Neurological disturbances, premature lethality, and central myelination deficiency in transgenic mice overexpressing the homeo domain transcription factor Oct-6.

Pit, Oct, Unc (POU) homeo domain transcription factors have been implicated in various developmental processes, including cell division, differentiation, specification, and survival of specific cell types. Although expression of the transcription factor Oct-6 in oligodendroglia is confined to the promyelin stage and is downregulated at the myelin stage of development, the effect of Oct-6 overexpression on oligodendrocyte development has not been established. Here we show that transgenic animals overexpressing Oct-6 at late oligodendrocyte development develop a severe neurologic syndrome characterized by action tremors, recurrent seizures, and premature death. Axons in the central nervous system of Oct-6 transgenics were hypomyelinated, hypermyelinated, or dysmyelinated, and ultrastructural analyses suggested that myelin formation was premature. The vulnerability of developing oligodendroglia to Oct-6 deregulation provides evidence that the POU factor may play a direct role in myelin disease pathogenesis in the mammalian CNS.

Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity.

c-myc is a member of the helix-loop-helix/leucine zipper family of proteins that modulate the transcriptional activity of specific target genes. Although aberrant c-myc expression has been reported to play a role in multistage carcinogenesis in astrocytic gliomas, little is known about the effects of the expression of c-myc on oligodendrocytes. Using transgenic animals expressing a human c-myc oncogene under transcriptional control of the myelin basic protein gene, we investigated the effect of overexpression of this oncogene in oligodendrocytes. The MBP/c-myc transgenic mice developed severe neurological disturbances characterized by action tremors and recurrent seizures, and premature death during postnatal weeks three to five. Affected transgenic mice of various strains had severely hypomyelinated central nervous systems and expressed low levels of c-myc, myelin basic protein (MBP) and proteolipid protein (PLP) mRNAs in the brain. These c-myc transgenic mice also exhibited an increased number of TUNEL positive nuclei, which in most cases were located in cells that expressed c-myc, as judged by double immunohistochemistry. There was no evidence of brain tumors in the c-myc transgenic mice, including heterozygous mice from two strains that had normal lifespans. These observations indicate that the myelin deficiency observed in the MBP/c-myc transgenic animals results from a cytotoxic effect of the c-myc transgene.

Postpartum thyroid dysfunction in pregnant thyroid peroxidase antibody-positive women living in an area with mild to moderate iodine deficiency: is iodine supplementation safe?

In moderately iodine-deficient, pregnant, thyroid peroxidase antibody (TPO-Ab)-positive women the role of iodine supplementation in the development of postpartum thyroid dysfunction (PPTD) was studied in a placebo-controlled, randomized, double blind trial. Screening for TPO-Ab was performed in early pregnancy in a population of healthy pregnant Danish women with no previous diagnosed thyroid disease (prevalence, 117 of 1,284; 9.1%). The participants were randomized, stratified according to TPO-Ab level, to three groups. All participants received a daily vitamin and mineral tablet with 150 microg iodine or no iodine. The +/+ group received iodine during pregnancy and the postpartum period, the +/- group received iodine during pregnancy only, and the -/- group received no iodine supplementation. A total of 66 TPO-Ab positive women were followed, and in the postpartum period sera were collected at 8-week interval for biochemical evaluation of thyroid function and antibody level. Compliance was evaluated by 24-h urinary iodine measurements. PPTD developed in 55% of the participants. In 67% of the cases abnormal TSH was accompanied by abnormalities in thyroid hormones, whereas 33% had abnormal serum TSH only. There was no statistically significant difference in the frequency of PPTD in the three groups: +/+ group, 59% (95% confidence interval, 36-79%); +/- group, 60% (36-81%); and -/- group, 46% (26-67%). There were also no differences in the severity of the PPTD, as evaluated by duration and grade of deviation of TSH and thyroid hormones from normality. The occurrence, severity, and type of PPTD predominantly depended on the TPO-Ab level: TPO-Ab below 200 U/L at screening, 35% developed PPTD; TPO-Ab of 200-900 U/L, 54%; and TPO-Ab above 900 U/L, 75% developed PPTD. Women with low levels of antibodies predominantly remained euthyroid or had hyperthyroidism only, whereas women with high antibody levels had hyperthyroidism followed by hypothyroidism or hypothyroidism only. We conclude that iodine supplementation (150 microg) during pregnancy and the postpartum period to TPO-Ab-positive women living in an area with mild to moderate iodine deficiency did not induce or worsen PPTD. The study confirmed that screening for TPO-Ab in early pregnancy can predict women at high risk for development of PPTD.

Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark.

Thyroid abnormalities are common in all populations, but it is difficult to compare results of epidemiological studies, because different methods have been used for evaluation. We studied the importance of the population iodine intake level for the prevalence rate of various thyroid abnormalities in elderly subjects. Random samples of elderly subjects (68 yr) were selected from the central person registers in Jutland, Denmark, with low (n = 423) and, in Iceland, with longstanding relatively high (n = 100) iodine intake. Females from Jutland had a high prevalence of goiter or previous goiter surgery (12.2%), compared with males from Jutland (3.2%) and females (1.9%) and males (2.2%) from Iceland. Abnormal thyroid function was very common in both areas, with serum TSH outside the reference range in 13.5% of subjects from Jutland and 19% of those from Iceland. In Jutland, it was mainly thyroid hyperfunction (9.7% had low, 3.8% had high serum TSH), whereas in Iceland, it was impaired thyroid function (1% had low, 18% had high serum TSH). All subjects with serum TSH more than 10 mU/L had autoantibodies in serum, but antibodies were, in general, more common in Jutland than in Iceland. Thus, thyroid abnormalities in populations with low iodine intake and those with high iodine intake develop in opposite directions: goiter and thyroid hyperfunction when iodine intake is relatively low, and impaired thyroid function when iodine intake is relatively high. Probably, mild iodine deficiency partly protects against autoimmune thyroid disease. Thyroid autoantibodies may be markers of an autoimmune process in the thyroid or secondary to the development of goiter.

Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation.

Knowledge of the effect of differences in iodine intake levels on public health in areas with no endemic goiter is limited. Groups at risk when iodine intake is relatively low are pregnant and lactating women and their newborns. A prospective randomized study was performed to evaluate the effect of iodine supplementation in an area where the median daily iodine excretion in urine is around 50 micrograms. Fifty-four normal pregnant women were randomized to be controls or to receive 200 micrograms iodine/day from weeks 17-18 of pregnancy until 12 months after delivery. In the control group, serum TSH, serum thyroglobulin (Tg), and thyroid size showed significant increases during pregnancy. These variations were ameliorated by iodine supplementation. Iodine did not induce significant variations in serum T4, T3, or free T4. Cord blood Tg was much lower when the mother had received iodine, whereas TSH, T4, T3, and free T4 levels were unaltered. The results suggest that a relatively low iodine intake during pregnancy leads to thyroidal stress, with increases in Tg release and thyroid size. However, the thyroid gland is able to adapt and keep thyroid hormones in the mother and the child normal, at least under normal circumstances, as evaluated in the present study. It is not known whether this stress is sufficient to be of importance for late development of autonomous thyroid growth and function.

Large-scale isolation of polymorphonuclear leucocytes from bovine blood.

A method for the isolation of an enriched population (greater than 96%) of bovine polymorphonuclear leucocytes (PMNs) from 70 liters of blood was developed using a two-step procedure involving separation of the blood, in a packed red blood cell fraction containing the PMNs and a plasma fraction, by continuous flow blood separation. Hypotonic lysis of erythrocytes was then followed by centrifugation at 200 g sedimenting the PMNs. The yield was 93 +/- 30 g, the recovery was 62 +/- 20%, viability was greater than 95%. Since bovine blood can be obtained in unlimited amounts, the procedure described here can be applied to obtain large amounts of bovine PMNs for incubation studies and large-scale purification of intracellular enzymes suitable for biochemical characterization.

