Eskalith

Dr Kees Polderman

• Associate Professor in Intensive Care Medicine,
• Department of Intensive Care
• University medical center Utrecht
• Heidelberglaan 100
• Utrecht 3584 CX
• The Netherlands

A 29-year-old woman comes to a cognitive therapist with a 6-month history of sudden feelings that she is going to die anxiety buy generic eskalith 300mg on line. The patient reports that during these episodes her pulse races depression glass purchase eskalith 300mg fast delivery, she feels short of breath la depression test cheap eskalith 300mg overnight delivery, and she gets chest pain mood disorders symposium johns hopkins cheap eskalith 300 mg online. She notes that she feels like she is going to die on the spot and therefore has begun to restrict her movement outside the house so that she can remain near a phone in case she needs to call an ambulance mood disorder mania order eskalith 300 mg overnight delivery. Which of the following treatment interventions should the therapist employ first to begin to help this patient with her problem Taking the patient to a crowded place and preventing her escape until her anx iety has peaked b anxiety yoga exercises buy eskalith master card. Educating the patient about the harmless nature of the physical symptoms experienced during a panic attack d. Replying empathically to the patient about the suffering that must be endured with panic attacks 280. A physician with a very busy practice feels satisfied and fulfilled when he can make a difference in the lives of his patients. Which of the fol lowing defense mechanisms is being used, according to psychoanalytic theory An 18-year-old girl comes to the psychiatrist because she pulls out her hair in patches when she is anxious or upset. She is taught to make a tight fist whenever she has this impulse rather than pull out her hair. A 34-year-old man comes to the psychiatrist complaining of marital problems, which seemed to begin just after the death of his mother. In ther apy, it is discovered that the patient had an intensively ambivalent relation ship with his mother. However, when he discusses his mother, the patient appears unemotional and detached. A 32-year-old man comes to a therapist with the chief complaint of not being able to have a successful and happy relationship with a woman. During the course of the therapy, it becomes obvious that the patient has deep-seated anger against women, even though he is consciously unaware of it. When confronted about the behavior, he denies that this has anything to do with what is going on in the therapy, though the therapist does not believe this to be true. Interpersonal psychotherapy was developed in the 1970s by Gerard Klerman as a time-limited treatment for major depressive disorders. A young woman with obsessive-compulsive disorder has suffered from contamination fears for years, and now her hands are raw from so much washing. Although this defense is occasionally used by patients with neurotic disturbances, splitting is encountered mostly in more severely dis turbed patients, such as those with personality disorders and, in particular, borderline personality disorder. According to the object relation theory, patients with severe personality disorders as a result of faulty parenting during infancy have not been able to form stable and realistic intrapsychic representations of themselves and of the important people in their lives. Instead of seeing themselves and others as consistent entities containing both good and bad traits, they perceive the negative and positive aspects as separate, irreconcilable parts. In the case described, in order to preserve her view of her therapist as helpful and kind (and her positive feelings toward him), the patient has to split the less-than-perfect traits of the therapist as well as all her negative thoughts and feelings toward him. Unfortunately, when disappointments, real or imagined, bring the negative side of the ambivalence into focus, patients who use splitting as a main defense temporarily lose contact with the positive side. Clinicians and patients who are proponents of this system prefer it to other treatment options and say it is just as effective, or in some cases more so. Transference causes patients to unconsciously reenact old scripts with new others (in this case, the physician). In this example, it is likely that this patient has experienced authority figures in his past who have attempted to control him in unwelcome and oppressive ways. Verbal and nonverbal communication, overt behavioral patterns, omissions, and dreams are some of the ways transference manifests itself. Insight-oriented psychotherapy requires a strongly motivated patient who can tolerate a great deal of frustration and has a good capacity for insight. These patients must be able to have good impulse control so that they may talk about their feelings without acting them out. Patients with low intelligence or with cognitive dysfunctions do not generally get benefit from this kind of therapy. Harm to the patient must be minimized, which means all invasive tests and procedures should be kept to an absolute minimum. Splitting is common, so regular interdisciplinary team meetings are called for to manage these patients. A primary care physician should be appointed gatekeeper of all treatment, medical and psychiatric. On the contrary, these patients tend to blame others for their difficulties and deny that they have any problems. Resis tance takes place at any point in the treatment, and particularly when unac ceptable impulses or thoughts threaten to come into consciousness or a maladaptive defense mechanism is challenged. Resistance can manifest itself in many different ways, including withholding important thoughts from the analyst, falling silent during sessions, forgetting appointments, forgetting to pay the analyst, falling asleep during the session, and consid ering dropping out of treatment. Freud thought that resistance should be uncovered by the analyst but not challenged or interpreted. The other items listed are also factors that facilitate the therapeutic group process. Group cohesion refers to the sense that the group is working together toward a common goal. Shared belief system refers to the notion that the group may come to have a framework of beliefs and ideas about issues that is common to everyone in the group. Although insight-oriented strategies such as interpretations can be used, they are not the main therapeutic instruments. Supportive psychotherapy aims to foster and maintain a pos itive transference all the time in order to provide the patient with a consis tently safe and secure atmosphere. Consolation, advice, reality testing, environmental manipulation, reassurance, and encouragement are strategies commonly used in supportive psychotherapy. The therapist encourages the patient to recreate the panic attack in the office to demonstrate that, though they are uncomfortable, the attacks themselves will not cause the patient to die, have a heart attack, or go crazy. In essence, this kind of therapy encourages patients to face their fears and see that they are experiencing an irrational or unrealistic concern with them. Once the patient in this question experiences the panic attack in the office and nothing terrible occurs, she will begin to prove to herself that her initial bodily sensations were no cause for alarm. There are no data to support the use of psychodynamic psychotherapy or psychoanalysis for the treatment of social phobia. Psychoanalysis would also use the understanding of the patient and the recreation of the past through clarification, con frontation, and interpretation, but typically the patient comes to the office more frequently than once per week, and often, though not always, the patient lies on a couch facing away from the therapist. A cognitive therapy would most likely focus on the negative worldview of this patient and attempt to restructure those thoughts. A behavioral therapist would most likely instruct the patient to change his/her behavior as an antecedent to recovery (such as exercising or another activity). Repression is the expelling or withholding of an idea or feeling from consciousness. This defense dif fers from suppression by affecting conscious inhibition of impulses to the point of losing and not just postponing goals. Reaction formation refers to the substitution of an unacceptable feeling or thought with its opposite. Sublimation is the achieving of impulse gratification and the retention of goals by altering a socially objectionable aim or object to a socially accept able one. Sublimation is a mature defense, together with humor, altru ism, asceticism, anticipation, and suppression. Somatization is the conver sion of psychic derivatives into bodily symptoms and reacting with somatic manifestations rather than psychic ones. Intellectualization is the excessive use of intellectual processes to avoid affective expression or experience. Isolation of affect is the splitting or separation of an idea from the affect that accompanies it but that is repressed. When used as a defense, it can obliterate the dis tinction between the subject and the object. Projection is the perception of and reaction to unacceptable inner impulses and their derivatives as though they were outside the self. For example, it is not uncommon for the victim of child abuse to grow up to be an abusive parent him or herself. Projective identification occurs