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A follow-up study of first-degree relatives of type 2 diabetic patients presented the opportunity to study the association of components of the metabolic syndrome with oral glucose tolerance in these subjects. In 1992, 25 years after the first analysis of the cohort, we performed 75-g oral glucose tolerance tests and measured anthropometric data (body mass index, waist-hip ratio), insulin and C-peptide concentrations, and parameters of lipoprotein metabolism (free fatty acids, triglycerides, cholesterol, HDL cholesterol). Of 135 participants, 71 had normal glucose tolerance (GT), 22 had impaired GT, and 42 had diabetic GT (WHO 1985 criteria). Impaired glucose tolerance and diabetes were significantly (Kruskal-Wallis test) associated with advanced age (p=0.001), higher body mass index (p=0.005) and waist-hip ratio (p=0.027), systolic hypertension (p=0.031), elevated basal insulin concentrations (p<0.001), higher free fatty acids (p<0.001) and triglycerides (p=0.017), and lower HDL cholesterol (p=0.003); no associations were found with total and LDL cholesterol levels (Friedewald's formula, p=0.25). Abnormalities (obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, pathological oral glucose tolerance) were associated with significant deterioriations in all other components of the metabolic syndrome, if their number exceeded three. Disturbances of oral glucose tolerance are present in a high percentage of first-degree relatives after 25 years of follow-up (51% of those tested). Impaired or diabetic glucose tolerance in such a cohort was associated with overweight, hypertension and disturbances of lipoprotein metabolism characteristic of the metabolic syndrome. Hypercholesterolemia (LDL-cholesterol) is not a component of the metabolic syndrome in a German population with a high hereditary burden regarding type 2 diabetes. A metabolic syndrome should certainly be diagnosed if three components are present, although even in the presence of only two components, an elevated risk is evident.

Although the case for thyroid surgery is based on morphologic and physiologic criteria, it is mainly based on individual therapeutic goals. The goals are influenced by various biographic, medical and personal facts and by many environmental conditions. Thus, there is no rationale for cataloguing indications. With the euthyroid goitre the indication for surgery is usually given by the size of the thyroid gland, especially since it has become clear in various studies that with drug therapy the achievable size reduction is rather small. With Graves' disease the pros and cons of the three main methods, surgery, medical treatment or radioiodine, have to be considered in each case. Surgery is mainly indicated when the goal is a rapid and reliable normalization of the hormonal status. Thyroid autonomy is a clear-cut case for radioiodine. Only isolated autonomous nodules can equally well be treated by surgery. In addition, a case for surgery is given when besides the autonomy a large goitre is present. A special indication is iodine-induced thyrotoxicosis that cannot be normalized by medical treatment. All kinds of thyroid carcinoma, with very few exceptions, usually have to be operated on as the first choice.

The so-called "waddling gait" caused by paresis or mechanical insufficiency of the hip muscles is an ambiguous clinical guiding symptom. This pelvifemorally accentuated muscular weakness coinciding with pain in the range of the locomotor system should make one consider the diagnosis of osteomalacia due to deficiency of vitamin D, especially in Asian patients. In the present case, the course of investigation is described in detail, as well as the effective therapy. The diagnosis of this clinical picture ought to be familiar to any neurologist, since its more frequent appearance must be expected as an increasing number of Asians seek asylum in the years ahead. Social integration of the affected persons may be made easier by treatment on the lines described here.

The cold agglutinin disease is a hemolytic anemia induced by antibodies. Beside other etiological factors the disease is associated with tumors. In this paper cold agglutinin disease combined with erythroblastosis and combined with polycythemia vera is presented at the first time. In one case malignant proliferation followed the appearance of cold agglutinin antibodies. Blood transfusion, plasmapheresis, corticosteroids and chlorambucil were not successful. In the other case antibodies were temporarily expressed after a long time of malignant proliferation. Blood transfusion and corticoids were sufficient. Production of antibodies as a kind of tumor defence is discussed as reason for hemolysis. "Cross reacting antigenity" between normal and malignant erythrocytes is postulated.

Of 743 first degree relatives of diabetics in whom oral glucose tolerance tests had been performed in 1967 488 were re-tested in 1972. Among the original "normals" (n = 353) 17.6% had developed a "subclinical" and 1.3% an "overt diabetes" within 5 years. The original "subclinical diabetes" (n = 118) showed a remission to "normal" in 35.6% and a progression to "overt diabetes" in 13.6%. 3 out of the 17 formerly "overt diabetes" were found to be "normal" after 5 years and 3 were "subclinical diabetics". Thus the performance of an oral glucose tolerance test is of limited prognostic value in the individual case. In both studies a higher prevalence of abnormal test results occurred in the older age groups and in overweight subjects. Remission or deterioration did not depend, however, on age or on weight changes. The frequency of abnormal tests was higher in males than in females, but the tendency towards the development of diabetes was more pronounced in females, in accordance with a previous observation of a higher age dependance of glucose tolerance in females.