Purification and properties of glycogen synthase I from bovine polymorphonuclear leucocytes.

Glycogen synthase I was purified from bovine polymorphonuclear leucocytes (PMNs) by a procedure involving concanavalin A-Sepharose affinity chromatography. The purified glycogen-bound glycogen synthase I had a specific activity of 9.83 U/mg protein and the glycogen free enzyme 21 U/mg protein. Molecular ratio of the native enzyme and the subunit were 340 K and 85 K respectively. After phosphorylation by the catalytic subunit of cAMP-dependent protein kinase the phosphorylated sites were studied using high-performance liquid chromatography (HPLC) of the tryptic 32P-peptides. The enzyme was phosphorylated at three different sites with retention times identical to site 1a, site 1b, and site 2 from rabbit skeletal muscle glycogen synthase.

Urinary iodine excretion and individual iodine supplementation among elderly subjects: a cross-sectional investigation in the commune of Randers, Denmark.

Several studies have demonstrated that the iodine intake is relatively low in Denmark. However, the results are difficult to interpret because no information has been given on the frequency of individual iodine supplementation. We performed a cross-sectional study of elderly subjects living in the commune of Randers, Denmark. Urinary iodine excretion was measured in the 423 participants (185 males, 238 females) and a careful history was taken on any possible intake of supplementary iodine. The median urinary iodine excretion was 48.3 micrograms/g creatinine for the whole population (40.8 micrograms/g creatinine in males, 53.2 micrograms/g creatinine in females). In the part of the population that did not take iodine supplementation (46.7%) the median value was 36.1 micrograms/g creatinine (males 33.8; females 38.8). Regular iodine supplementation taken as an iodine-containing vitamin/mineral tablet was found in 30.8% of the population. This increased the urinary iodine excretion to a median level of 80.5 micrograms/g creatinine (males 62.0; females 88.0). The study shows that the basic iodine intake level is overestimated if individual iodine supplementation is not taken into account. Such supplementation may lead to median iodine excretion values that seem reasonable, even if the iodine intake of the part of the population not taking iodine (in this study, nearly half of the population) is low.

Iodine in drinking water varies by more than 100-fold in Denmark. Importance for iodine content of infant formulas.

The iodine intake level of the population is of major importance for the occurrence of thyroid disorders in an area. The aim of the present study was to evaluate the importance of drinking water iodine content for the known regional differences in iodine intake in Denmark and for the iodine content of infant formulas. Iodine in tap water obtained from 55 different locations in Denmark varied from <1.0 to 139 microg/l. In general the iodine content was low in Jutland (median 4.1 microg/l) with higher values on Sealand (23 microg/l) and other islands. Preparation of coffee or tea did not reduce the iodine content of tap water with a high initial iodine concentration. A statistically significant correlation was found between tap water iodine content today and the urinary iodine excretion measured in 41 towns in 1967 (r=0.68, P<0.001). The correlation corresponded to a basic urinary iodine excretion in Denmark of 43 microg/24h excluding iodine in water and a daily water intake of 1.7 l. The iodine content of infant formulas prepared by addition of demineralized water varied from 37 to 138 microg/l (median 57 microg/l, n=18). Hence the final iodine content would depend heavily on the source of water used for preparation. We found that iodine in tap water was a major determinant of regional differences in iodine intake in Denmark. Changes in water supply and possibly water purification methods may influence the population iodine intake level and the occurrence of thyroid disorders.

Variations in urinary iodine excretion and thyroid function. A 1-year study in healthy men.