mostly in borderline personality disorder and consists of three steps: (1) an aspect of the self is projected onto someone else, (2) the pro jector tries to coerce the other person to identify with what has been pro jected, and (3) the recipient of the projection and the projector feel a sense of oneness or union. Denial is the avoidance of awareness of some painful aspect of reality by negating sensory data. Concrete suggestions about improving functioning in the outside world (in this case, suggestions about a job search) are appropriate in this kind of therapy, which is often reserved for those patients with severe psychopathology. This kind of therapy is not 162 Psychiatry considered curative but, rather, helps the patient maintain functioning at the current level without the worsening of the preexisting symptoms. In this instance, the patient was taught to control his own behavioral responses to anxiety, and thus presumably, he will do bet ter on his multiple-choice exams. The patient in question 265 presents with a myriad of symptoms, all of which seem neurotic in nature (there is no psychosis or vegetative signs/symptoms of a major mood disorder). The history of sexual abuse and the long-standing history of these symptoms mean that the use of short-term therapy is unlikely to be helpful. Her many symptoms in many spheres indicate that an eclectic approach will offer the highest chance of improvement in the least amount of time. Desensitization is based on the concept that when the feared stimulus is presented paired with a behavior that induces a state incompatible with anxiety (eg, deep muscle relaxation), the phobic stimulus loses its power to create anxiety (counterconditioning). This pairing of feared stimulus with a state incom patible with anxiety is called reciprocal inhibition. Treatment starts with exposure to stimuli that produce minimal anxiety and proceeds to stimuli with higher anxiety potential. Operant conditioning refers to the concept that behavior can be modified by changing the antecedents or the consequences of the behavior (contingency management). Flooding is another exposure-based treatment for phobia, based on extinction rather than counterconditioning. Reframing is an intervention used in family therapy and refers to giving a more acceptable meaning to a problematic behavior or situation. Another category of patients who may have unplanned and potentially negative reactions to hypnosis are individuals with a history of trauma, who may undergo spontaneous abreactions. Ideally, interpretations help the patient become more aware of unconscious material that has come close to the surface.

It is sometimes possible to identify other psychiatric conditions anxiety lymph nodes purchase eskalith amex, but the limited level of language development may make diagnosis difficult and dependent upon information obtained from others who are familiar with the individual mood disorder teens order eskalith cheap. Includes: imbecility moderate mental subnormality moderate oligophrenia F72F72F72F72 Severe mental retardationSevere mental retardationSevere mental retardationSevere mental retardation Clinical description this category is broadly similar to that of moderate mental retardation in terms of the clinical picture depression test for elderly buy eskalith 300mg on line, the presence of an organic aetiology mood disorder treatments order cheap eskalith line, and the associated conditions depression definition business cycle best purchase eskalith. The lower levels of achievement mentioned under F71 are also the most common in this group depression mayo clinic trusted eskalith 300mg. Most people in this category suffer from a marked degree of motor impairment or other associated deficits, indicating the presence of clinically significant damage to or maldevelopment of the central nervous system. Most such individuals are immobile or severely restricted in mobility, incontinent, and capable at most of only very rudimentary forms of nonverbal communication. They possess little or no ability to care for their own basic needs, and require constant help and supervision. Comprehension and use of language is limited to , at best, understanding basic commands and making simple requests. The most basic and simple visuo-spatial skills of sorting and matching may be acquired, and the affected person may be able with appropriate supervision and guidance to take a small part in domestic and practical tasks. Severe neurological or other physical disabilities affecting mobility are common, as are epilepsy and visual and hearing impairments. Pervasive developmental disorders in their most severe form, especially atypical autism, are particularly frequent, especially in those who are mobile. Includes: idiocy profound mental subnormality profound oligophrenia F78F78F78F78 Other mental retardationOther mental retardationOther mental retardationOther mental retardation this category should be used only when assessment of the degree of intellectual retardation by means of the usual procedures is rendered particularly difficult or impossible by associated sensory or physical impairments, as in blind, deaf-mute, and severely behaviourally disturbed or physically disabled people. F79F79F79F79 Unspecified mental retardationUnspecified mental retardationUnspecified mental retardationUnspecified mental retardation There is evidence of mental retardation, but insufficient information is available to assign the patient to one of the above categories. It includes self injury which would cause tissue damage if protection or restrain were not used. Repeated self injurious behaviour includes head banging, face slapping, eye poking and biting of hands, lips or other body parts. The conditions listed here are among those encountered most frequently whether causative or not. Infections and parasitic diseasesInfections and parasitic diseasesInfections and parasitic diseasesInfections and parasitic diseases A17 Tuberculosis of the nervous system A50 Congenital syphilis A81. A50A50A50A50 CongenitalCongenital syphilisCongenitalCongenital syphilissyphilissyphilis Congenital syphilis has been known as a cause of mental handicap for many years. The spirochaete responsible may produce abortion, stillbirth or a very large variety of disorders in surviving children depending on the stage of development at which the infection has taken place and the nature of the treatment given. The protean manifestations of this condition include failure to thrive, rashes, jaundice, hepatosplenomegaly, anaemia, inflammation of the joints and nerve deafness. The brain is involved in about 60% of cases and some of those so affected will have mental handicap of varying degree. The general decline of syphilis in many countries has lead to a great reduction of mental handicap due to this cause. The most effective form of prevention is the serological detection and immediate treatment of syphilitic infection in women as soon as they are known to be pregnant. E00-03 HypothyroidismE00-03 HypothyroidismE00-03 HypothyroidismE00-03 Hypothyroidism Underfunctioning of the thyroid gland has been associated with mental handicap for many years. The thyroid hormones are essential for protein synthesis and any condition which interferes with the production of these hormones may affect both the development and the function of the brain. The synthesis of thyroxine and triiodothyronine may be interfered with in many ways. Hypothyroidism, which may also be cause by auto-immune mechanisms, goitrogenic agents, drugs, congenital partial absence of the thyroid gland and genetic disorders may cause mental handicap or mental slowing, often associated with mental disorders depending upon the age of onset. It is therefore, necessary to test thyroid function periodically in order not to miss the diagnosis. The diagnosis of hyperthyroidism is relatively easy to make and the treatment which is pure replacement therapy by the administration of oral thyroxine, is both inexpensive and completely effective. E70E70E70E70 PhenylketonuriaPhenylketonuriaPhenylketonuriaPhenylketonuria this disorder, when untreated, is characterised by severe mental handicap, epilepsy, behaviour disorders, light pigmentation, poor co-ordination and autistic-like behaviour. It is an autosomal recessive disorder in which an increase in cellular concentrations of the amino acide phenylalanine hydroxilase, which is necessary for the conversion of this amino acide to tyrosine. The resulting deficiency of tyrosine leads to a shortage of melanin and this, in turn, to a lack of this pigment in the skin and hair. The diagnosis is established by measuring the concentrations of phenylalanine in the urine or blood. The treatment is based on providing an artificial diet containing reduced amounts of phenylalanine. In order to ensure the best result this should be instituted from birth and accompanied by other supportive measures. G04-05 Cerebral infectionsG04-05 Cerebral infectionsG04-05 Cerebral infectionsG04-05 Cerebral infections A very large number of infections of the brain may cause damage of a nature and extent sufficient to cause mental handicap of any degree of severity. The main emphasis in this group of disorders lies in primary prevention with the use of suitable hygiene measures and vaccines. Once an infection has become established the outcome depends very largely on early diagnosis and the nature of the infecting organism. While the treatment