous repeated sequences will renature more rapidly than the fragments containg portions of the unique sequence. For example, consider a molecule containing 50,000 base pairs and consisting of 100 copies of a tandemly repeated sequence of 500 base pairs. If the molecules are broken into about 100 fragments of roughly equal size, each fragment will be about 500 base pairs. Althugh the renaturation curve for the fragments will have a single step, the renaturation rate will be characteristic of molecules 500 nucleotides in length. Renaturation kinetics can be described in a simple mathematical form, because the reaction is one in which the ratelimiting step is the initial collision of two molecules. The expression C0t is commonly called cot, and a plot of C/C0 versus C0t is called a cot curve. When renaturation is half completed, C/C0 = 1/2 and the value of 1/k depends on experimental conditions, but for a particular set of conditions, the value is proportional to the number of bases in the renaturing sequences. The longer the sequence, the greater will be the time to achieve half-complete renaturation for a particular strating concentration (because the number of molecules will be smaller). If a molecule consists of several subsequences, then one needs to know C0 for each subsequence, and a set of values of 1/k will be obtained (one for each step in the renaturation curve), each value depending on the length of the subsequence. What is meant by the length of the sequence that determines the rate is bese described by example. Experimentally, the number of bases per repeating unit is not determined directly. Generally, renaturation curves for a series of molecules of known molecular weight with no repeating elements in their sequences (and hence yielding one-step renaturation curves) serve as standards. With the standard conditions for Cot analysis used to obtain this set of curves, the sequence length N (in base pairs) that yields a particular value of C0t1/2 is in which t is in seconds, C is in nucleotides per liter, and 5 fi 105 is a constant dependent on the conditions of 0 renaturation. Through this formula, the experimentally determined value of Cot (C0t1/2) yields an estimate of the repeat length, N, of a repetitive sequence. How one obtains the necessary value of C0 will become clear when we analyze a Cot curve. Such an analysis begins by first noting the number of steps in the curve (each step of which represents a sequence or class of sequences of a particular length) Page 238 and the fraction of the material represented by each step. The observed value of C0t1/2 for each step must be corrected by first inferring the value of C0 for each sequence class. The lengths of the sequences are then determined from these corrected values by comparison to standards, and the sequence lengths and sequence abundances, as a proportion of the total, are compared to obtain the number of copies of each sequence. The scale at the top of the figure was obtained from Cot analysis of molecules that 0 1/2 have unique sequences of known lengths, as in Figure 6. To determine the number of copies of each sequence, we make use of the fact that the number of copies of a sequence having a particular renaturation rate in inversely proportional to t1/2 and hence to the observed (uncorrected) C0t1/2 values for each class. The black arrows pointing up to the red scale indicate the number of nucleotide pairs for each sample; they align with the intersection of each curve with the horizontal red line (the point of half-renaturation, or C0t1/2). The method used is to allow renaturation to proceed only to a particular C0t1/2 value. The sequences in this class are typically from 5 to 300 base pairs per repeat and are duplicated as many as 105 times per genome. Page 240 Unique Sequences Most gene sequences and the adjacent nucleotide sequences required for their expression are contained in the unique-sequence component. With minor exceptions (for example, the repetition of one or a few genes), the genomes of viruses and prokaryotes are composed entirely of single-copy sequences; in contrast, such sequences constitute only 38 percent of the total genome in some sea urchin species, a little more than 50 percent of the human genome, and about 70 percent of the D. Highly Repetitive Sequences Many highly repetitive sequences are localized in blocks of tandem repeats, whereas others are dispersed throughout the genome. An example of the dispersed type is a family of related sequences in the human genome called the Alu family because the sequences contain a characteristic restriction site for the enzyme AluI (Section 5.