Three oral glucose tolerance tests (oGTT) have been performed in 312 non-diabetic relatives of diabetics over a period of 10 years. In a second study 6 identical oGTT's have been performed at weekly intervals in 55 individuals. In this study the variance, calculated from the logarithmic values, increased in the following order: fasting (0.026), 1 h (0.035), 2 h (0.044) and 3 h values (0.047). The sum of the 1 h and 2 h values showed the lowest variance (0.024). No significant difference of the variances was found in the 43 individuals in whom both the long-term and the short-term studies have been performed. Thus, a great proportion of the total variance of glucose observed over longer periods only represents a random variation. This random variation is much higher than most other factors which might influence the result of an oGTT. A diagnosis based on a single oGTT is of only limited value.

The hypothesis that goitrogenesis in iodine deficiency can be attributed to the stimulatory effect of thyrotropin (TSH) on the thyroid gland and has long been held to be valid. The task of this review is to describe the reasons why this concept is being challenged. In addition, we report on the autoregulation of the thyroid gland and on in vitro investigations dealing with TSH as a growth factor, which have yielded conflicting results. Finally, we summarize preliminary studies comparing the therapeutic effect of thyroxine and iodine on goiter size. In comparison to thyroxine, iodine application in doses of 300-500 micrograms/day may represent an equally effective way of treatment in areas of endemic goiter, especially in younger patients. In this age group, the risk of side-effects, e.g., iodine-induced thyrotoxicosis, should be low.

Eight diabetics were found among 464 children, mean age 11.2 years, of 311 unselected insulin-treated mothers. By a method of age correction the total diabetes prevalence among the children at the age of 25 years was calculated as 3.4%. Three children were non-insulin dependent and these patients and their mothers may belong to the autosomal dominant type of diabetes, so-called MODY. In two of the other five families the fathers also had insulin-dependent diabetes; in two more cases first or second degree paternal relatives were insulin-dependent diabetics. Thus the prevalence of insulin-dependent diabetes among the children of insulin dependent mothers married to non-diabetics is calculated as 1.5% at the age of 25 years.

Thirty-eight patients with refractory supraventricular and ventricular tachyarrhythmias were administered a mean oral dosage of 400 mg amiodarone daily (200-600 mg). A high-pressure liquid chromatography method was used to measure serum concentrations of amiodarone and its metabolite desethylamiodarone after one week, one month, three months, and then at 6-month intervals. In 24 patients subcutaneous fatty tissue concentrations were also measured. The mean follow-up was 9 months (4 days to 29 months). A linear correlation was found between amiodarone and its metabolite in serum (r = 0.56, p less than 0.001) as well as in subcutaneous fatty tissue (r = 0.67, p less than 0.001). While serum concentrations were dose dependent, tissue concentrations accumulated during chronic therapy (p less than 0.01, both). Clinical efficacy was achieved in 84% of the patients. No statistically significant difference was found between responders and non-responders as regards serum and subcutaneous fatty tissue concentrations. Side effects of amiodarone occurred in 63%. The incidence of adverse effects was related to significantly higher serum and subcutaneous fatty tissue concentrations of amiodarone and its metabolite (p less than 0.001, both). Thus, although the determination of serum and subcutaneous fatty tissue concentrations does not seem to be helpful for assessing clinical efficacy of this antiarrhythmic drug, these values may predict the occurrence of adverse effects.

HLA-typing was performed in two groups of juvenile-onset diabetics, one with (n = 58) and one without (n = 109) a family history of the disease. The association of this type of diabetes with certain HLA antigens (excess of B8 and B15, shortage of B7) was confirmed. No heterogeneities could be established between the two groups. This suggests that the aetiologic basis in single and familial cases of juvenile diabetes is the same. The hypothesis, that the B8 associated gene is more penetrant than the B15 associated gene, cannot be confirmed. Haplotypes were determined in families with one and two diabetic siblings. The findings of high haplotype concordance among diabetic siblings was confirmed: concordance of 2, 1 and 0 haplotypes in 7, 5 and 3 pairs respectively. There was a low degree of haplotype concordance between diabetics and nonaffected siblings in the families with two diabetics: 2, 1, and 0 haplotypes in 2, 8 and 6 pairs respectively. This led to the hypothesis of negative selection against these HLA-linked "diabetogenic" genes. This tendency was not, however, observed in families with only one diabetic. The report of a high recombination rate in families with juvenile diabetics could not be confirmed.

