Treatment of young patients with HNF1A mutations (HNF1A-MODY).

AIM: Children and adolescents with a molecular diagnosis of HNF1A-MODY should be treated with oral sulfonylurea according to current International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines. METHODS: We surveyed the German-Austrian DPV database of 50 043 people and included 114 patients with a confirmed molecular-genetic diagnosis of HNF1A mutation and diabetes onset at below age 18 years. We analysed hypoglycaemic episodes, metabolic control (HbA1c ) and other clinical variables according to treatment groups. RESULTS: People with HNF1A-MODY were included and analysed according to treatment with insulin alone (n = 34), sulfonylurea (n = 30), meglitinides (n = 22) or lifestyle (n = 28). In those receiving any drug treatment (n = 86), severe hypoglycaemia did not occur with meglitinide and was highest (at 3.6 events per 100 patient-years) with insulin. HbA1c was highest with insulin treatment (insulin = 58 mmol/mol, 7.5%; sulfonylurea = 55 mmol/mol, 7.2%; meglitinides = 52 mmol/mol, 6.9%; P = 0.008), whereas weight (BMI SD score), serum lipids and blood pressure were not different. CONCLUSIONS: Of note, 40% of people with HNF1A-MODY and medical treatment were receiving insulin alone and thus were not being treated in line with up-to-date International Society for Pediatric and Adolescent Diabetes/International Diabetes Federation guidelines, despite insulin treatment being associated with worse metabolic control and the risk of hypoglycaemia. The unlicensed use of oral drugs in patients below age 18 years and adherence by both doctors and patients to the initial insulin treatment might contribute to this finding.

Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison.

AIMS: Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries. METHODS: Data were obtained for children and/or adults with Type 1 diabetes from the following countries (or regions): Western Australia, Austria, Denmark, England, Champagne-Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales) from population or clinic-based registries. The sample size with available data varied from 355 to 173 880. Proportions with HbA1c < 58 mmol/mol (< 7.5%) and ≥ 75 mmol/mol (≥ 9.0%) were compared by age and sex. RESULTS: Data were available for 324 501 people. The proportions with HbA1c 58 mmol/mol (< 7.5%) varied from 15.7% to 46.4% among 44 058 people aged < 15 years, from 8.9% to 49.5% among 50 766 people aged 15-24 years and from 20.5% to 53.6% among 229 677 people aged ≥ 25 years. Sex differences in glycaemic control were small. Proportions of people using insulin pumps varied between the 12 sources with data available. CONCLUSION: These results suggest that there are substantial variations in glycaemic control among people with Type 1 diabetes between the data sources and that there is room for improvement in all populations, especially in young adults.

Impact of regular physical activity on blood glucose control and cardiovascular risk factors in adolescents with type 2 diabetes mellitus--a multicenter study of 578 patients from 225 centres.

INTRODUCTION: Regular physical activity (RPA) is a major therapeutic recommendation in children and adolescents with type 2 diabetes mellitus (T2DM). We evaluated the association between frequency of RPA and metabolic control, cardiovascular risk factors, and treatment regimes. METHODS: The Pediatric Quality Initiative (DPV), including data from 225 centers in Germany and Austria, provided anonymous data of 578 patients (10-20 yr; mean 15.7 ± 2.1 yr; 61.9% girls) with T2DM. Patients were grouped by the frequency of their self-reported RPA per week: RPA 0, none; RPA 1, 1-2×/wk; RPA 2, >2×/wk. RESULTS: The frequency of RPA ranged from 0 to 9×/wk (mean 1.1×/wk ±1.5). 55.7% of the patients reported no RPA (58.1% of the girls). Hemoglobin A1c (HbA1c) differed significantly among RPA groups (p < 0.002), being approximately 0.8 percentage points lower in RPA 2 compared to RPA 0. Body mass index (BMI-SDS) was higher in the groups with less frequent RPA (p < 0.00001). Multiple regression analysis revealed a negative association between RPA and HbA1c (p < 0.0001) and between RPA and BMI-SDS (p < 0.01). The association between RPA and high density lipoprotein (HDL)-cholesterol was positive (p < 0.05), while there was no association to total cholesterol, low density lipoprotein (LDL)-cholesterol or triglycerides. Approximately 80% of the patients received pharmacological treatment (oral antidiabetic drugs and/or insulin) without differences between RPA groups. CONCLUSION: More than half of the adolescents with T2DM did not perform RPA. Increasing physical activity was associated with a lower HbA1c, a lower BMI-SDS, a higher HDL-cholesterol, but not with a difference in treatment regime. These results suggest that regular exercise is a justified therapeutic recommendation for children and adolescents with T2DM.

