Defective prevention of immune precipitation in autoimmune diseases is independent of C4A*Q0.

Increased prevalence of C4 null alleles is a common feature of autoimmune diseases. We have shown previously that complement-dependent prevention of immune precipitation (PIP) is defective in patients with systemic lupus erythematosus (SLE), and correlated this defect with C4A*Q0 and low levels of the C4A isotype. To further clarify the role of C4A in the aetiology of SLE, we now extend our studies to other diseases which have been associated with C4A*Q0. The frequency of C4A*Q0 was increased in Icelandic patients with coeliac disease (0.50; P < 0.001), Grave's disease (0.30; P = 0.002) and insulin-dependent diabetes mellitus (0.23; P = 0.04) and in British patients with dermatitis herpetiformis (0.42; P = 0.002) and this was reflected in low levels of C4A. In spite of this, PIP was normal in these patients, and in marked contrast to our previous observations on connective tissue diseases, PIP measurements in these patient groups correlated more strongly with levels of C4B (r = 0.51, P = 0.0000004) than C4A. Patients with increased levels of anti-C1q antibodies had significantly lower PIP than patients without such antibodies (P < 0.01) and a negative association of PIP with anti-C1q antibodies was also reflected in an increased prevalence (P = 0.006) and levels (P = 0.006) of anti-C1q antibodies in patients with subnormal PIP, as well as a negative correlation between PIP and anti-C1q antibodies (r = - 0.25, P = 0.02). These results show that the PIP defect cannot be explained by low levels of C4A alone and suggest that measurements of anti-C1q antibodies may be useful in future studies on the molecular cause of the PIP defect in autoimmune connective tissue disease.

Unchanged incidence of diabetic nephropathy in Type 1 diabetes: a nation-wide study in Iceland.

AIMS: Diabetic nephropathy is an uncommon cause of end-stage renal disease in Iceland in contrast to most industrialized countries. The aim of this study was to examine the incidence of diabetic nephropathy in Iceland. METHODS: All patients diagnosed with Type 1 diabetes in Iceland before 1992 were studied retrospectively. Patients diagnosed before age 30, who were insulin dependent from the onset, were defined as having Type 1 diabetes. Diabetic nephropathy was defined as persistent proteinuria measured with a dipstick test (Albustix) on three consecutive clinic visits at least 2 months apart. Patients were followed to the end of year 1998, to their last recorded outpatient visit, or until death. The cumulative incidence of diabetic nephropathy was calculated with the Kaplan-Meier method and presented according to the duration of diabetes divided into 5-year intervals. RESULTS: A total of 343 patients with Type 1 diabetes were identified. The mean follow-up period was 20.2 +/- 11.4 (mean +/- sd) years. Only 9.3% of patients were lost to follow-up. Sixty-five patients developed diabetic nephropathy. The cumulative incidence was 22.6% at 20 years and levelled off at 40.3% after approximately 35 years of diabetes duration. No significant changes in cumulative incidence were observed over time. Mean glycated haemoglobin was 8.4% in patients with proteinuria and 7.8% in a group of patients without proteinuria that was matched for age, gender and duration of diabetes (P = 0.04). CONCLUSIONS: The cumulative incidence of diabetic nephropathy in Iceland is comparable with previously reported cumulative incidence rates and has remained unchanged. Glycaemic control was significantly better in patients without proteinuria.

MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1.

AIMS/HYPOTHESIS: Five different types of maturity-onset diabetes of the young (MODY) have been identified until now but mutation screening suggests that more MODY genes exist. Mutations in genes encoding transcription factors essential for normal development and function of pancreatic beta cells has recently become important in studying the genetics of Type II (non-insulin-dependent) diabetes mellitus. Patients with MODY and their families in Iceland were screened for mutations in the transcription factor genes. METHODS: Clinical and biochemical information on individuals with MODY was collected and their family trees constructed. Linkage analysis was carried out on chromosomal regions known to harbour genes previously shown to be associated with MODY. Mutations were identified by direct sequencing. RESULTS: Three families were identified. Two of these showed linkage to chromosome 12 and carried mutations in exon 4 of the HNF-1alpha gene (290fsdelC and R272C). However, the third family showed no linkage to the previously described MODY genes but shared a novel mutation in the NeuroD1 gene on chromosome 2q32. This mutation, a glutamate to lysine substitution at codon 110, resides in the basic domain of the protein. CONCLUSION/INTERPRETATION: Mutations in MODY subjects have been identified in the Icelandic population. In addition this study identified the NeuroD1 gene as the gene responsible for the sixth type of MODY.

