[A 31-year-old pregnant woman with refractory hypercalcemia]. / 31-jährige Schwangere mit refraktärer Hyperkalzämie.

A 31-year-old pregnant woman presented with refractory severe hypercalcemia due to an advanced neuroendocrine tumor masquerading as hyperemesis gravidarum. Octreotide therapy and extensive tumor debulking surgery resulted in symptom control. After a prolonged stay in the intensive care unit due to parapneumonic acute respiratory distress syndrome, the patient delivered a healthy child. Neuroendocrine tumors are a rare complication of pregnancy and a seldom cause of refractory hypercalcemia.

C-11 methionine positron emission tomography/computed tomography localizes parathyroid adenomas in primary hyperparathyroidism.

In patients with primary hyperparathyroidism (pHPT), positive preoperative localization studies enable to perform a minimally invasive approach for parathyroid surgery. However, current imaging techniques are not always successful. We therefore conducted a study to determine the sensitivity of C-11 methionine positron emission tomography/computed tomography (Met-PET/CT) in localizing parathyroid adenomas in pHPT. Met-PET/CT scans of the neck and mediastinum of 33 patients undergoing parathyroidectomy for primary HPT were compared with intraoperative and histological findings. Primary HPT was caused by a single gland adenoma in 30 patients, while another 3 patients had multiglandular disease. Met-PET/CT scan correctly located a single gland adenoma in 25 out of 30 (83%) patients with pHPT, among them 2 patients with persistent disease, 7 patients with prior neck surgery, and 8 patients with concomitant thyroid nodules. In 3 patients with multiglandular disease, Met-PET/CT showed only one enlarged parathyroid gland in two individuals and was negative in the third patient. Statistical analysis found a significant correlation between true-positive results and the weight (2.42+/-4.05 g) and diameter (2.0+/-1.18 cm) of parathyroid adenomas while the subgroup with false negative findings had significantly smaller (0.98+/-0.54 cm) and lighter (0.5+/-0.38 g) glands. Sensitivity was 83% for single gland adenomas and 67% for multiglandular disease. Met-PET/CT correctly localized 83% of single gland parathyroid adenomas in patients with pHPT. However, preoperative localization of multiglandular disease due to double adenomas or parathyroid hyperplasia remained difficult.

Association between asymmetric dimethylarginine and neopterin in patients with and without angiographic coronary artery disease.

The increase of circulating asymmetric dimethylarginine (ADMA) concentrations, a competitive inhibitor of the nitric oxide synthases, is associated with an increased cardiovascular risk and is considered to play a role in endothelial dysfunction. Recently, ADMA production was observed in stimulated human peripheral mononuclear cells. In this study, we examined a potential relationship between concentrations of ADMA and of the immune activation marker neopterin in patients scheduled for coronary angiography. In a cross-sectional approach, blood concentrations of ADMA, homocysteine, neopterin, folic acid and vitamins B6 and B12 were compared in 2030 patients, which were recruited as participants of the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. ADMA concentrations did not differ between patients with coronary artery disease (CAD) (mean +/- SD: 0.82 +/- 0.15 micromol/l) and controls (0.81 +/- 0.14 micromol/l; Welch's t-test: P = n.s.). ADMA concentrations correlated with homocysteine (r(s) = 0.207) and vitamin B6 (r(s) = -0.190), and an even stronger correlation with neopterin (r(s) = 0.276; all P < 0.0001) was observed. In conclusion, increased ADMA concentrations in patients at risk for atherosclerosis are associated with increased neopterin concentrations. Data suggest that immune activation may contribute to increased ADMA production in CAD patients.

MHC-environment interactions leading to type 1 diabetes: feasibility of an analysis of HLA DR-DQ alleles in relation to manifestation periods and dates of birth.