OBJECTIVE: The iodine intake level in a population is determined in cross-sectional studies. A fraction of samples with iodine content below a certain level, e.g. 25 microg/l, may suggest iodine deficiency in part of the population. However, urinary iodine varies considerably from day to day and the fraction of low samples caused by dispersion remains unsettled. DESIGN: A longitudinal study of 16 healthy men living in an area of mild to moderate iodine deficiency. METHODS: We measured urinary iodine and creatinine concentrations, and serum TSH, total thyroxine (T4), free T4 index and total tri-iodothyronine (T3) in samples collected monthly for 1 year. RESULTS: Average urinary iodine excretion was 57.0 microg/l (49.1 microg/24 h (corrected for creatinine excretion)) and varied from 29 to 81 microg/l (28 to 81 microg/24 h) between participants. Individual samples varied between 10 and 260 microg/l, and the variation around the mean was 2.4 times larger when calculated for the 180 individual samples compared with the 15 average annual values (1.7 times larger for estimated 24 h iodine excretion values). The fraction of individual samples below 25 microg/l was 6.7% (7.2% < 25 microg/24 h), whereas none of the participants had average iodine excretion below 25 microg/l or 25 microg/24 h. Participants with average annual iodine excretion below 50 microg/24 h had a negative correlation between iodine excretion and TSH, whereas a positive correlation was observed when average annual iodine excretion was above this level. CONCLUSIONS: Seven per cent of individual urine samples indicated severe iodine deficiency without this being present in the group studied. Dispersion was reduced by 24% when using estimated 24 h urinary iodine excretion rather than urinary iodine concentration. Participants with moderate iodine deficiency (average annual urinary iodine excretion 25-50 microg/24 h) showed clear signs of substrate deficiency for thyroid hormone synthesis while participants with mild iodine deficiency (50-100 microg/24 h) did not.

Low incidence rate of overt hypothyroidism compared with hyperthyroidism in an area with moderately low iodine intake.

In areas with relatively high iodine intake, the incidence rate of hypothyroidism is several-fold higher than that of hyperthyroidism. Recently, we found a similarly high prevalence rate of subclinical hypothyroidism compared with hyperthyroidism in a high iodine intake area, while a relatively low prevalence of subclinical hypothyroidism was observed in a low iodine intake area. In the present study we compared the incidence rate (newly diagnosed in primary care and at hospital) of overt hypothyroidism with that of hyperthyroidism in a well-defined geographical area in Jutland, Denmark, with an iodine intake around 60 microg/day. The number of personsxyears studied was 569,108. Data on hyperthyroidism have been published previously. The overall incidence of hypothyroidism was 13.5/100,000 per year (F/M 22.9/3.6), hyperthyroidism 38.7/100.000 per year (F/M 63.0/13.0). The incidence of hypothyroidism was steadily increasing with age up to 80/100,000 per year in subjects older than 70 years of age, but apart from congenital hypothyroidism it was lower than that of hyperthyroidism at all ages. The majority of patients (79%) was diagnosed to have spontaneous autoimmune hypothyroidism (16% with goiter, 84% with no thyroid visible or palpable). In conclusion, in an area with moderately low iodine intake, hypothyroidism was considerably less common than hyperthyroidism. This is in contrast to findings in high iodine intake areas. The iodine intake of an area seems to be of major importance for the pattern of thyroid disorders observed.

Thyroid disorders in mild iodine deficiency.

Comparative epidemiologic studies in areas with low and high iodine intake and controlled studies of iodine supplementation have demonstrated that the major consequence of mild-to-moderate iodine deficiency for the health of the population is an extraordinarily high occurrence of hyperthyroidism in elderly subjects, especially women, with risk of cardiac arrhythmias, osteoporosis, and muscle wasting. The hyperthyroidism is caused by autonomous nodular growth and function of the thyroid gland and it is accompanied by a high frequency of goiter. Pregnant women and small children are not immediately endangered but the consequences of severe iodine deficiency for brain development are grave and a considerable safety margin is advisable. Moreover, a shift toward less malignant types of thyroid cancer and a lower radiation dose to the thyroid in case of nuclear fallout support that mild-to-moderate iodine deficiency should be corrected. However, there is evidence that a high iodine intake may be associated with more autoimmune hypothyroidism, and that Graves' disease may manifest at a younger age and be more difficult to treat. Hence, the iodine intake should be brought to a level at which iodine deficiency disorders are avoided but not higher. Iodine supplementation programs should aim at relatively uniform iodine intake, avoiding deficient or excessive iodine intake in subpopulations. To adopt such a strategy, surveillance programs are needed.