Intelligence is usually within the normal range but may be Gametes about 10 points lower than in siblings and learning difficulties may require additional input at school erectile dysfunction stress order sildalist with paypal. Behavioural problems can include hyperactivity erectile dysfunction at age of 30 sildalist 120mg generic, distractability and impulsiveness erectile dysfunction pump prescription generic 120 mg sildalist mastercard. Risks within an affected family are often high and are calculated by knowing the mode of inheritance and the structure of the family pedigree erectile dysfunction quality of life buy sildalist 120 mg on-line. Autosomal dominant inheritance Autosomal dominant disorders affect both males and females impotence with beta blockers purchase sildalist online pills. Mild or late onset conditions can often be traced through many generations of a family erectile dysfunction 40 year old man purchase generic sildalist on line. Affected people are heterozygous for the abnormal allele and transmit this to half their offspring, Figure 6. Estimation of risk is therefore apparently simple, but in practice several Parents factors may cause difficulties in counselling families. Aa aa Late onset disorders Dominant disorders may have a late or variable age of onset of signs and symptoms. People who inherit the defective gene will A a a a Gametes be destined to become affected, but may remain asymptomatic well into adult life. Young adults at risk may not know whether they have inherited the disorder and be at risk of transmitting it to their children at the time they are planning their own families. The possibility of detecting the mutant gene before Offspring symptoms become apparent has important consequences for conditions such as Huntington disease and myotonic dystrophy. In some disorders this variability is due to instability of the underlying mutation, as in the disorders caused by trinucleotide repeat mutations (discussed in chapter 7). A mildly affected parent may have a severely affected child, as illustrated by tuberous sclerosis, in which a parent with only skin manifestations of the disorder may have an affected child with infantile spasms and severe mental retardation. Tuberous sclerosis also demonstrates pleiotropy, resulting in a variety of apparently unrelated phenotypic features, such as skin hypopigmentation, multiple hamartomas and learning disability. Each of these pleiotropic effects can demonstrate variable expressivity and penetrance in a given family. Penetrance A few dominant disorders show lack of penetrance, that is, a person who inherits the gene does not develop the disorder. Non-genetic factors may also influence Myotonic dystrophy Noonan syndrome the expression and penetrance of dominant genes, for example Neurofibromatosis (types 1 and 2) diet in hypercholesterolaemia, drugs in porphyria and Osteogenesis imperfecta anaesthetic agents in malignant hyperthermia. Spinocerebellar ataxia Tuberous sclerosis New mutations New mutations may account for the presence of a dominant disorder in a person who does not have a family history of the disease. When a disorder arises by new mutation, the risk of recurrence in future pregnancies for the parents of the affected child is very small. Care must be taken to exclude mild manifestations of the condition in one or other parent before giving this reassurance. This causes no problems in conditions such as achondroplasia that show little variability, but can be more difficult in many other conditions, such as neurofibromatosis and tuberous sclerosis. It is also possible that an apparently normal parent may carry a germline mutation. In some cases the mutation will be confined to gonadal tissue, with the parent being unaffected clinically. This patient had no skin manifestations elsewhere lead to segmental or patchy involvement of the skin. In either case, there will be a considerable risk of recurrence in future children. A dominant disorder in a person with a negative family history may alternatively indicate non-paternity. Homozygous achondroplasia is a lethal condition and the risks to the offspring of two affected parents are 25% for being an affected homozygote (lethal), 50% for being an affected heterozygote, and 25% for being an unaffected homozygote. Autosomal recessive inheritance Most mutations inactivate genes and act recessively. Autosomal recessive disorders occur in individuals who are homozygous for a particular recessive gene mutation, inherited from healthy parents who carry the mutant gene in the heterozygous state. Although the defective gene is passed from generation to generation, the disorder appears only within a single sibship, that is, within one group of brothers and sisters. The offspring of an affected person must inherit Affected Carrier one copy of the mutant gene from them, but are unlikely to inherit a similar mutant gene from the other parent unless the gene is particularly prevalent in the population, or the parents Figure 6. Autosomal recessive disorders are commonly severe, and Parents many of the recognised inborn errors of metabolism follow this type of inheritance. Many complex malformation syndromes Aa Aa are also due to autosomal recessive gene mutations and their recognition is important in the first affected child in the family because of the high recurrence risk. Common recessive genes Worldwide, the haemoglobinopathies are the most common autosomal recessive disorders. In white populations 1 in 10 people carry Offspring the C282Y haemochromatosis mutation. One in 400 people are therefore homozygous for this mutation, although only one third to one half have clinical signs owing to iron overload. Variability Autosomal recessive disorders usually demonstrate full penetrance and little clinical variability within families. Oculocutaneous albinism In cystic fibrosis, delta F508 is the most common mutation and Phenylketonuria most affected homozygotes have pancreatic insufficiency. New mutations New mutations are rare in autosomal recessive disorders and it can generally be assumed that both parents of an affected child are carriers. Uniparental disomy Occasionally, autosomal recessive disorders can arise through a mechanism called uniparental disomy, in which a child inherits two copies of a particular chromosome from one parent and none from the other. If the chromosome inherited in this uniparental fashion carries an autosomal recessive gene mutation, then the child will be an affected homozygote. Heterogeneity Genetic heterogeneity is common and involves multiple alleles at a single locus as well as multiple loci for some disorders. Affected children Allelic heterogeneity implies that many different mutations can (;) have been born to several couples