A facial flush provoked by alcohol in chlorpropamide treated diabetics has been described as a genetic marker for a dominantly inherited type of non-insulin dependent diabetes. In this study a chlorpropamide alcohol flush was observed in 16.9% of control subjects (n = 154), 23.3% of insulin dependent diabetics (n = 437) and 16.5% of patients with non-insulin dependent diabetes (n = 145). Among the non-insulin dependent diabetics no difference in the frequency of the chlorpropamide alcohol flush was found between those with and without a family history of diabetes. Specificity was not improved by skin temperature measurement or additional placebo tests. According to these data the chlorpropamide alcohol flush does not seem to be specific for non-insulin dependent diabetes and hypotheses about the aetiology of this type of diabetes based on the chlorpropamide alcohol flush should be regarded with caution.

Iodine-induced thyrotoxicosis (IIT), due to iodine application in high amounts in patients with circumscript or disseminated thyroid autonomy, is complicated by a prolonged course, mainly due on the body's resistance to conservative therapy with thiourea derivates. Therefore, we decided to perform subtotal thyroidectomy in 16 thyrotoxic patients. This is in contrast to the common opinion that surgery should only be performed after normalization of thyroid hormones. In all 16 patients with severe IIT, including three patients with thyroid storm, hormone levels decreased within a few days after surgery to normal or subnormal values and the clinical picture of thyrotoxicosis disappeared. In the case of thyroid storm the signs of disorientation normalized within 1-3 days. One patient died 5 weeks after surgery due to severe concomitant diseases. One patient exhibited transitory respiration distress and another had postoperative hypocalcaemia. In nine patients L-thyroxine replacement became necessary because of subclinical or clinical hypothyroidism. Only by this procedure will the high intrathyroidal storage of iodine and performed hormone be extracted. Surgery as a treatment for thyrotoxicosis should be reserved for patients with severe IIT, where conservative treatment has been shown to be ineffective. Furthermore, in rare selected cases, when a rapid normalization is required, surgery without preoperative treatment seems to be justified. The effect of surgery was impressive in all our cases and there were only minor perioperative complications. Thus, it could be shown that subtotal thyroidectomy may be a rational and effective treatment in severe IIT which should be carefully considered and weighed against other types of therapy.

We offered a questionnaire to 52 physicians in order to study the appreciation of the fecal occult blood test as an example of a diagnostic procedure. We asked for an indication of the overall appreciation of the test, and for an estimation of the probabilities of colorectal cancer before the test and with a positive or a negative test result--each of them for three situations with different a priori probabilities. The answers demonstrated that the estimated value of the test, representing the personal experience of the physicians is very low (predictive factor between 0.61 and 0.78). About half of the physicians' estimations showed no improvement of probability by using Haemoccult. This contrasts with the expressed very positive general opinion about Haemoccult testing, including its use in symptomatic patients. This result underlines the necessity of careful evaluation of diagnostic tests.

According to Bayes' rule the predictive value (PV) of a diagnostic test (= probability of disease if the test is positive) depends on the prevalence of the disease (= a priori probability), the sensitivity (c1) and the specificity (c2) of the test. A new variable has been introduced, the predictive factor (c), which is calculated as follows: c = c1/(c1 +1 -c2). Since the PV only depends on this factor and on the prevalence, the calculation is much easier and a general graphical solution is possible. This simplification renders several additional advantages and facilitates the understanding of the dependence of PV on prevalence.

Iodine-induced thyrotoxicosis due to iodine application in high amounts in patients with circumscript or disseminated thyroid autonomy, is complicated by a prolonged course, mainly due to a resistance to conservative therapy with thiourea derivates. We therefore decided to perform an early subtotal thyroidectomy in 24 thyrotoxic patients. This measure is in contrast to the common opinion that surgery should only be performed after normalization of thyroid hormones. In all 24 patients with severe hyperthyroidism, including three patients with thyroid storm, hormone levels decreased within a few days after surgery to normal or subnormal values and the clinical picture of thyrotoxicosis disappeared. In the case of thyroid storm the signs of disorientation normalized within 1-3 days. One patient died five weeks after surgery due to severe concomitant diseases. One patient exhibited transitory respiration distress and another had postoperative hypocalcemia. In 13 patients L-thyroxine replacement became necessary due to subclinical or clinical hypothyroidism. Surgery as a early treatment for thyrotoxicosis should be reserved for patients with severe illness where conservative treatment has been shown to be ineffective. In rare selected cases, when a rapid normalization is required, surgery without preoperative treatment seems to be justified. The effect of surgery was impressive in all our cases and there were only minor perioperative complications.