Seasonal variation in month of diagnosis in children with type 1 diabetes registered in 23 European centers during 1989-2008: little short-term influence of sunshine hours or average temperature.

BACKGROUND: The month of diagnosis in childhood type 1 diabetes shows seasonal variation. OBJECTIVE: We describe the pattern and investigate if year-to-year irregularities are associated with meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population-based European registries during 1989-2008. METHODS: Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends. RESULTS: Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from ± 11 to ± 38% (median ± 17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10-14 yr. There were no differences in seasonal pattern between four 5-yr sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 °C excess) but not with sunshine hours. CONCLUSIONS: Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.

Microvascular autoregulation in children and adolescents with type 1 diabetes mellitus.

AIMS/HYPOTHESIS: Deterioration of microvascular function may have an early onset in individuals with type 1 diabetes mellitus. We hypothesised that microvascular autoregulation is impaired in children with type 1 diabetes and can be detected non-invasively by postocclusive reactive hyperaemia (PORH). METHODS: Microvascular autoregulation was assessed in 58 children with type 1 diabetes and 58 age- and sex-matched healthy controls by PORH using laser Doppler fluxmetry. Baseline perfusion, biological zero (defined as a 'no flow' laser Doppler signal during suprasystolic occlusion), peak perfusion following occlusion, time to peak and recovery time (time until baseline perfusion is resumed) were recorded and compared between the groups. RESULTS: Peak perfusion was higher in children with type 1 diabetes than in healthy controls (1.7 ± 0.93 AU [arbitrary units] vs 1.29 ± 0.46 AU; p = 0.004), and biological zero was lower in children with type 1 diabetes vs controls (0.14 ± 0.04 AU vs 0.19 ± 0.04 AU; p < 0.0001). No differences were seen between the groups in baseline perfusion, time to peak during PORH and recovery time following PORH. CONCLUSIONS/INTERPRETATION: PORH reveals impaired microvascular autoregulation in children with type 1 diabetes. The higher peak perfusion might reflect a decline in the vasoconstrictive ability of arteriolar smooth muscle cells upstream of capillary beds in children with type 1 diabetes.

Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase.

AIMS/HYPOTHESIS: The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989-1998) and second (1999-2008) halves of the period. METHODS: All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied. RESULTS: Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half. CONCLUSIONS/INTERPRETATION: The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.

Diabetic ketoacidosis at diagnosis in Austrian children in 1989-2008: a population-based analysis.

AIM: The aim of the study was to analyse the prevalence of diabetic onset ketoacidosis (DKA) during a period of 20 years (1989-2008) on a population basis in the whole of Austria. METHODS: A prospective population-based incidence study (1989-2008) was performed. The registered data set comprised blood glucose, pH, ketonuria and clinical symptoms of DKA at manifestation. DKA was defined as pH < 7.3 and severe DKA as pH < 7.1. Time trends were estimated using linear regression models. RESULTS: During the study period, 3331 children <15 years of age (1,797 boys and 1,534 girls) were registered with newly diagnosed type 1 diabetes. Of these, 1,238 (37.2%) presented with DKA, 855 (25.7%) had a mild and 383 (11.5%) a severe form, and one patient died at onset. DKA frequency was negatively associated with age at onset (p < 0.0001). In children <2 years the prevalence was 60%, with a higher risk for girls (70% vs 54% for boys, p < 0.05). Despite a significant increase in diabetes incidence in Austria during the observation period from 8.4 to 18.4/100,000 (p < 0.0001), no significant change in the prevalence of DKA at manifestation was observed. CONCLUSIONS: The overall frequency of DKA in children with newly diagnosed type 1 diabetes in Austria is high and has not changed during the last 20 years despite a clear increase in the manifestation rate. In particular, children less than 2 years of age have a high risk of DKA at onset.

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data.