AIM: The region on chromosome 6p21 (IDDM1) confers the largest part of genetic susceptibility to type 1 diabetes (T1D) with particular human leucocyte antigen (HLA) alleles predisposing and others protecting from it. As T1D is primarily a "sporadic" disease, the pathophysiology must involve gene-environment interactions. We searched for indirect evidence for such major histocompatibility complex (MHC)-environment interactions by asking two questions: (i) can the degree of an HLA association vary over time periods? and (ii) if a prenatal event like an intrauterine infection - that might cluster in seasons - leads to differences of HLA associations in patients with particular birth months? METHODS: We screened the Type 1 Diabetes Genetics Consortium (T1DGC) database (in addition our own database and the original UK, US and SCAND databases) for MHC DR-DQ and CTLA4 associations. First, we separated the groups of patients with onset of disease before 1980 in comparison with onset after 1980. Second, we analysed the data according to dates of birth (grouped in months). Not all patients' dates of birth or manifestation periods were available, leading to different group sizes. There were 282 patients analysed for manifestation periods and 329 for birth month. RESULTS: The cohorts of manifestation before 1980 demonstrated a significantly lower frequency of DQ2/X (2 vs. 14.2%; p = 0.03). There was a trend for DQ8/x to be more frequent for manifestations before 1980 (34 vs. 21.6%; p < 0.10). Other alleles did not differ significantly. The months of birth were not evenly distributed. Significant deviations from the whole group were seen in August (DQ2/8 trough and DQx/x high), whereas birth in September was more frequent in DQ8/x or DQ8/8 carriers. This pattern was significantly different from the expected distribution of months at birth (13.9 vs. 7.6%; p < 0.04). CONCLUSIONS: We demonstrate the feasibility of an analysis that searches for indirect evidence of gene-environment interactions. These preliminary data need to be confirmed in larger data sets.

[82-year old patient with hyperostosis frontalis, prognathism, makroglossia and cutis gyrata. Acromegaly]. / 82-jährige Patientin mit Hyperostosis frontalis, Prognathie, Makroglossie und Cutis gyrata. Akromegalie.

We present a 82 year old female patient with typical acral enlargement. There were no signs of visceromegaly. Magnetic resonance imaging of the pituitary region showed a macroadenoma. Oral glucose tolerance test revealed missing suppression of the Human Growth Hormone (HGH), which could be achieved with a long acting somatostatin analog. A HGH suppressive therapy with a long acting dopamine agonist (Cabergolin) was induced. The patient died one year later following cardiovascular complications.

Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation.

Specific point mutations of the RET proto-oncogene have been demonstrated to be responsible for multiple endocrine neoplasia (MEN) types 2A and 2B, for familial medullary thyroid carcinoma (MTC) syndromes, as well as for sporadic MTC. Here we show that nuclear factor (NF)-kappaB is activated in RET-associated C-cell carcinoma specimens. TT cells, a human MTC cell line expressing MEN 2A type RET, display transcriptionally active RelA(p65) in the nucleus. NF-kappaB activity in these cells is attributable to constitutive IkappaB kinase (IKK) activity and high turn over of IkappaBalpha. RET harboring the mutations C634R (MEN 2A) or M918T (MEN 2B), in contrast to wild-type RET, activates a NF-kappaB-dependent reporter construct upon transient transfection in HeLa cells. We show that the prototype RET mutation C634R enhances phosphorylation of IkappaBalpha by IKKbeta but not by IKKalpha. RET-induced NF-kappaB and IKKbeta activity requires Ras function but does neither involve the classical mitogen-activated protein kinase kinase/extracellular signal-regulated kinase nor the phosphoinositide 3-kinase/Akt pathways. In contrast, RET-induced NF-kappaB activity is dependent on Raf and MEKK1. Inhibition of constitutive NF-kappaB activity results in cell death of TT cells and blocks focus formation induced by oncogenic forms of RET in NIH 3T3 cells. These results suggest that RET-mediated carcinogenesis critically depends on IKK activity and subsequent NF-kappaB activation.

[Clinical and biochemical diagnosis of pHPT and sHPT, surgical indications from the internal medicine viewpoint]. / Klinische und biochemische Diagnostik des pHPT und sHPT, Operationsindikation aus internistischer Sicht.

Hypercalcemia and a relative nonsuppressibility of parathyroid hormone by calcium are the biochemical hallmarks of primary hyperparathyroidism. An elevated PTH level should be defined in a highly sensitive and specific test system. Primary HPT is the single major cause of hypercalcemia in outpatients. A definitive medical option to manage PHP does not exist. Surgical neck exploration by an experienced surgeon has a very high success rate for cure in both symptomatic and asymptomatic disease forms. Secondary HPT is mostly due to renal failure. Nonsuppressibility of PTH by use of vitamin D sterols indicates parathyroid gland hyperplasia and autonomy of PTH secretion. Surgery should correct PTH excess and should lead to an optimal bone status.

Increase of bone mineral density with sodium fluoride in patients with Crohn's disease.