Self-care within a model for demand for medical care.

Self-care is interpreted from a health economic point of view. Various approaches are presented. It is stressed that the decision-oriented approach used by other health service researchers is an integral part of the economic approach to the topic as is the idea of a continuum of care, from self-care to professional care. A new approach is taken to the modeling of self-care, in that self-care becomes part of a four-part demand for care model. This makes it possible to model the demand for care for three different groups separately: 1--persons with zero episodes; 2--persons with pure illness episodes and illness episodes with self-care; 3--persons with episodes involving professional care or professional care combined with self-care. Another contribution is due to the so-called episodic approach to the demand for care. The natural counting units are illness and treatment episodes, i.e. instead of counting for instance number of times a general practitioner is consulted we ought to count the number of episodes involving professional care, self-care or both types of care. The episodic approach seems to be well suited for work with self-care. The empirical part is based on a unique Danish panel study using health diaries returned weekly. Data from 27 of the 52 reporting weeks are used, involving more than 14,000 episodes distributed across about 2800 persons belonging to about 1000 households. The use of health diaries seems to be very well suited to the study of self-care in that less salient events and activities than professional care are picked up far better in prospective health diary studies than in retrospective questionnaire based surveys. Descriptive and regression (logistic and ordinary) results are presented.

An investigation of the effect of regional variation in the treatment of hypertension.

Over a period both a monetary and physical measure of antihypertensive drug consumption has increased in Denmark, but the consumption has varied considerably between counties in any given year. Concurrently, SMR for myocardial infarctions and cerebrovascular diseases due to hypertension has declined. The relation between intensity of treatment and outcome in terms of reduced loss of life time or healthy time is analyzed at an aggregate level within a health economic framework. The relation is analyzed by using a pooled time series cross section regression analysis. Two models, a covariance and an error component model are used. Within the range of observed drug consumption, loss of life years and loss of good health show a tendency towards negative regression on consumption of drugs when controlled for relevant variables such as occupational structure, degree of urbanization, and hardness of the drinking water.

Socioeconomic demand model for dental visits.

The purpose of the present study was to develop structural socioeconomic demand models for dental visits. The explanatory variables were chosen selectively from the various theories concerning health services utilization. The models were constructed on data from a sociodental survey carried out among workers and staff members at a Danish shipyard. A sample of 988 employees was drawn by stratified random sampling and 841 persons were interviewed regarding dental visits and attitudes towards teeth and dental health services. The structural equations were estimated by means of multiple regression analysis using the two-stage least-squares method. Dental visits were influenced by dental health status, expectations about value of dental care, income, and price of dental care. Dental health was affected by the number of dental visits and age. Residence in rural areas during childhood and age had a negative effect on dental care early in life while years of schooling had a positive effect. Years of schooling had also a positive effect on expectations about value of dental care. The present study has shown that it is possible to construct structural models for the demand for dental care.

Dental health status and attitudes to dental care in families participating in a Danish fluoride tablet program.

The caries experience and dental fluorosis of 84 Danish children, who had used fluoride tablets for 1-4 yr in the period 1976-80, were compared with those of a group matching in sex, age, place of living, and socioeconomic status. The average age of the children at the time of examination was 5.8 yr. A recording of mothers' attitudes to dental care, knowledge about tooth brushing, attitudes to candy, and number of teeth in the maxilla showed no difference between the fluoride tablet group and the non-users' group. Moreover, there was no significant difference between the two groups with respect to dental caries. The findings are discussed in relation to recent reports on the decline of dental caries resulting from widespread use of local administration of fluorides.

Determinants of weak femoral artery pulse in dogs with mitral valve prolapse.