of infections by viruses remains basically supportive, infections due to bacteria tend to respond to appropriate treatment with antibiotics. Infection of the foetus with the rubella virus tends to result in serious neurological damage often associated with blindness, deafness, self-injurious behaviour and severe mental impairment. The correlation stems from the fact that the increase in the degree of mental handicap is highly correlated with the extent of associated brain damage. Virtually every known type of epilepsy is found but mixed types of epilepsy are relatively commoner. Temporal lobe disorders are also relatively common and may give rise to serious difficulties in diagnosis since they may result in behaviours which closely resemble conventional psychiatric and behavioural disorders. Epilepsy should always be considered in the assessment of any handicapped person with any type of disturbance of consciousness, movement disorder or unusual mental state. Treatment is conventional but is frequently very difficult because of the higher incidence of multifocal forms of epilepsy. G80G80G80G80 Cerebral PalsyCerebral PalsyCerebral PalsyCerebral Palsy this condition is difficult to define but is conventionally described as a group of motor disorders with or without associated sensory and intellectual deficits where the cause is injury to the immature brain. Such damage to the brain has been associated with oxygen deprivation for any reason, trauma and infection as well as many metabolic disorders. However the cause of cerebral palsy is still unknown in a significant number of cases. The types of movement disorder are generally classified in the following five categories; hypotonic, ataxic, spastic, athetoid, and tremulous. The ataxic form shows involuntary movements, disorders of balance and co-ordination and abnormal muscle tone. The hypotonic form shows a combination of decreased resistance to movement, less spontaneous movement and poor balance. In the athetoid type there is hyperextension of the torso, open mouth, drooling and writhing movements of the limbs but no increase in the stretch reflexes. The tremulous form is characterised by a regular tremor which may increase in frequence and amplitude with emotion. The limbs may be affected by pareses of varying degree and in varying combinations (hemiplegia, paraplegia, quadriplegia) and a large number of other neurological deficits might be found depending upon the site and type of the brain damage. The association between cerebral palsy and mental handicap depends upon the site and extent of brain damage and this accounts for the fact that the range of intelligence found in people with cerebral palsy cover the entire range of abilities. It is a Herpes virus and may lie dormant for variable periods becoming reactivated from time to time; mostly in the cervix or uterus. The incidence of antibodies in females of child-bearing age varies from 40% to 100% in different populations and the incidence of congenital infections varies from 1 in 50 to 1 in 500. Damage to the foetus of varying degrees may be produced at any stage of gestation. P57P57P57P57 KernicterusKernicterusKernicterusKernicterus High levels of bilirubin in the blood attack nervous tissue and may lead to brain damage in the newborn. Elevated levels of bilirubin may result from any cause of excessive intravascular haemolysis or impaired hepatic conjugation. Among the causes are neonatal sepsis, prematurity, a variety of drugs, haemolytic disease of the newborn and glucose-6-phosphase dehydrogenase deficiency. If the blood levels of bilirubin are low or adequately treated there may be no resulting brain damage but prolonged high levels may result in mental handicap, movement disorders and sensorineural hearing loss. The diagnosis is made by measuring blood level of bilirubin and treatment methods include exchange-transfusion and hyperimmune Rh gammaglobulin to prevent maternal Rh sensitisation. Q02Q02Q02Q02 MicrocephalyMicrocephalyMicrocephalyMicrocephaly this condition, which may be defined as having a head smaller than 3 standard deviations below the mean for the particular age, is mostly secondary to more than 50 conditions where brain growth is inhibited although there appear to be some primary causes which are genetically determined. Q05Q05Q05Q05 Spina BifidaSpina BifidaSpina BifidaSpina Bifida Spina Bifida is an example of one of the many disorders which result from defects of midline closure of the central nervous system (spinal dysraphism). This group includes hydrocephalus, meningomyelocele, spina bifida and variations on all these conditions. A variable percentage of people with this condition have mental handicap the severity of which covers a wide range. Haematosis implies an organisational defect producing an abnormal mixture of tissues. Tuberose Sclerosis, also known as adenoma sebaceum, is an autosomal dominant condition with very variable expressivity and is found in about 0. Most people with this condition have it as a result of a new mutation from unaffected parents. The brain almost always shows areas of calcification and particularly in periventricular areas as well as local distortion by abnormal masses of neural tissue. Fibro-angiomatous lesions, the so-called adenoma sebaceum develop in the nasolatial fold and elsewhere on the face. Those who have the mild form of the condition may live perfectly normal lives and the diagnosis may only come to light when the diagnosis of the severe form comes to light in one of their children. In the severe form many organ systems may be affected and this is characterised by developmental delay, epileptic seizures and severe behaviour disorders. The associated behavioural disorders include feeding problems, absence of speech and self injurious actions. They tend to avoid physical contact and social interaction and typically exhibit difficult, unpredictable behaviour which is very difficult to manage. They tend to be floppy babies who have feeding problems and show developmental delay. At about two years of age persistent appetite develops and this is accompanied by excessive weight gain. The associated mental handicap covers a wide range of severity but is mostly in the mild to moderate range. The main behaviour abnormalities are excessive appetite which may be associated with pica, scavenging and food stealing. Severe temper tantrums and aggressive behaviour is often associated with the frustration of not obtaining food. It is an example of genetic imprinting in that both copies of chromosome 15 need to come from the mother in this condition. The level of intelligence covers a wide range, the most frequent lying in the 40-50 range. The physical findings are very variable and there may be other anatomical disorders. It is the commonest cause of severe mental handicap with an incidence of 1 in 650 live births in virtually all countries. They are prone to infections because of an immunological defect and are particularly prone to problems of vision and hearing. Fifty percent are born with cardiac disorders of varying severity with a cumulative mortality of 40%. In males it is characterized by moderate to severe mental handicap, long thin faces with prominent jaws, large protuberant ears, macroorchidism and autistic features. S06S06S06S06 Intracranial injuryIntracranial injuryIntracranial injuryIntracranial injury Any trauma to the brain, depending upon the site and extent, may affect intellectual function. Common causes in children are associated with birth trauma and road traffic accidents while non accidental injury and domestic accidents account for a minority. This latter cause of mental handicap is often overlooked any may become evident only on careful history taking. Whilst this axis can be used to record the physical injury and sequelae, the psychological and behavioural effects are recorded on the other axes. T74T74T74T74 Non-accidental injuryNon-accidental injuryNon-accidental injuryNon-accidental injury Although reliable data on non-accidental injury is not available there is evidence that a substantial proportion of children injured in this way are subjected to head injuries as well. The effect of this trauma ranges from the trivial to lesions which may result in death and an unknown proportion may develop mental handicap. Its importance lies in recognising it as a diagnostic category in order to prevent recurrence in the same child or any of its siblings. A non-organic diagnosis should usually be made unless there is firm evidence of an organic aetiology (see discussion of the terms organic and non organic in the introduction to F0). It is usually possible to establish the diagnosis of a psychiatric disorder for people with mild mental retardation in the same way as for the non-retarded population. This may be much more difficult or impossible for people with severe and profound retardation. Factors influencing the ability to establish diagnoses include language and communication problems, the effect of low intelligence on the capacity to describe complex subjective experiences, and the presence of additional disorders or impairments (such as epilepsy, sensory impairments or autism). These may have a pathoplastic effect on psychopathology, may prevent the description of cardinal features of a disorder, or may result in behaviour which resembles that seen in psychotic disorders. Some additional disorders (such as epilepsy) amy predispose to psychiatric disorder.