BACKGROUND AND AIMS: Low bone density with an increased risk of vertebral fractures is a frequent complication in inflammatory bowel disease. Since the aetiology of osteopathia in these patients is different compared to postmenopausal or steroid-induced osteoporosis, no treatment strategy is established. Supplementation of calcium and vitamin D has been shown to prevent further bone loss, but no data are available showing the anabolic effect of sodium fluoride in Crohn's disease. METHODS: We carried out a one-year prospective clinical trial in 33 patients with chronic active Crohn's disease who were randomly assigned to receive either calcium (500 mg b.i.d.) and 1000 IU vitamin D3 only, or retarded-release sodium fluoride (25 mg t.i.d.) additionally. The diagnosis of Crohn's disease had been made at least two years ago, and all patients had received systemic high-dose steroid therapy during the previous year. Eleven of 15 patients who received calcium/vitamin D and 15 of 18 patients who additionally received sodium fluoride completed the study. The primary endpoint of the study was the increase of bone mineral density, measured by dual energy X-ray absorptiometry (DXA) after one year of treatment. Bone-specific alkaline phosphatase and osteocalcin were used as markers for bone turnover. RESULTS: In the calcium/vitamin D only group, bone density was not significantly changed after one year of treatment, whereas in the calcium/vitamin D/fluoride group, bone density of the lumbar spine increased from -1.39+/-0.3 (Z-score, mean +/- SEM) to -0.65+/-0.3 (P<0.05) after one year of treatment. Increase of bone density was positively correlated to the osteoblastic markers bone-specific alkaline phosphatase (r = 0.53) and osteocalcin (r = 0.43). CONCLUSIONS: Sodium fluoride in combination with vitamin D and calcium is an effective, well-tolerated and inexpensive treatment to increase lumbar bone density in patients with chronic active Crohn's disease and osteoporosis.

Epitope spreading and a varying but not disease-specific GAD65 antibody response in Type I diabetes. The Childhood Diabetes in Finland Study Group.

AIMS/HYPOTHESIS: The aim of this study was to analyse the conformational and linear epitope profiles of glutamic acid decarboxylase antibody (GAD65-ab)-positive sera to find disease-specific epitope profiles and to study, whether GAD65-ab epitope recognition changes or spreads during the prediabetic period and, thus, can provide markers to differentiate early from later stages of progression to diabetes. METHODS: Sera from subjects before (n = 21), at onset (n = 44), or at increased risk of Type I (insulin-dependent) diabetes mellitus (n = 20) and from patients with stiff-man syndrome (SMS, n = 18) or polyendocrine autoimmune syndrome (PAS, n = 21) were analysed for conformational and linear GAD65 epitope recognition by an immunohistochemical blocking test based on human monoclonal GAD65-ab (MICA 1-10) and western blotting of a GAD65 epitope-cDNA-library. RESULTS: A redundant reactivity of many GAD65-ab positive sera to three major conformational (EP-1, EP-2, EP-3) and two dominant linear epitope clusters (amino acid 1-124 and 535-585) was observed in diabetes, polyendocrine autoimmune syndrome and stiff-man syndrome and no disease-specific epitopes or epitope-profiles were detected. Epitope recognition broadened with higher titres and with the vulnerability of patients to acquire additional autoimmune diseases apart from diabetes. Low GAD65-ab serum titres (< 1200 arbitrary units) and EP-1 recognition in the absence of EP-2 binding characterised the early immune response. Changing epitope profiles combined stable recognition of EP-1 with gain or loss of reactivity to C-terminal epitopes during follow-up. CONCLUSION/INTERPRETATION: A maturing autoantibody response, which could spread from EP-1-recognition to other regions of GAD65, resulted in titre-related rather than disease-specific epitope profiles which were not sufficient to predict whether GAD65-ab positive subjects will progress to Type I diabetes, autoimmune polyendocrine syndrome or stiff-man syndrome.

[Decreased serum level of free bioavailable IGF-I in patients with diabetic retinopathy]. / Verminderte Serumspiegel von freiem bioverfügbarem IGF-I bei Patienten mit diabetischer Retinopathie.