AIMS/HYPOTHESIS: We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes. METHODS: Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders.Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies. RESULTS: Data were available for 29 predominantly European studies (five cohort, 24 case-control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01-1.11]; p=0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04-1.19]; p=0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00-1.06]; p=0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings. CONCLUSIONS/INTERPRETATION: Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes.

Cognitive functions and glycemic control in children and adolescents with type 1 diabetes.

BACKGROUND: The relationship between metabolic control and cognitive function in adolescents with type 1 diabetes (DM type 1) is not clear. We compared the quality of glycemic control (GC) and cognitive measures in adolescents with DM type 1 to find out if the quality of diabetes management is related to cognitive impairment. METHOD: We assessed executive functions (EFs) and other neuropsychological and psychosocial variables in 70 adolescent patients with DM type 1 and 20 age-matched controls. Patients were divided into two groups according to their last hemoglobin A1c (HbA1c): acceptable (HbA1c 5.9-8.0%, mean 6.9%, 36 patients, mean age 14 years) and non-optimal (HbA1c 8.2-11.6%, mean 9.3%, 34 patients, mean age 15.6 years). RESULTS: We found impaired EFs, mainly problems of concept formation (p=0.038), cognitive flexibility (p=0.011) and anticipation (p=0.000), in the patients with DM type 1. Both groups did not differ in intelligence, most assessed EFs and adjustment to chronic illness (Youth Self-Report; YSR). Younger patients (<15 years) were cognitively less flexible. GC was worse in older patients and in patients with longer duration of the disease. We also found significant differences between patients with diabetes and controls concerning somatic complaints, internalizing problems (Child Behavior Checklist; CBCL) and social activity (CBCL and YSR). CONCLUSIONS: DM type 1 is associated with cognitive deficits in adolescents independent of the quality of metabolic control and the duration of the disease. These deficits are probably related to the disease, especially in patients with early-onset diabetes.

Entities and frequency of neonatal diabetes: data from the diabetes documentation and quality management system (DPV).

AIMS: The aim of this study was to elucidate the entities and the frequency of neonatal diabetes mellitus (NDM) in a large representative database for paediatric diabetes patients in Germany and Austria. METHODS: Based on the continuous diabetes data acquisition system for prospective surveillance (DPV), which includes 51,587 patients with onset of diabetes before the age of 18 years from 299 centres in Germany and Austria, we searched for patients with onset of diabetes mellitus in the first 6 months of life. RESULTS: Ninety patients were identified, comprising 0.17% of all paediatric cases in the DPV registry. This represented an incidence of approximately one case in 89,000 live births in Germany. A monogenic basis for NDM was established in 30 subjects (seven UPD6, 10 KCNJ11, seven ABCC8, two FOXP3, two PDX1, one INS, one EIF2AK3). Pancreatic hypoplasia or agenesis was reported in 10 patients and seven subjects were classified as having Type 1 diabetes by their centres. Transient neonatal diabetes (TNDM) accounted for approximately 10% of all cases with NDM. No aetiology was defined in 41 subjects, which may reflect incomplete genetic testing or novel genetic aetiologies. CONCLUSION: Based on a large database, we identified a higher rate of NDM in Germany than has been reported previously. Full molecular genetic testing should be performed in all patients diagnosed before 6 months of age.

Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with Type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database.

AIMS: To analyse and compare clinical characteristics in young patients with maturity-onset diabetes of the young (MODY) and Type 2 diabetes mellitus (T2DM). METHODS: We conducted an observational investigation using the DPV-Wiss database containing clinical data on 40 757 diabetic patients < 20 years of age from Germany and Austria. RESULTS: Three hundred and thirty-nine cases were clinically categorized as MODY (0.83%); 562 patients were diagnosed as T2DM (1.4%). In 20% of cases, the diagnosis of MODY was based on clinical findings only. Of the 272 subjects where genetic testing was available, 3% did not carry mutations in the three examined MODY genes. Glucokinase-MODY was commoner than HNF1A-MODY and HNF4A-MODY. Age at diagnosis was younger in MODY patients. The body mass index of T2DM was significantly higher compared with all MODY subgroups. Macrovascular risk factors such as dyslipidaemia and hypertension were commoner in T2DM, but 23% of MODY patients had dyslipidaemia and 10% hypertension. Glycaemic control was within the therapeutic target (HbA(1c) < 7.5%) in 86% of MODY and 70% of T2DM patients. CONCLUSIONS: The prevalence of MODY in children and adolescents in Germany and Austria is lower than that of T2DM in this age group. Dyslipidaemia and hypertension are less frequent in MODY compared with T2DM patients, but do occur.