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.

Prevalence and incidence of NIDDM in Iceland: evidence for stable incidence among males and females 1967-1991--the Reykjavik Study.

This is the first large survey carried out in Iceland to estimate the prevalence and incidence of known and unknown non-insulin-dependent (Type 2) diabetes (NIDDM) among males and females, aged 34-79. The population in this survey was 9128 males and 9759 females born between 1907 and 1935 and examined in the prospective Reykjavik Study 1967-1991. Participants were invited from one to five times during the 24 years. The overall age-standardized prevalence (95% confidence limits) was 2.9% (2.5 to 3.3) for males and 2.1% (1.8 to 2.5) for females, aged 30-79, according to the European standard population. The overall annual age-standardized incidence rate per 100,000 was 377 (303 to 457) for males and 266 (212 to 320) for females, aged 35-74, standardized to the European population. Our study indicates that the prevalence of NIDDM is relatively low compared to other Nordic and western countries, and has not been increasing over the past 20 years. Furthermore, the incidence of NIDDM has not been changing during the past 20 years of follow-up among Icelandic males and females aged 34-79.

[Autonomic nervous dysfunction in insulin-dependent (type 1) diabetic men.].

The development of autonomic nervous dysfunction (AND) in subjects with diabetes influences life expectancy and may cause sudden death. The present study evaluates disturbances of AND in 41 men with type 1 diabetes mellitus, but without heart symptoms, and the relationship with other long term diabetic complications and blood sugar control. Their age ranged 18-50 years (mean 34 +/-8 years) and the duration of diabetes 1-43 years (mean 13 +/-10 years). A control group consisted of 18 healthy men of similar age. Heart rate and blood pressure responses during standard autonomic tests were assessed by a computer program, vibration sensibility by a Biothesiometer, and an exercise test was performed. AND was more frequent in diabetics than controls (39% versus 6%, p<0.01), and increased with the duration of diabetes (r=0.34, p<0.05), but not significantly with HbAl-levels (r=0.21, p=0.19). Diabetics with AND had an earlier onset p<0.05) and a longer duration of (p<0.01) diabetes, decreased vibration sense (p<0.05), more frequent hypoglycaemic episodes (p<0.05), intermittent claudication (p<0.01), a higher resting heart rate (p<0.05), and a shorter treadmill time (p<0.05). Consequently, at maximal exercise their systolic (p<0.05) and diastolic (p=0.08) blood pressure increased less. With longer duration of diabetes, retinopathy (p

Reduced pupillary unrest. Autonomic nervous system abnormality in diabetes mellitus.

Pupillary unrest (fluctuations in pupil size) was measured by infrared television videopupillography in 80 insulin-dependent diabetic patients (age 25-43 yr, diabetes duration 0-35 yr) and 26 control subjects (age 26-39 yr). In darkness, pupillary unrest was 21% less in diabetic subjects than in controls. During prolonged and brief illumination, pupillary unrest was 35 and 37% less in diabetic subjects than in controls, respectively, and in both cases the unrest was inversely correlated to the duration of diabetes. There were inverse correlations between 1) vibratory perception threshold, long-term high blood glucose levels, and severity of retinopathy, and 2) pupillary unrest in darkness and during prolonged illumination. The fractional reduction in pupil size (relative miosis) was 19% less during prolonged illumination in diabetic subjects than in controls and was positively correlated to the pupillary unrest in both groups. For a given fractional reduction in pupil size during illumination, diabetic subjects still had a smaller unrest than controls. Pupil size in darkness was 19% smaller in diabetic subjects than in controls, and in diabetic subjects it was positively correlated to the unrest in darkness and during prolonged and brief illumination. None of the pupillary abnormalities showed correlation to biomicroscopic changes in the iris. The autonomic nervous system abnormalities reflected in the pupil in longstanding diabetes are 1) a reduction in pupillary unrest in light and in darkness, more pronounced in light, 2) a reduction in the ability to maintain miosis in continuous light, and 3) a reduction in size.