BACKGROUND: Growth factors like IGF-I have been implicated in the pathogenesis of diabetic retinopathy. To investigate the role and bioavailability of IGF-I we measured not only total but also free serum levels of IGF-I in diabetic patients. METHODS: A total of 159 patients with and without diabetic retinopathy were investigated (60 diabetic patients without and 99 with clinically and angiographically diagnosed diabetic retinopathy). One hundred ten healthy volunteers served as controls. The data were analyzed by Student's t-test, analysis of variance and correlation; P < 0.05 was considered statistically significant. RESULTS: Diabetic patients with retinopathy showed significantly lower serum levels of free IGF-I than diabetics without retinopathy. Free IGF-I was negatively correlated with glycosylated hemoglobin 1c. IGFBP-3 levels were diminished in type 2 patients with diabetic retinopathy, while type 1 patients with diabetic retinopathy showed higher IGFBP-1 levels. CONCLUSION: Diabetic patients with retinopathy showed significantly reduced serum levels of free IGF-I. Low IGF-I was associated with poor metabolic control.

[Augmentation of the immune response to islet cell antigens with development of diabetes mellitus caused by interferon-alpha therapy in chronic hepatitis C]. / Augmentation der Immunantwort gegen Inselzellantigene mit Diabetesentwicklung durch Interferon-alpha-Therapie bei chronischer Hepatitis C.

We report on a 36-year-old patient suffering from chronic hepatitis C. Because of elevated liver enzymes and histology showing chronic inflammation and periportal fibrosis, interferon-alpha (IFN) therapy was started with a dosage of 5 Mio units three times a week. Four months later the patient hat to be hospitalized due to the typical clinical features of a recent onset type 1 diabetes (BG > 300 mg/dl, HbA1c 9.6%, ketonuria). In serum samples prior to and following interferon therapy, we analyzed titers of diabetes-related autoantibodies responding to GAD65 (glutamic acid decarboxylase), IA2c (tyrosine phosphatase) and ICA (islet cell autoantibodies). While ICA were negative before starting therapy, IA2c-antibodies were highly elevated. In contrast. GAD65-antibodies were elevated only slightly over the cut-off of the assay before therapy (controlled by a second different RIA assay) and increased 100 fold during IFN-alpha treatment. Additionally thyroid antibodies appeared. After the end of the IFN therapy, GAD65- and IA2c antibodies remained on high levels and also ICA could now be found. The patient was positive for HLA-DR4. This case supports the hypothesis that IFN-alpha therapy may lead to an augmented autoimmune reaction against islet cell antigens resulting in the development of diabetes mellitus type 1, especially if there are other predisposing factors before IFN treatment. We further discuss the possible involvement of interferon-alpha in the pathogenesis of autoimmune diabetes with reference to recent studies.

Angiotensinogen M235T polymorphism is associated with plasma angiotensinogen and cardiovascular disease.

BACKGROUND: Genes encoding components of the renin-angiotensin system have been associated with elevated blood pressure (BP) and an increased risk of coronary artery disease. To explore the role of the angiotensinogen (AGT) gene in coronary atherosclerosis and thrombosis, we studied the effect of the AGT M235T gene variant on plasma AGT levels and BP in patients with coronary artery disease and in the subgroup of survivors of myocardial infarction as compared with angiographically defined control subjects. METHODS AND RESULTS: This was a case-control study of 301 white male subjects examined at Frankfurt University medical center. Plasma AGT levels increased stepwise according to the number of T235 alleles present (no T235 allele, 14.8 +/- 3.9 nmol/L; 1 allele, 15.7 +/- 5.1 nmol/L; 2 alleles, 17.3 +/- 4.7 nmol/L; P =.006). In a multivariate model, circulating AGT emerged as the most important predictor of diastolic pressure (P =.001). In addition, AGT M235T gene polymorphism remained a significant predictor of diastolic BP in a multivariate model adjusted for age, body mass index, fasting glucose, apolipoprotein B, presence of coronary artery disease, and treatment with antihypertensive agents ( P <.05). Finally, homozygosity for T235 was associated with increased univariate risk of coronary artery disease and myocardial infarction (odds ratio estimates 1.5; 95% confidence intervals 1.1 to 2.1, P =.03, and 1.0 to 2.1, P =.05, respectively). CONCLUSIONS: The significant relations observed between the AGT M235T variant, its protein product, and the cardiovascular disease phenotypes provide evidence for a possible role of elevated circulating AGT in the pathogenesis of coronary artery disease.

[Pathological bone density in chronic inflammatory bowel diseases--prevalence and risk factors]. / Pathologische Knochendichte bei chronischentzündlichen Darmerkrankungen--Prävalenz und Risikofaktoren.