Glycemic control may also bene at an initial medical evaluation mood disorder nos dsm 5 buy eskalith with american express, and and lifestyle therapy depression definition us history buy generic eskalith 300mg. B cially modify plasma lipid levels anxiety quiz online discount 300 mg eskalith free shipping, particularly every 5 years thereafter definition depression in elderly discount 300 mg eskalith with mastercard, or more c For patients with diabetes aged in patients with very high triglycerides and frequently if indicated anxiety zone als purchase eskalith online from canada. Multiple clinical trials have dem tion of saturated fat neonatal depression definition order eskalith 300mg otc, trans fat, and response to medication. B goals (56), suggesting that the initiation atherosclerotic cardiovascular dis and intensication of statin therapy ease risk factors, consider using be based on risk prole (Table 9. As dia high-intensity statin and lifestyle diabetes type, pharmacologic treatment, betes itself confers increased risk for therapy. Ongoing Therapy and Monitoring With Lipid Panel In adults with diabetes, it is reasonable use for assessing cardiovascular risk in based on risk prole. High-intensity sta to obtain a lipid prole (total choles individuals with diabetes. Clinicians should attempt to nd a dose or alternative statin that is tol Table 9. Individuals were $50 large trial in patients with diabetes, fe to those with diabetes risk factors. In those with diabetes Statin and Fibrate lar event rate reduction with statins far (27%), the combination of moderate Combination therapy (statin and outweighed the risk of incident diabetes intensity simvastatin (40 mg) and ezetimibe brate) is associated with an increased even for patients at highest risk for di (10 mg) showed a signicant reduction of risk for abnormal transaminase levels, abetes (74). The absolute risk increase major adverse cardiovascular events with myositis, and rhabdomyolysis. The risk was small (over 5 years of follow-up, an absolute risk reduction of 5% (40% vs. Severe hypertriglyceridemia or symptom-driven coronary or cere c Dual antiplatelet therapy is reason (. There was some risk factor (family history of premature creased cardiovascular risk. While risk calcu major risk factor (family history stroke in men but signicantly reduced lators such as those from the American of premature atherosclerotic car stroke in women. However, there was College of Cardiology/American Heart As diovascular disease, hypertension, no heterogeneity of effect by sex in the sociation my. The condence interval aspirin therapy, particularly in those at atherosclerotic cardiovascular dis was wider for those with diabetes be low risk (87), but are not generally recom ease risk factors, as the potential ad cause of smaller numbers. Sex differences in the antiplate verse effects from bleeding likely Aspirin appears to have a modest ef let effect of aspirin have been suggested offset the potential benets. The the presence of such differences in indi years of age with multiple other main adverse effects appear to be an viduals with diabetes. The excess risk may be as high as Aspirin Use in People <50 Years of Age is required. There is little evidence to large trials of aspirin for primary pre multiple recent well-conducted studies support any specic dose, but using the vention in the general population. These and meta-analyses have reported a risk lowest possible dose may help to re trials collectively enrolled over 95, 000 of heart disease and stroke that is duce side effects (90). Overall, they found that pared with men with diabetes, including Although platelets from patients with aspirin reduced the risk of serious among nonelderly adults. Despite that more frequent dosing regimens of infarction, b-blockers should be abnormal myocardial perfusion imaging aspirin may reduce platelet reactivity in continued for at least 2 years after in more than one in ve patients, cardiac individuals with diabetes (93); however, the event. B outcomes were essentially equal (and these observations alone are insuffi c In patients with symptomatic very low) in screened versus unscreened cient to empirically recommend that heart failure, thiazolidinedione patients. Accordingly, indiscriminate higher doses of aspirin be used in this treatment should not be used. Any benet of newer noninva and may have benets beyond this sive coronary artery disease screening period. Evidence supports use of either Cardiac Testing methods, such as computed tomography ticagrelor or clopidogrel if no percuta Candidates for advanced or invasive car and computed tomography angiography, neous coronary intervention was per diac testing include those with 1)typical toidentifypatient subgroups for different formed and clopidogrel, ticagrelor, or or atypical cardiac symptoms and 2)an treatment strategies remains unproven. In adults with diabetes (100, 106, 107), the role of these tests be pirin signicantly reduces the risk of $40 years of age, measurement of cor yond risk stratication is not clear. Their recurrent ischemic events including car onaryarterycalciumisalsoreason routine use leads to radiation exposure diovascular and coronary heart disease able for cardiovascular risk assessment. More studies are needed to Pharmacologic stress echocardiography testing such as coronary angiography investigate the longer-term benets of or nuclear imaging should be considered and revascularization procedures. Screening testing and are unable to exercise should undergo pharmacologic stress Lifestyle and Pharmacologic c In asymptomatic patients, routine echocardiography or nuclear imaging. In patients with prior diovascular disease or at high risk for tients with diabetes remains unknown. Gaede P, Lund-Andersen H, Parving H-H, had diabetes for more than 10 years, and Pedersen O. Effect of a multifactorial interven avoided in patients with symptomatic tion on mortality in type 2 diabetes. Centers for Disease Control and Prevention the relationship between dipeptidyl over a median follow-up of 3. The cardiovascular disease as rst-listed diagnosis death by 14% (absolute rate 10. Saxagliptin Assessment of Vascular Out per 1, 000 diabetic population, United States, 12. Available from comes Recorded in Patients with Diabetes vascular death by 38% (absolute rate Prog similar effect in lower-risk patients with nostic value of ambulatory and home blood diovascular Outcomes with Alogliptin diabetes remains unknown. Study participants had a mean age of type 2 diabetes: a systematic review and meta no effect on the composite end point of analysis. Over 80% of study partici pressure targets for hypertension in people sion for heart failure in the post hoc anal pants had established cardiovascular dis with diabetes mellitus. Effects of intensive blood-pressure of candesartan on mortality and morbidity in Pregnancy. Use of di nation of perindopril and indapamide on mac parative efficacy and safety of blood pressure uretics during pregnancy. Effects of intensive as compared with enalapril on cardiovascular 27 randomised trials. Appropriate blood pressure control in hy from 90, 056participants in 14 randomised trials et al. Collins R, Armitage J, Parish S, Sleigh P, Peto in the Veterans Affairs Diabetes Trial. Primary prevention of hypertriglyceridemia: an Endocrine Society clin b4531 cardiovascular disease with atorvastatin in type 2 ical practice guideline. Effects of long-term feno American Diabetes Association; American Heart in18, 686peoplewithdiabetesin14randomised brate therapy on cardiovascular events in Association; American College of Cardiology trials of statins: a meta-analysis. Reporting rate of Association, a scientic statement of the Amer vascular disease. Intensive versus moderate lipid and risk of incident diabetes: a collaborative differences in diabetes and risk of incident lowering with statins after acute coronary syn meta-analysis of randomised statin trials. Daily Force of the European Society of Cardiology aspirin in the primary prevention of cardiovas and intermittent rosuvastatin 5 mg therapy in and Other Societies on Cardiovascular Disease cular disease: shared decision making in clinical statin intolerant patients: an observational Prevention in Clinical Practice (constituted by practice. Role of Thrombosis, 9th ed: American College of study: a randomized controlled trial. Optimal medi graphic angiography in diabetic patients with a meta-analysis of randomized trials. A randomized trial of therapies for ment of subclinical coronary atherosclerosis in tigators. Liraglutide and cardiovascular prospective evaluation of the combined use of converting