Painful autoimmune thyroiditis occurring on amiodarone therapy.

A 51-year-old housewife, who had been on treatment with amiodarone for ten months, developed a painful enlargement of the thyroid gland. Thyroid antibody titers were highly elevated and a fine needle aspirate of the gland showed infiltration of lymphocytes and plasma cells. Initially the patient was hyperthyroid, later she developed hyperthyroidism which required thyroid substitution. The possibility of amiodarone provoking autoimmune thyroiditis is discussed.

The pupillary response to light in type 1 (insulin-dependent) diabetes.

The pupillary response to light was examined by infrared television-videopupillography in 93 Type 1 (insulin-dependent) diabetic patients (aged 25-42 years, duration of diabetes 0-32 years), and 37 control subjects (aged 26-41 years) with techniques ensuring equality of stimulus and retinal sensitivity, and allowing a detailed computerized calculation of the various parameters of the response. There was no difference in latency time or constriction time between diabetic patients and control subjects. The diabetic patients had a smaller initial pupil size (p = 0.012) and a smaller response amplitude (p less than 0.001) than the control subjects, and these two parameters were correlated to each other (r = 0.49, p less than 0.000001) and inversely correlated to the duration of diabetes (r = 0.26, p = 0.013 and r = 0.29, p = 0.0051, respectively). As a group, the diabetic patients had a relative response amplitude that was similar to that of the control subjects. However, more detailed analysis showed that the diabetic patients with pupil size in the normal range had a small, but significant, reduction in relative response amplitude (p = 0.0021). The maximal velocities of constriction and re-dilatation were reduced in the diabetic patients (p less than 0.001 in either case), but both parameters were intimately correlated to the response amplitude (r = 0.91, p less than 0.000001, and r = 0.79, p less than 0.000001, respectively), and this relationship was identical in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Enflurane hepatitis. A report of a case with a previous history of halothane hepatitis.

"Enflurane hepatitis" has only recently been accepted as a disease entity. As far as the authors know, this paper is the first report on enflurane hepatitis in a patient with a previous history of halothane hepatitis. Our conclusion is that a potent halogenated inhalation agent should never be given to a patient if a prior administration of another such agent has led to the development of hepatic injury.

Angiotensin-converting enzyme in diabetes mellitus dependence on metabolic aberration.

Serum angiotensin-converting enzyme (s-ACE) was measured in 56 diabetic outpatients and in 6 juvenile insulin dependent diabetics who developed mild to moderate ketosis after insulin withdrawal. In the outpatients mean s-ACE was increased by 24% compared to healthy controls. However, development of ketosis resulted in significant reduction of s-ACE from 29.2 +/- 1.6 U/ml (+/- SEM) to 23.1 +/- 1.9 U/ml (p less than 0.05). In addition, a clearcut inverse correlation was observed between blood-3-hydroxybutyrate rise and s-ACE decrement (p less than 0.01). The reduction observed may be mediated through the metabolic acidosis.

Evaluation of pupillary function in thyroid disease.

Employing the technique of infrared television pupillography, the pupil area in darkness, pupillary unrest, and various parameters of the light response were measured in 5 patients with clinical and biochemical overt thyrotoxicosis and in 2 patients with longstanding severe primary myxoedema. The patients were studied before and after medical treatment. The treatments did not induce significant alterations in any of the parameters measured. Thus pupillary measurements are not a convenient method for recording of peripheral thyroid hormone action.