Long-term non-surgical therapy of severe persistent congenital hyperinsulinism with glucagon.

BACKGROUND: Congenital hyperinsulinism (CHI) is characterized by severe hypoglycemia caused by dysregulated insulin secretion. The long-term outcome is dependent on prevention of hypoglycemic episodes to avoid the high risk of permanent brain damage. Severe cases are usually resistant to diazoxide or nifedipine. In addition, somatostatin analogues are ineffective in a subgroup of patients to achieve stable euglycemia. In these infants the only remaining long-term option has been subtotal pancreatectomy with high risk of diabetes mellitus. Intravenous infusions of glucagon are used as immediate treatment to stabilize euglycemia in affected newborns. The rationale of this treatment comes from the observation of an increased glycogen content of the liver when glycogenolysis is inhibited by insulin. OBJECTIVE: To review the efficacy and safety of long-term subcutaneous glucagon infusion as a potential therapeutic option for blood glucose stabilization in infants with severe CHI without the need of additional intravenous glucose or immediate surgical intervention. METHOD: Retrospective review of 9 children with CHI who received continuous subcutaneous infusion of glucagon for weeks or months. Glucagon was added to octreotide to replace octreotide-induced suppression of endogenous glucagon secretion, thereby liberating glucose by stimulation of hepatic glycogenolysis. In 3 cases, a stabilized formulation of glucagon was used to prevent glucagon crystallization that frequently occurs in smaller volumes. RESULTS: Introduction of glucagon allowed the reduction or discontinuation of central glucose infusion in all children studied. In 2 patients, glucagon was introduced due to recurrent hypoglycemia despite subtotal pancreatectomy. Six out of 9 children were discharged home on this treatment, which their parents were able to continue without further symptomatic hypoglycemia, convulsions or unconsciousness. In 3 children, subcutaneous glucagon was continuously administered for 1-4 years leading to stable euglycemia. However, 2 children with diffuse type still required subtotal pancreatectomy. As a possible side effect, 2 children developed erythema necrolyticum, which resolved after discontinuation of the glucagon infusion. This has been described before in glucagonoma. CONCLUSION: In this retrospective series, combination therapy of low-dose octreotide and subcutaneous glucagon infusion has been effective in preventing hypoglycemic episodes in severe CHI. We propose this may serve as a therapeutic option in place of high rates of glucose infusion through a central venous catheter and as an alternative to subtotal pancreatectomy in diffuse type of CHI.

Thyroid autoimmunity in children with coexisting type 1 diabetes mellitus and celiac disease: a multicenter study.

BACKGROUND: Children with type 1 diabetes mellitus (DM1) are more prone to developing thyroid autoimmunity (TAI); TAI also occurs more frequently in patients with celiac disease (CD). AIM: To determine whether TAI occurs more frequently in children with coexisting DM1 and CD compared to children with DM1 only, and whether the clinical course of DM1 is influenced by concomitant TAI. PATIENTS AND METHODS: We performed a multicenter retrospective case-control study comparing data from 84 diabetic children with CD (group 1) to 167 diabetic children without CD (group 2), matched by age at DM1 onset, duration of DM1 and center. Markers of TAI, thyroid function and HbA1c were recorded. The TAI follow-up lasted 4.9 +/- 2.8 years. RESULTS: TAI was diagnosed in 13% of children in group 1 and 19% of children in group 2 (ns). Diabetes control was not influenced by TAI in either group. CONCLUSIONS: Occurrence of TAI in diabetic children is not related to coexisting CD. TAI does not lead to worsening of metabolic control in children with DM1.

Iodide iontophoresis as a treatment for dry eye syndrome.