enzyme inhibitors: a randomised con outcomes in type 2 diabetes. B Treatment c Optimize glucose control to reduce the risk or slow the progression of diabetic kidney disease. A c Optimize blood pressure control to reduce the risk or slow the progression of diabetic kidney disease. A c For people with nondialysis-dependent diabetic kidney disease, dietary pro tein intake should be approximately 0. For patients on dialysis, higher levels of dietary protein intake should be considered. E c Patients should be referred for evaluation for renal replacement treatment if 2 they have an estimated glomerular ltration rate, 30 mL/min/1. A c Promptly refer to a physician experienced in the care of kidney disease for Suggested citation: American Diabetes Associa uncertainty about the etiology of kidney disease, difficult management issues, tion. It has not been deter propriately, and determine whether ne urine creatinine (Cr) is less expensive but mined whether application of the more phrology referral is needed (Table 10. Early vaccination S90 Microvascular Complications and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017 Table 10. Blood pressure control reduces risk of of achieving near-normoglycemia has the presence of diabetic kidney dis cardiovascular events (30). B, 70 mmHg and especially, 60 mmHg in albuminuria in short-term studies of dia c Patients with type 2 diabetes older populations. B encounters patients with diabetes and sure but may not be superior to alterna c Eye examinations should occur be kidney disease. However, development of albuminuria but in trimester and for 1 year postpartum other specialists and providers should creased the rate of cardiovascular events as indicated by the degree of reti also educate their patients about the pro (41).

Innformation reeliability: exaample of appplied metricss Functionn Display aand Visualiization the City-zen radar mmode is depictted in Figuree 6 depression symptoms espanol generic eskalith 300mg on line. We have designed annd implementted a prototyype of the interface targeeting users with mobbile devices endogenous depression definition psychology discount 300 mg eskalith fast delivery. Sokhn depression definition illness order eskalith american express, the new Information Technologies at the Service of Historical and Display of information quality assessment and scoring As shown mood disorder support group long island eskalith 300 mg low price, the requested information is displayed in this app with a specific rank of quality depression nos icd 9 300mg eskalith sale. At this stage of testing depression symptoms tiredness purchase eskalith discount, in order to simplify screen view of this service, we reduced the 5 quality levels in 3 levels: the green star corresponds to fourth and fifth, the blue star indicates a medium quality and the grey star refers to the first and second level ure 7). Conclusion As explained in this paper, the City-Zen project has proposed an application in a smartphone that offers a resident or a visitor quality information which on one side vulgarize the material heritage (architecture, museum object, historical site, etc. This stage of the project enable the testing of this innovative approach based on open liked data. City-Zen offers through its functionalities an access economy approach that is helpful both for visitors (as they can improve their experience by having full access to aggregated content) and policy makers (as they may promote their cultural heritage through this platform and their city more visible and accessi ble). On the other hand, several aspects need to be improved such as the section on quality and its metrics to increase the automation of its application. We will also integrate a gamification dimension to motivate citizens to upload their data and share their knowledge. Emergent semantics: rethinking interoperability for large scale decen tralized information systems. Authenticity, Accuracy and Reliability: Reconciling Arts-related and Archival Litte rature. Digital diplomatics and measurement of electronic public data quali ties: What lessons should be learned Digital cultural heritage marketing: the role of digital technologies in cultural heritage valorization. The mentioned economic role of digital archives is manifested in the long-term promotion of cultural heritage, thus turning archived content into the promoter of the cultural property itself, a place where it is located or with which the cultural property is connected with its origin, while a local community has economical, socials or historical links with this cultural property. The visibility of digital archives is closely related to the platform where the archival material is presented. This paper analyses ar chive collection of novel Vilijun as an example of open digital archives dedi cated to one contemporary novel with heritage content. Topotheque Vilijun is private collection related to interactive novel Vilijun whose content promotes heritage. The presented content (the book product of the publish ing industry) through the reach and visibility of the Topotheque platform be comes a product of the cultural and creative industry whose promotion is hap pening and documenting on the long-term. Key words: cultural geography, digital archives, Topotheque, heritage, econ omy, novel Vilijun Introduction Memory is at the subject of interest of various sciences, ranging from humani ties (history, art, philosophy), social sciences (sociology, anthropology, econ omy, information and communication), nature (medicine, chemistry, biology) 1 till technical sciences (computer, robotics). Digital archives are connected with memory and technology and many global processes, as such centre of interest of archives, information managers, heritage professions and many other disci plines. These identities are rooted in memories and these memories need inscription and need a space. Both inscription and space will in creasingly be "located" "in the cloud" and maintained (in distributed custody) by individuals, groups, and memory institutions. Together they are actors in an ecology which comprises archives/records and other 2 memory texts in a societal context" the memory of cultural heritage in the digital age is realized twice: on the In ternet itself and in cultural monuments whose presentation is (not) realized on the Internet. Key role for this lays in archives, libraries and museums as memory institutions: they organise the [. Their collections contain the memory of peoples, communities, institutions and individuals, the scientific and cultural heritage, and the products throughout time of our imagination, craft and learning. Filipovic, Potentials of digital archives the emergence of transnational public digital archival platforms (like Monaste rium, Mapire, Topotheque) and digital archives such is Archives Portal Europe transcends some of the major controversies regarding trust in digitized memory, their content, and their source. At the same time, public digital archives prevail the network entropy where democracies in the advertising of data/information are crucial to phenomena such are: the difficult finding of relevant content, in sufficient verifiability of relevant content and insufficient maintenance of ad vertised content. This paper will consider the assumptions and opportunities that arise from the presenting of cultural content in the public digital archive as well as its cost-effectiveness in the promotion of heritage and cultural memory. Archives in digital age Contemporary information society has influenced archives towards outreach, enhancing public knowledge on archival sources and encourages easy access to archives on the international level, while archival programs are connected with information society development and cultural heritage policy in general. Great number of projects under the "culture and history" framework are focused on programs and activities related to digital heritage, democratization of access to cultural heritage, social inclusion, information use and re-use, cultural industries and similar topics, including digital platforms, cultural networks and e-services. Declaration recognizes archives as unique and authentic whiteness of administrative, cultural and intellectual activities and as reflection of society evolution. Contemporary archives are expected to be a public administration service re garding document management and protection and also to be providers of new services which would ensure better availability, visibility and presentation of archives and archival sources in the public by using new technologies. The in ternational archival community