Pupil size in insulin-dependent diabetes. Relationship to duration, metabolic control, and long-term manifestations.

The pupil area was measured in complete darkness by infrared TV-videopupillography in 109 insulin-dependent diabetics, aged 25-43 yr, diabetes duration 0-35 yr, and 39 control subjects, aged 26-41 yr. In darkness the pupil was 19.6% +/- 4.2 (SEM) smaller in diabetics than in controls (2 P less than 10(-5). There was an inverse relationship between diabetes duration and pupil area (Kendall's coefficient of correlation, tau = -0.33, 2 P less than 10(-4). There was also an inverse correlation between pupil size and vibratory perception threshold (tau = 0.32, 2 P less than 10(-3). Long-term diabetics (duration greater than or equal to 15 yr) with proliferative retinopathy had a 28.4% +/- 8.1 (SEM) smaller pupil than those without (2 P = less than 10(-3). Likewise, long-term diabetics with nephropathy had a 19.8% +/- 9.1 smaller pupil than those without nephropathy (2 P = 0.035). In the long-term diabetics there was an inverse relationship between the level of blood glucose throughout the years and pupil area (tau = -0.49, 2 P less than 10(-3). Also, high blood glucose levels throughout the years were correlated to severity of retinopathy (tau = 0.43, 2 P less than 10(-3) and nephropathy (tau = 0.30, 2 P = 0.024). There was no correlation between biomicroscopic changes in the iris and the diminished pupil area. Pupil area in light was measured in 85 patients and 31 controls. In continuous light only the long-term diabetics had a smaller pupil size than the controls. Both the absolute and relative change in pupil size from darkness to light was less in the diabetic group. Measuring the pupil size in darkness is a simple, noninvasive and reproducible method that may yield information about autonomic nervous involvement in diabetes.

Suppression of the night increase in serum TSH during development of ketosis in diabetic patients.

The alterations in metabolic parameters, circulating iodothyronines and serum TSH were studied during a 21 h period of insulin withdrawal in 6 young patients with juvenile type diabetes mellitus. Concomitant with the derangement of metabolic state a significant fall in serum T3 (in average 27%), serum free T3 (28%), and T4 (12%) was observed. SErum free T4 remained unchanged. Before and after the period of ketosis the normal diurnal pattern of high serum TSH at night and low levels during the daytime period was observed. During the period of ketosis the night level of serum TSH was significantly depressed (46 +/- 9% lower at 23.00 h, p less than 0.01) while no significant alterations occurred in daytime TSH. Both the variations in T3, reverse T3 (rT3) and night TSH were correlated to the increase in blood-3-hydroxybutyrate. The depression of the night surge in serum TSH may be of importance for the fall in circulating levels of active iodothyronines during the initial phase of illness, together with the well known inhibition of T4 deiodination to T3 in peripheral tissues occurring in acute illness.

Acute, reversible autonomic nervous system abnormalities in juvenile insulin-dependent diabetes. A pupillographic study.

Autonomic nervous function was studied by infrared TV-pupillography in nine insulin-dependent diabetic subjects with 0 to 3 years duration of diabetes, during poor and good metabolic control. During poor control there was no change in the latency time, the maximal contraction velocity or the amplitude of the light response, whereas the redilatation time was prolonged by 28%, from 2.26 +/- 0.27 to 2.90 +/- 0.58 s (mean +/- SD) (2p = 0.012). The pupil size after adaptation to darkness was unchanged, but the light induced pupillary unrest was reduced by 35% from 1.68 +/- 0.62 to 1.10 +/- 0.36 mm2 (2p = 0.0037), and the degree of miosis in continuous illumination was reduced by 47% from 0.32 +/- 0.13 to 0.17 +/- 0.08 (2p = 0.0011), during metabolic derangement. The study has thus demonstrated reversible changes in autonomic nervous function, which are related to the diabetic metabolic state and thereby analogous to the previously well established reversible functional changes in the somatic nervous system in early diabetes.