Based upon preliminary observations that tumor response to MPA was correlated to cortisol suppression 42 patients were treated with MPA at different dose levels. 1500 mg MPA p.o. almost completely suppressed endogenous cortisol production in 23 out of 23 patients. Consequently, 51 patients with advanced stage metastatic breast cancer were treated with Medroxyprogesteroneacetate (HD-MAP) at a dosage of 1500 mg p.o. daily or 500 mg i.m. on 5 days per week. There were 5 complete and 7 partical remissions, 23 patients with no change and 10 with progressive disease. 7 patients were not evaluable. Clinical results correlated to plasma cortisol and prolactin blood levels bot not to LH, FSH, TSH, TBI, T3, T4, ACTH and aldosterone measurements. There was no patient with relapse and suppressed cortisol or normal prolactin measurements. The development of pituituary resistance to MPA is suggested. HD-MPA was equally effective in estrogen and/or progesterone receptor positive as in receptor negative patients. It is proposed that cortisol and prolactin determinations are useful to monitor for effective MPA treatment and the early detection of MPA resistance.

Cold agglutinin disease is a normo- or macrocytic anemia due to antibodies, active under body temperature, mostly belonging to the immunoglobulin class M. Initially the agglutination of erythrocytes with acrocyanosis is reversible at body temperature. High antibody activity or long lasting period of coldness lead to intravascular or intrahepatic hemolysis, but high risk anemia is rare. Beside the idiopathic form, infection induced (especially infectious mononucleosis, cytomegalovirus, Mycoplasma pneumoniae, Klebsiella), and drug induced (especially quinidine, alpha methyldopa, penicillin, para-aminosalicylic acid, various analgetics, sulfonylurea), tumor associated (especially malignant lymphomas), and autoimmune disease associated (especially systemic lupus erythematosus) cold agglutinin anemias are discribed. "Cross reacting antigenity" to the hemolysing agent and the membrane of erythrocyte, exogenous induced changing of erythrocytic antigenity, and diversification concerning the production of antibodies are discussed as pathophysiological explanations.

A female patient with the following symptoms has been observed: complete absence of subcutaneous fat on the arms and legs, well developed adipose tissue on the trunk and face, severe hyperlipidemia, eruptive xanthomas, insulin resistant diabetes mellitus with lack of ketoacidosis, hepatomegaly and elevated basal metabolic rate. The patient thus exhibited all characteristics of lipatrophic diabetes (Lawrence type of diabetes). The mother and a sister of the patient were found to have the same peculiar appearance and a slight hyperlipidemia but no diabetes mellitus. The combination of this type of partial lipodystrophy with severe hyperlipidemia, insulin resistant diabetes mellitus without ketoacidosis and elevated basal metabolic rate was further observed in 2 unrelated patients without known familial occurrence. Thus partial lipodystrophy of the extremities is another, previously undescribed, syndrome associated with the Lawrence type of diabetes mellitus. In the 1 family the syndrome of lipodystrophy and hyperlipidemia is dominantly inherited. Besides the autosomal recessively inherited syndrome of congenital generalized lipodystrophy there is a heterogenous group of dominantly inherited syndromes with various types of lipodystrophy.

The fundamental terms in the evaluation of diagnostic tests are described and the differences to corresponding test parameters in clinical chemistry are emphasized. The derivation of a two-by two contingency table is explained in detail and basic characteristics of diagnostic tests, i.e. sensitivity and specificity as well as their independence of the prevalence (in the sense of a-priori-probability) is pointed out. The importance of the so-called predictive values is shown graphically, also the problem of selecting a cut-off-level (discrimination value) for the evaluation of quantitative data. The various attempts to find a single value for the description of a diagnostic test are discussed and it is stressed that there is no principal necessity to use other terms than those mentioned above. Nevertheless it is possible to give a prevalence-independent measure which has some additional advantages in rating and comparing simple diagnostic tests.

The course of disease of a patient with membranoproliferative glomerulonephritis and partial lipodystrophy is described. The case is further characterized by a deficiency of C3 and C3- activator, by normal values of C4, by evidence of the nephritogenic factor, by raised fibrin degradation products and by an unselective proteinuria. The course of the glomerulonephritis runs parallel to a pronounced susceptibility to infection (at first varicella, tonsillitis and measles, later pneumonia, meningitis, encephalitis and hepatitis). On account of a nephrotic syndrome and an initative impairment of the renal function, a cytostatic treatment was begun, which although raising the C3 level did not influence the further course of the disease. As the patient has a healthy identical twin sister without lipodystrophy, who shows no reduction in C3 and no nephritogenic factor, this case proves that these diseases are acquired and not genetically determined.