through its documents and activities also em phasizes interaction and cooperation between archives, public administration and other professions and various public and private sectors. Cultural memory and memory economy the global era is characterized by information overwhelming and hence entropy as a result of semantic and informational controversy in finding content that is presenting online. Already Escarpit notes that the book as a product of the cul tural and creative industries intended for mass selling differs books whose life on the book market primarily appears as a category of "short-term" creative product (best-sellers) to continue under certain circumstances its course towards 6 a product that on the market lives as a "long-term book. In terms of entropy of data published on the Internet, public digital archives can also con tribute to the promotion of creative products in the long term, and thus the lon gevity of content that a given product represents. Although the purpose of the public digital archives is not primarily aimed at promoting the creative indus tries, their role can also be observed from this perspective, aligned with re-use of public sector information directions and outreach initiatives. This opens the possibility to consider the public digital archives as a platform where "archival certified memory" contrib ute to the economy and social benefit of mapped areas, themes and archive ma terial. Memory economy thus becomes a platform for long-term promotion of (cultural and/or creative) products, but for the first time in the history of literary engagement, it is possible to build a long-term memory at the time of its crea tion. Filipovic, Potentials of digital archives International project co:op is financed through the Creative Europe program and it brings together 17 archival and academic institutions with more than 40 asso ciated partners from all around Europe aiming at strengthening transnational 8 cooperation between institutions and user groups. A variety of creative, pedagogical and didactic activities planned inside a four year schedule (includ ing Topoteque, "Adventure in the archives" and "Bring your history days" pro grams, educational material for schools, historical workshops, scientific re search etc. The administrational work within every Topotheque collection done by a registered topothequers, while visitors and users can also be engaged through answering questions online and, as guest-topothequers, uploading and indexing data (crowd work). During the last two years more than 120 Topotheque collections all across Eu rope were published online and they helped visibility of its local communities on regional and national level, encouraged local programs and events (history and memory days) and helped the promotion of cultural and other manifesta tions and history specifics of local areas. Through them one can meet private family documents and photographs (like Bischoff family), monitor the changes in life and landscape of some small places (all around Europe) or famous sights (like Viennese Prater). All material and data on common Topotheque platform are delivering further to Europeana, thus building individual and local stories in 10 shared European history. Smart novel Vilijun Topotheque Smart novel Vilijun Topotheque was open to the public on 20 June 2017. It is private collection made by author of novel, consisting of various materials (ar chival records) connected with the novel: parts of the original text, illustrations in the novel, recordings made on book promotions, photos made on novels 8 Project partners list is available at: coop. In the annottation of the novel is the following descriptioon: "The pprotagonists of Vilijun arre Marco Poolo and Kublaai Khan in thhe year of theeir farewell. In her Afterwords in the print novel, Dubravka Oraic-Tolic states the following: " A new shift in the work of Jasna Horvat occurred in the book Vilijun (2016). This is, on the one hand, conscious, planned, organized and thematic re-conceived permutation of the Vilikon novel. In the first, textual layer of a novel, the author is playing with her own novel Vilikon and his reconceptualization. Sincee in Vilijun novel there is a "non fictive, leexical part" tthat "fully fufunctions in accordance with the prininciples of 14 lexicon aas a lexicogrraphic type oof text", Taable 1 lists tthe lexicograaphic sec tions that the novel brrings forth. Thus, it becomes part of an "open society" and affects the understanding and use of terms such as "access" and "re-use". This problem begins with the well-known phenomenon of a broken link if a website is no longer maintained and no more of use to verify information. This is a collective task, which includes many stakeholders, from re 16 searchers to digital preservation specialists. Considering the basic role of Topotetheque in linking the places of crea tion of archival records with the main theme of Topotheque collection, it is pos sible to conclude that Topotheque realizes the mapping of "cultural geography" and that the "archive map", along with the effects of long-term memory, also promotes archived content on long time. Conclusion Topotheque Vilijun is real example how archives can "come out of a box". It also shows how digital archives can actively link heritage, education, community, creative industries and other potentials, be resource and inspiration for creation of new information and cultural products and services, speed up and facilitate sharing, gathering, presentation, research, publishing and documenting sources and making it accessible to the whole world. Scientific, Industrial, and Cultural Heritage: A Shared Approach // Ariadne 22 (Tuesday, 21 December 1999). Archives, memories and identities // Records, archives and memory: selected pa pers from the Conference and School on records, archives and memory studies, University of Zadar, Croatia, May 2013 / Willer, M. Survey and Analysis of Basic Social Science and Humani ties Research at the Science Academies and Related Research Organisations of Europe. The results of the research study indicate high level of awareness of students about internet security threats as well as the fact that they are exposed to widely internet security known threats to a certain degree. While students demonstrated knowledge about ap plication of security threats countermeasures, that part of their activities could be improved further. Generally, students need additional and updated knowledge to raise the level of their readiness in order to be able to respond to known and emerging internet security threats. The results of the research will be applied in planning of university courses related to the internet security. Recent cyber-attacks showed the importance of intrusion preven tion by monitoring vulnerabilities and reducing security threats (Abazari, Madani and Gharaee, 2016). At this moment, there are many ac tive security threats related to the use of the internet (Sherr, 2017; Burgess, 2017; Schroeder, 2017) that could exploit weaknesses in computer and other networked systems and cause substantial financial and other damages. To investigate the current level of awareness of students about well-known internet security threats and their ex posure to these threats as well as their awareness about security threats coun termeasures, a research study was initiated. In addition to computer related threats, a category of their own are internet related threats. In addition to viruses, Vernon included hacks into the list of threats, and hacks have become very fre quent in recent periods of time. While some threats aim at a single system vul nerability, other involve multiple exploits (Technopedia) and target both busi nesses and individuals. The oppose threats, individuals must protect information with the prevention and detection of unauthorized actions by users of a com puter (Microsoft). To reach the adequate level of security, one must also apply adequate countermeasures or protective measures. The internet users can inform themselves about the latest internet threats by using many available information resources as the internet security is a topic of high interest to the widest possible circle of users of the internet. In addition to informing oneself about the internet threats and protective measures by using online courses and written, video and audio materials available on the internet, students at the Faculty of Humanities and Social Sciences at the University of Zagreb (who are in focus of this paper) 250 R. Vrana, Confronting internet security threats have a possibility of acquisition of knowledge about internet security.