BACKGROUND/AIMS: Among the causes related to the development or perpetuation and aggravation of dry eye disease, oxidative reactions may have a role in the pathogenesis of this disorder. Antioxidants, such as iodide, have shown a strong effect in preventing the oxidative damage to constituents of the anterior part of the eye. In this clinical trial the effectiveness of iodide iontophoresis and iodide application without current in moderate to severe dry eye patients was compared. METHODS: 16 patients were treated with iodide iontophoresis and 12 patients with iodide application without current for 10 days. Subjective improvement, frequency of artificial tear application, tear function parameters (break up time, Schirmer test without local anaesthesia), vital staining (fluorescein and rose bengal staining) as well as impression cytology of the bulbar conjunctiva were evaluated before treatment, 1 week, 1 month, and 3 months after treatment. RESULTS: A reduction in subjective symptoms, frequency of artificial tear substitute application, and an improvement in certain tear film and ocular surface factors could be observed in both groups. A stronger positive influence was seen after application of iodide with current (iontophoresis), as observed in a distinct improvement in break up time, fluorescein and rose bengal staining, and in a longer duration of this effect compared with the non-current group. No significant change in Schirmer test results and impression cytology were observed in both groups. CONCLUSIONS: Iodide iontophoresis has been demonstrated to be a safe and well tolerated method of improving subjective and objective dry eye factors in patients with ocular surface disease.

Increasing incidence of IDDM in Austrian children. A nationwide study 1979-1993. Austrian Diabetes Incidence Study Group.

OBJECTIVE: A nationwide population-based study was conducted to assess the insulin-dependent diabetes mellitus (IDDM) incidence in childhood over a 15-year period (1979-1993). RESEARCH DESIGN AND METHODS: A questionnaire was sent to all Austrian pediatric departments and diabetologists. The secondary data source was based on patient organization lists and hospital administration data. The data from 1979-1987 were collected retrospectively, while from 1988 to 1993 the registration of cases was performed prospectively in the same network. Estimates of probability of ascertainment were calculated according to the capture-recapture method. RESULTS: The achieved ascertainment was 94% . The overall annual incidence was 7.9/100,000 person-years in children 0-14 years old. During the observation period, the incidence rose by 2.4% annually. CONCLUSIONS: The incidence of childhood IDDM in Austria, a European country with an intermediate risk for IDDM, showed a proportionally similar increase to that of Northern European countries over the past decade. The increase seems to be continuous, following mainly a linear trend with superimposed sudden outbreaks indicating environmental causative factors.

Immunogenicity of human insulin (Novo) or pork monocomponent insulin in HLA-DR-typed insulin-dependent diabetic individuals.

The immunogenicity of human insulin (Novo, Monotard, Actrapid) or pork monocomponent (MC) insulin (Monotard, Actrapid) was studied in 102 HLA-DR-typed patients with newly diagnosed insulin-dependent diabetes mellitus (type I diabetes). After 6 mo of treatment, IgG-insulin antibodies were found in only 14% of the patients receiving homologous MC insulins, but in 29% of the patients on heterologous MC insulins. IgG-insulin antibody titers were significantly lower in patients treated with human insulin compared with diabetic patients who received the corresponding pork MC insulin preparations from the onset of their disease. The previously reported strong influence of immunogenetic factors in determining the magnitude of the anti-insulin immune response was supported by the findings obtained in the pork MC insulin-treated diabetic individuals. Incidence of circulating immune complexes was 14% and 5% after 3 and 6 mo, respectively, of treatment with human insulin, which is considerably lower than previously reported in patients using heterologous non-monocomponent insulin preparations.

Brainstem auditory evoked potentials and visually evoked potentials in young patients with IDDM.