In three substudies encompassing 247 dogs from two breeds predisposed to myxomatous mitral valve disease (MMVD), femoral artery pulse strength was palpated and related to potential explanatory factors, including quantitative echocardiographic measures of MMVD, aortic and femoral artery diameter and wall thickness and blood pressure. In addition, in 109 Cavalier King Charles Spaniels (of which 61 were included in the three substudies mentioned above), the relation between femoral artery pulse strength and presence of thrombocytopenia was investigated. In 26% of the dogs, a pulse

[A young woman with metabolic acidosis and recently discovered IDDM without ketonuria. A rare autoimmune (?) combination of hypothyroidism, diabetes mellitus and distal renal tubular acidosis]. / Ung kvinde med metabolisk acidose og nyopdaget IDDM uden ketonuri. En sjaelden autoimmun? kombination af hypotyreose, diabetes mellitus og distal renal tubulaer acidose.

A case of a 29-year-old woman with a multiple autoimmune disorder is reported. She had a history of hypothyroidism since the age of 18. She was admitted to hospital due to hyperglycaemia. At admission she had hyperglycaemia, metabolic acidosis, but no urinary ketone bodies. Further laboratory studies revealed that the acidosis was due to distal renal tubular acidosis rather than diabetic ketoacidosis (although the patient had type 1 diabetes mellitus). Blood tests revealed antibodies to glutamic acid decarboxylase (GAD-65; associated with type 1 diabetes mellitus), thyroid and adrenal tissue, and gastric parietal cells. The patient had not developed pernicious anaemia or Addison's disease. The multiple positive antibody titres in this patient indicate that the diabetes, hypothyroidism and distal renal tubular acidosis are part of an autoimmune syndrome.

[Knee arthroscopy under local anesthesia with or without anesthesiologic assistance. A cost-benefit analysis]. / Knaeledsartroskopi i lokalanaestesi med eller uden anaestesiologisk assistance. En omkostnings-effekt-analyse.

The benefit of anaesthesiological assistance during arthroscopy of the knee in local anaesthesia was evaluated in a cost-effectiveness analysis. One hundred consecutive patients had arthroscopy of the knee performed in local anaesthesia without anesthesiological assistance. In 15% of the cases the arthroscopy was insufficient because of pain reaction. Sixteen percent of the patients indicated that they would prefer general anaesthesia for a similar procedure in the future. The costs for arthroscopy of the knee in local anaesthesia without anaesthesiological assistance were calculated to Dkr. 2055. The amount includes costs for rearthroscopy in local anaesthesia with anaesthesiological assistance for 15% of the patients. Thirty-three patients had arthroscopy of the knee done in local anaesthesia with anaesthesiological assistance. General anaesthesia was needed for twelve percent of the patients. The cost for this procedure, including the costs of possible general anaesthesia were calculated to Dkr. 2458. Any significant difference in the sensation of pain during the arthroscopy could not be demonstrated between the two groups. Based on this study it is recommended that arthroscopy of the knee in local anaesthesia is planned without anaesthesiological assistance.

[What is healthy economy?]. / Hvad er sundhedsøkonomi?

Health economics is the branch of economics which is concerned theoretically and practically with the health sector and related subjects such as e.g. the market for medicine and medico-technical equipment. In health economics, the universal basic problem is: Distribution of scarce resources to competing ends and establishment of rules for this. In this respect, (health) economics is knowledge about priorities based on the methodical an appreciative basis of economics. The essence is the absolute or relative scarcity and the existence of alternative uses for the limited resources. Many identify health economics with societal economic analyses: cost-benefit analyses or cost-effectiveness analyses. A great many analyses of this type have been published and these have been employed to an increasing extent in connection with decisions about introduction or alteration of the existing therapeutic or diagnostic methods. Health economics is, however, much more: theoretical and empirical analysis of the demand for health and health services, including the effect of payment-for-service; supplier and producer behaviour including questions about the existence and consequence of supplier-induced demand i.e. the professional health groups may, themselves, determine the extent of the demand and employment for their services to a considerable extent. Analyses of productivity and effectiveness and methods for measuring and assessing health status are two other typical subjects. Thus, in the course of the past 15-20 years, health economy has become established as an academic subject with its own professorships and scientific journals.