The Working Group considered that some clarification of these criteria was desirable anxiety 7 year old son generic 300 mg eskalith amex. Animals used in hormonal assays should be treated by the same route and dose as animals in which tumours developed in bio assays for carcinogenicity anxiety disorders 70 purchase eskalith overnight delivery. General statement regarding the determination of genotoxicity or non genotoxicity of a substance There is no general agreement about the numbers or types of tests that are needed to determine the genotoxicity or non-genotoxicity of a substance bipolar depression genetics buy cheap eskalith online. It is generally agreed depression test español generic 300 mg eskalith free shipping, however depression nursing definition purchase eskalith overnight, that tests for gene mutation and for chromosomal damage are required (McGregor et al bipolar depression 7 months buy eskalith 300 mg online. The tests for gene mutation most widely used involve bacteria (usually Salmonella) and mammalian cells in vitro, with and without exogenous metabolic activation. As a rule, a substance that reproducibly induces gene mutation or chromo somal damage (measured as aberrations or micronuclei) is to be considered a geno toxic agent. It should be specified whether the evidence of genotoxicity is based on the results of in-vitro tests, in-vivo tests or both. It is more difficult to find agreement on the tests and patterns of test results necessary to declare a substance non-genotoxic. In order to do so, a consistent pattern of negative results should have been found in bacteria and mammalian cells in vitro and in mammals in vivo. For most of the agents reviewed in this Monographs volume, few data were available from adequate tests of genetic toxicity. The lack of adequate data on geno toxicity precluded application of the above criteria to a number of the substances considered in this volume. Trade names for methimazole include Basolan, Danantizol, Favistan, Frentirox, Mercazole, Metazole, Metibasol, Metothyrine, Strumazol, Tapazole, Thacapzol, Thia methazole, Thycapzol, Thyrozol and Tirodril (Budavari, 2000; Royal Pharmaceutical Society of Great Britain, 2000; Swiss Pharmaceutical Society, 2000). Methods have been reported for the analysis of methimazole in biological fluids (blood, milk, serum, urine), tissues, incubation material and dried animal feed. Methimazole is an anti-thyroid drug, developed in 1949, that is widely used in the treatment of hyperthyroidism. Studies have shown better compliance with methimazole than with propylthiouracil (see monograph in this volume), most likely due to the single daily dose of the former (Nicholas et al. The long duration of action of methimazole makes multiple dosing unnecessary in the vast majority of patients (Roti et al. There are no intravenous preparations of methimazole, but it has been administered rectally to seriously ill patients who cannot take oral medications. The dose of methimazole is not different for infants, children or the elderly (Cooper, 1998), and it is considered unnecessary to alter the dose for patients with hepatic or renal disease (Cooper, 2000; see also section 4). Carbimazole, the 3-carbethoxy derivative of methimazole, is converted to methi mazole in vivo. The doses used are similar to those for non-pregnant women, with an effort to minimize them when possible to avoid fetal hypothyroidism. Methimazole is considered to be safe for use at low doses by lactating women (Azizi, 1996; Azizi et al. The time that it takes a patient to achieve a euthyroid state depends on a variety of clinical factors, including the severity of the hyperthyroidism at baseline, the size of the thyroid (correlated with intrathyroidal hormonal stores) and the dose of the anti-thyroid drug. Low doses of anti-thyroid drugs are most successfully used in areas of the world with marginal iodine sufficiency, as high intrathyroidal iodine concentrations would be expected to offset the effects of the drugs (Azizi, 1985). Methimazole and carbimazole are also used to treat feline hyperthyroidism (Prince, 2000). Methimazole has been used illegally in cattle as a fattening agent (Martinez-Frias et al. Studies of Cancer in Humans No information was available specifically on methimazole. Results were given for patients treated only with drugs but not for those given drugs with other treatment. The use of anti thyroid medications was not associated with an increased risk [relative risks not shown]. In a study carried out in northern Sweden between 1980 and 1989, 180 cases of thyroid cancer and 360 population controls were evaluated (Hallquist et al. Studies of Cancer in Experimental Animals Studies on the carcinogenicity of anti-thyroid chemicals, including methimazole, in experimental animals have been reviewed (Paynter et al. No statistically significant increase in the incidence of tumours was seen at any site. An increased incidence of hyperplasia of thyroid gland epithelium in treated mice was described, but the actual incidences were not provided (Jemec, 1970). Groups of 50 male and 50 female mice fed the low-iodine diet served as untreated controls. The control groups, consisting of 50 males and 50 females, received the diet without methimazole. The incidence of thyroid follicular-cell tumours was increased at the two higher doses, the incidences for follicular adenoma in males and females combined being 1/55 (2%), 1/8 (13%), 31/55 (56%) and 17/32 (53%) at 0, 5, 30 and 180 mg/kg of diet, respectively [statistical significance not stated], the denominators representing the number of rats surviving when the first tumour was detected in each group. A treatment-related increase in the incidence of follicular adenocarcinoma was found in survivors, the incidences for males and females combined being 1/17 (6%), 5/42 (12%) and 5/24 (21%) at 0, 30 and 180 mg/kg of diet, respectively. The incidence of thyroid follicular hyperplasia was increased in both males and females receiving methimazole at 30 and 180 mg/kg of diet (Owen et al. Rats initiated with the nitrosamine underwent nephrectomy of the left kidney and were fed the renal tumour promoters, either alone or in combination with methi mazole, in the diet for 20 weeks at concentrations of 1% for trisodium nitrilotriacetate, 2% for hydroquinone, 10% for potassium dibasic phosphate and 300 mg/kg of diet for methimazole. Although methimazole reduced the incidences of renal tubule hyperplasia in each group, it had no effect on the incidence of renal tumours (Konishi et al. Almost complete oral absorption was observed, with an absolute bioavailability of 93% in fasting persons. There were only minor interindividual variations in the pharmacokinetics, with the exception of one hypothyroid patient who showed a rapid elimination half-time in both the hypothyroid and euthyroid states (2. The elimination rate was lower in the hyperthyroid patients than in euthyroid subjects and was not restored when normal thyroid function was achieved. Although renal insufficiency had no effect, patients with hepatic failure had a prolonged elimination half-time of methimazole, the prolongation being proportional to the degree of impairment (Jansson et al. The