OBJECTIVE: To investigate whether young IDDM patients develop central nervous dysfunction and to establish a possible relationship with various disease parameters. RESEARCH DESIGN AND METHODS: Thirty-two patients, aged 13.5 +/- 2 years, with disease duration of 6 +/- 2.6 years and age of onset of 7.7 +/- 3.2 years (group 1), and 21 patients with short-term disease, age 9.7 +/- 3.5 years, duration of disease < 2 years and age of onset of 9.4 +/- 3.3 years (group 2) were compared with age- and sex-matched control subjects. Exclusion criteria were clinical signs of neuropathy, retinopathy, nephropathy, or hearing impairment. Neurophysiological studies included auditory and visually evoked potentials (EPs). RESULTS: Patients in group 1 revealed increased P100 latencies of visually EPs (103.4 +/- 4.5 vs. 96.8 +/- 3.7 ms) and interpeak latencies I-V of auditory EPs (4.16 +/- 0.10 vs. 3.99 +/- 0.09 ms) and had abnormal latencies (values outside 2.5 SD) in 37%. However, short-term patients (group 2) had results within normal limits compared with control subjects. In group 1, longer disease duration and younger age at onset correlated with an increase of P100 latency (P < 0.001) and IPL I-V (P < 0.001). Patients with a history of severe hypoglycemic episodes had increased latencies compared with patients without hypoglycemia (P < 0.05). Furthermore, metabolic control during the last 2 years was related to P100 latencies (P < 0.05). CONCLUSIONS: EPs noninvasively detect subclinical central nervous system involvement in children and adolescents with IDDM. Most important risk factors are duration of disease and frequency of severe hypoglycemia.

Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency.

The GH1 genes of probands of two families with familial isolated GH deficiency (IGHD) were sequenced. Double stranded sequencing of the polymerase chain reaction (PCR) amplification products from genomic DNA of two affected cousins in a consanguineous Turkish family revealed a G-->A transition in the 20th codon of the GH1 signal peptide. This substitution converts a TGG (Trp) to a TAG (stop) codon and generates a new AluI recognition site. PCR amplification of the GH1 alleles of family members, followed by AluI digestion, revealed that the G-->A transition segregated with the IGHD phenotype. In a Saudi Arabian family, a G-->C transversion was found that alters the first base of the donor splice site of intron IV. This substitution should perturb mRNA splicing, resulting in an altered protein product which should be unstable or bioinactive. This transversion also destroys an HphI site, which was used to assay samples from relatives. Digestion of PCR amplification products with HphI demonstrated cosegregation of the G-->C transversion with IGHD. These results demonstrate that familial IGHD is a heterogeneous disease that perturbs different steps in the expression of the GH1 gene.

Long-term patterns in seasonality of insulin-dependent diabetes mellitus diagnosis in Austrian children.

The analysis of the seasonal pattern of incidence of childhood insulin-dependent diabetes mellitus in Austria was carried out among cases where the child was under the age of 15 when diagnosed between 1979 and 1993. The cases are registered in the nationwide population-based Austrian insulin-dependent diabetes mellitus registry. Seasonal variation was compared between boys and girls and between three 5-year age groups. We also tested whether the seasonal pattern changed over the 15-year observation period. We found a significant seasonal variation among boys aged 10-14 and girls aged 5-14, while in the 0-4 years age group no seasonal pattern could be demonstrated. Two peaks in incidence were identified during a calendar year (February-March and September-October) for girls aged 5-14. For boys aged 10-14, a yearly cycle was found with a peak in January and October. An extension of the Poisson regression model for testing seasonality by Jones et al. was developed to allow for estimation of a time-dependent amplitude of the seasonal component. The annual incidence rate increased by 36% during the observation period, but no significant change in seasonal pattern could be demonstrated.

Significant association of strictures and internal fistula formation in Crohn's disease.

Intestinal inflammation in Crohn's disease (CD) may be complicated by the occurrence of strictures and fistulae. The pathogenesis of fistula formation is unknown. We therefore wanted to determine whether mechanical factors might contribute to the development of fistulae. Furthermore, we tried to define the path of internal fistulae through the muscular layer. For this purpose, surgical resection specimens from 42 consecutive patients with CD were prospectively studied. In gross examination the whole bowel was cut into circumferential cross sections 0.3 cm thick. Abnormal areas were histologically examined. Strictures were found in 38 patients (90.5%), and fistulae were observed in 27 (64.3%) patients. In 11 (40.7%) specimens fistulae were found within a stricture, in 15 (55.6%) at the proximal end, and in 1 (3.7%) no stricture was found. In 7 (25.9%) cases with fistulae, herniated mucosa was found within the muscularis propria or the subserosa. In 7 (25.9%) cases a blood vessel was identified near a fistula traversing the muscularis propria. From these findings we conclude that that mechanical factors may contribute to fistula formation. This is further supported by the fact that fistulae appear to traverse the muscular layer along piercing vessels.