and the obligate gene carriers occur in a disease gene. The inheritance severity of the disorder may be influenced by the particular combination of mutations present. Consanguinity Consanguinity increases the risk of a recessive disorder because both parents are more likely to carry the same defective gene, that has been inherited from a common ancestor. The rarer the condition the more likely it is to occur when the parents were related before marriage. Overall, the increased risk of having a child with severe abnormalities, including recessive disorders, is about 3% above the risk in the general population. X linked recessive inheritance In X linked recessive conditions males are affected because they have only a single copy of genes carried by the X chromosome (hemizygosity), but the disorder can be transmitted through healthy female carriers. A female carrier of an X linked recessive disorder will transmit the condition to half her sons, and half her daughters will be carriers. An affected male will transmit the mutant gene to all his daughters (who must inherit his X chromosome), but to none of his sons (who Parents must inherit his Y chromosome). X X X Y Gametes Affected females Occasionally a heterozygous female will show some features of the condition and is referred to as a manifesting carrier. This is usually due to non-random X inactivation leading to the chromosome that carries the mutant allele remaining active in most cells. Alternatively, X chromosome abnormalities 1::: 1 such as Turner syndrome may give rise to X linked disorders in females since, like males, they are hemizygous for genes carried by Figure 6. The homozygous affected state may occur in females whose father is affected and whose mother is a carrier. This is only likely to occur in common X linked disorders such as Parents red-green colour blindness, or glucose-6-phosphate dehydrogenase deficiency in the Middle East. Genetic assessment is important because of the high recurrence risk and the severity of many X linked disorders. An X linked recessive condition must be considered when the family history Offspring indicates maternally related affected males in different generations of the family. Identifying female Carrier female: Normal male gene carriers requires interpretation of the family pedigree and: the results of specific carrier tests, including direct mutation Figure 6. Although dominant, females may be less severely affected than males, as in X linked hypophosphataemia (vitamin D-resistant rickets) and oculomotor nystagmus, because of X inactivation which results in expression of the mutant allele in only a proportion of cells. The gene is transmitted through families in the same way as X linked recessive genes: females transmit the mutation to half their sons and half their daughters; males transmit the mutation to all their daughters and none of their Figure 6. The pedigree, however, resembles autosomal dominant inheritance except that there is no male to male transmission and there is an excess of affected females. In some disorders the condition appears to be lethal in affected males, for example focal dermal hypoplasia (Goltz syndrome) and incontinentia pigmenti. In these families there will be fewer males than expected, half of the females will be affected and all surviving males will be unaffected. An affected woman therefore has a one in three chance of having an affected child and two thirds of her children will be girls. Rett syndrome is a disorder that affects girls almost exclusively and usually occurs sporadically, since affected females do not reproduce. This disorder has been shown to be due to a mutation in a gene located at Xq24, confirming that it is an X linked dominant condition. This pattern of inheritance has previously been suggested for such conditions as porcupine skin, hairy ears, and webbed toes. In most conditions in which Y linked inheritance has been postulated the actual mode of inheritance is probably autosomal dominant with sex limitation. Genes involved in male development and spermatogenesis are carried by the Y chromosome, but the mode of inheritance is not demonstrated because of the associated infertility. Premutations do not cause disease but pallidoluysian atrophy are unstable and likely to expand further when transmitted to offspring. Once the repeat reaches a certain size it becomes a full mutation and disease will occur. These mutations confer a specific gain of function and cause the protein to form intranuclear aggregates that result in cell death. Other types of mutations occur occasionally in these genes resulting in the same phenotype. In myotonic dystrophy the pathological mechanism of the expanded repeat is not known. It is likely that the expansion affects the transcriptional process of several neighbouring genes. It is occasionally detected by the unmasking of a recessive loss of one disorder for which only one parent is a carrier when there is chromosome isodisomy for the parental chromosome carrying such a Disomic mutation. In this rare situation the child would be affected by a zygote recessive disorder for which the other parent is not a carrier. Imprinting It has been observed that some inherited traits do not conform to the pattern expected of classical mendelian inheritance in which genes inherited from either parent have an equal effect. The term imprinting is used to describe the phenomenon by which certain genes function differently, depending on whether they are maternally or paternally derived. The imprint lasts for one generation and is then removed, so that an appropriate imprint can be re-established in the germ cells of the next generation. The effects of imprinting can be observed at several levels: that of the whole genome, that of particular chromosomes or chromosomal segments, and that of individual genes. When paternally derived, the placenta is large and cystic with molar changes and the fetus has a large head and small body. When the extra chromosome set is maternal, the placenta is small and underdeveloped without cystic changes and the fetus is noticeably underdeveloped. An analogous situation is seen in conceptions with only a maternal or paternal genetic contribution. Androgenic conceptions, arising by replacement of the female pronucleus with a second male pronucleus, give rise to hydatidiform moles which lack embryonic tissues. Gynogenetic conceptions, arising by replacement of the male pronucleus with a second female one, results in dermoid cysts that develop into multitissue ovarian teratomas. Angelman syndrome is quite distinct and is associated with severe mental retardation, microcephaly, ataxia, epilipsy and absent speech. Similar de novo cytogenetic or molecular deletions can be detected in both conditions.