concentrations of methimazole were measured in blood and milk from five lactating women after oral administration of 40 mg of carbimazole, which is rapidly and completely transformed to methimazole. After 1 h, the mean concentrations of methimazole had reached 253 g/L in serum and 182 g/L in milk. Methimazole was not bound to protein in the serum, and its concentration in serum was comparable to that in milk. The transfer of methimazole was similar to that of propylthiouracil (see monograph in this volume; Mortimer et al. Lee and Neal (1978) demonstrated that incubation in vitro of methimazole with rat hepatic microsomes led to the formation of 3-methyl-2-thiohydantoin and N-methyl imidazole. The cytochrome P450 and flavin-containing monooxygenase systems of rat hepatic microsomes have been implicated in these reactions (see section 4. In rats, glucuronidation is the main metabolic pathway; less is known about the metabolism of methimazole in humans. It inhibits intrathyroidal synthesis of thyroid hormones by interfering with thyroid peroxidase-mediated iodine utilization. As a result, the concentrations of thyroxine (T4) and triiodothyronine (T3) in serum are decreased (Cooper, 2000). In some studies, hyperthyroid patients became hypothyroid if the dose of methimazole was not monitored carefully. In one study, 100% of patients became hypothyroid within 12 weeks while taking 40 mg/day (Kallner et al. Agranulocytosis is the most significant major side effect, occurring in 4 of 13 patients investigated in one study. Other reports also indicate that rashes and agranulocytosis are the major side-effects (Wiberg & Nuttall, 1972; Van der Klauw et al. At high doses (up to 120 mg/day), the incidence (32%) and severity of side-effects were increased (Wiberg & Nuttall, 1972; Meyer-Gessner et al. Methimazole therapy induced changes in plasma lipid peroxidation and the anti oxidant system in hyperthyroid and euthyroid patients. Lipid peroxide plasma concen trations were decreased while ascorbic acid and vitamin E levels were significantly increased in euthyroid patients in comparison with hyperthyroid patients. Plasma glutathione peroxidase activity was increased and glutathione transferase activity was significantly decreased after euthyroidism was sustained with methimazole therapy (Ademoglu et al. Both iodide and cycloheximide (a protein synthesis inhibitor) inhibited the stimulatory effects of methimazole on protein synthesis (Leer et al. Marked hypertropy of follicular epithelial cells was observed, with a significant decrease in the plasma T4 concentration. Hyper trophied epithelial cells were filled with dilated rough endoplasmic reticulum and reabsorbed intracellular colloid, with vacuoles that were positive to anti-T4 immuno staining (Kurata et al. The concentrations of total and free T4 were reduced by more than 95% after 21 days of treatment with increasing dietary concentrations of 30, 100, 300 and 1000 ppm (mg/kg), and those of total and free T3 were reduced by 60%. Feeding rats with diets containing 30 ppm (mg/kg) methimazole for 21 days resulted in a 5. Methimazole given to mice with normal levels of glutathione produced only a marginal increase in serum alanine aminotransferase activity and was not hepatoxic. Competitive substrates for flavin-containing monooxygenases also eliminated the hepatotoxicity of the two compounds in combination, indicating that methimazole is metabolized to an active hepatotoxicant by both cytochrome P450 monooxygenases and flavin-containing monooxygenases, and that inadequate rates of detoxication of the resulting metabolite(s) are responsible for the hepatotoxicity in glutathione-depleted mice (Mizutani et al. Methimazole was toxic to the olfactory system in Long-Evans rats given a single intraperitoneal dose of 25 mg/kg bw or an oral dose of 50 mg/kg bw. A 300-mg/kg bw intraperitoneal dose resulted in almost complete destruction of the olfactory epi thelium (Genter et al. Extensive lesions of the olfactory mucosa were observed after two consecutive intraperitoneal doses of methimazole, but these were efficiently repaired within 3 months. Pretreatment with T4 did not protect against toxicity, but pretreatment with metyrapone (a cytochrome P450 inhibitor) completely prevented methimazole-induced toxicity and covalent binding in the olfactory mucosa and bulb. No differences in the rates of malformations were seen in the infants of hyperthyroid mothers who had and had not taken methimazole; however, 17 cases of aplasia cutis congenita were found in the offspring of women who had used methi mazole. They also reported that no signs of intellectual impairment were found in four studies involving 101 children whose mothers had undergone thioamide therapy (Mandel et al. Other cases of aplasia cutis have been reported in infants whose mothers were treated with methimazole during pregnancy (Sargent et al. In contrast, no significant increase in the overall incidence of congenital malformations was noted in 36 women on methimazole therapy, and, in particular, no scalp defects were observed in the exposed infants (Wing et al. Similarly, a review of nearly 50 000 pregnancies in the Netherlands found no association between exposure to methimazole and defects of the skin or scalp (Van Dijke et al. An association between use of methimazole and choanal and oesophageal atresia has also been reported (summarized by Clementi et al. Thyroid status at delivery was evaluated in the infants of 43 women who had been treated with methimazole for Graves disease for at least 4 weeks during pregnancy and compared with that of the infants of 32 women with no history of thyroid problems. A similar lack of effect was seen in 34 women treated with propylthiouracil (see monograph in this volume; Momotani et al. The growth of offspring was reduced relative to that of controls after postnatal day 2, and they showed significant delays in acquisition of the surface-righting response (at 14 days vs 7 days in controls), auditory startle reflex (at 18 vs 12 days) and eye opening (at 17 vs 15 days). They also showed a significant reduction in locomotor activity in a 10-min open-field test at 21 days (Comer & Norton, 1982). In a study of the same design, 6-week-old, 4-month-old and 6-month-old rat offspring showed a pattern of relative decreases in locomotor activity in a residential maze, the result of a lack of habituation and a lack of a diurnal motor pattern. The treated offspring also had an asymmetric walking gait and alterations in exploratory patterns in a radial-arm maze. In groups of three Wistar rats given drinking-water containing methimazole at a concentration of 0 or 0. The hypothyroid rats showed delayed maturation of the testes, as seen by a decrease in the diameter of the seminiferous tubules and a reduction in the number of germ cells per cross-section. With the exception of the reduction in total T4 concentration, the effects were reversible by concomitant administration of L-T3 (100 g/kg bw every other day) (Francavilla et al. The teratogenic potential of methimazole was compared with that of ethylene thiourea (see monograph in this volume) in rat embryo cultures.

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