INTRODUCTION: Osteopenia and osteoporosis are frequent but often underestimated complications in inflammatory bowel disease. In patients with IBD, several factors could contribute to osteopenia, but the pathogenetic mechanisms are still not completely understood. We carried out a prospective study to evaluate the prevalence and possible etiologic factors for osteopenia and subsequent osteoporosis in IBD-patients. METHODS: 140 patients with inflammatory bowel disease (Crohn's disease n = 125, ulcerative colitis n = 15) underwent clinical and spine radiological assessments. Lumbar bone mineral densities were measured by dual energy X-ray absorptiometry (DXA). Markers of bone formation and resorption and vitamin D were assessed in n = 95 patients. Patients were asked about medication, previous or actual intestinal stenosis, smoking and intestinal resection. A lactose-H2-breath test was undertaken if lactose intolerance was clinically suspected. RESULTS: Compared to age- and sex-matched healthy controls (Z-score), the prevalence of osteopenia (Z < -1) was 62%, while osteoporosis (Z < -2) occurred in 38%. The mean bone density of IBD-patients was osteopenic with no significant differences between Crohn's disease (Z = -1.24) and ulcerative colitis (Z = -1.25). Osteoporotic fractures were seen in three patients (2.1%). Crohn's disease patients with osteoporosis showed a significant lower body mass index (BMI) than patients with normal bone density. 52.9% of patients with manifest osteoporosis underwent systemic steroid treatment in the preceding year, but only 34% of those with normal bone density. Except hemoglobin, none of the biochemical markers showed a significant difference between osteoporosis, osteopenia and patients with normal bone density. CONCLUSION: The results show a high prevalence of osteopenia and osteoporosis in IBD. Since osteoporosis is often associated with low body mass index, multiple intestinal resections and previous systemic steroid treatment, we suggest a bone densitometry in these patients. Since etiology of osteoporosis in IBD is multifactorious and not completely understood, there is still no standard treatment. The effect of osteoanabolic and antiresorptive agents must be evaluated in further studies.

Serum levels of insulin-like growth factor system components and relationship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients.

Osteopenia has been ascribed to diabetics without residual insulin secretion and high insulin requirement. However, it is not known if this is partially due to disturbances in the IGF system, which is a key regulator of bone cell function. To address this question, we performed a cross-sectional study measuring serum levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, IGFBP-4 and IGFBP-5 by specific immunoassays in 52 adults with Type 1 (n=27) and Type 2 (n=25) diabetes mellitus and 100 age- and sex-matched healthy blood donors. In the diabetic patients, we further determined serum levels of proinsulin, intact parathyroid hormone (PTH), 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3 and several biochemical bone markers, including osteocalcin (OSC), bone alkaline phosphatase (B-ALP), carboxy-terminal propeptide of type I procollagen (PICP), and type I collagen cross-linked carboxy-terminal telopeptide (ICTP). Urinary albumin excretion was ascertained as a marker of diabetic nephropathy. Bone mineral density (BMD) of hip and lumbar spine was determined by dual-energy X-ray absorptiometry. Data are presented as means+/-s.e.m. Differences between the experimental groups were determined by performing a one-way analysis of variance (ANOVA), followed by Newman-Keuls test. Correlations between variables were assessed using univariate linear regression analysis and partial correlation analysis. Type 1 diabetics showed significantly lower IGF-I (119+/-8 ng/ml) and IGFBP-3 (2590+/-104 ng/ml) but higher IGFBP-1 levels (38+/-10 ng/ml) compared with Type 2 patients (170+/-13, 2910+/-118, 11+/-3 respectively; P<0.05) or healthy controls (169+/-5, 4620+/-192, 3.5+/-0.4 respectively; P<0.01). IGFBP-5 levels were markedly lower in both diabetic groups (Type 1, 228+/-9; Type 2, 242+/-11 ng/ml) than in controls (460+/-7 ng/ml,P<0. 01), whereas IGFBP-4 levels were similar in diabetics and controls. IGF-I correlated positively with IGFBP-3 and IGFBP-5 and negatively with IGFBP-1 and IGFBP-4 in all subjects. Type 1 patients showed a lower BMD of hip (83+/-2 %, Z-score) and lumbar spine (93+/-2 %) than Type 2 diabetics (93+/-5 %, 101+/-5 % respectively), reaching significance in the female subgroups (P<0.05). In Type 1 patients, BMD of hip correlated negatively with IGFBP-1 (r=-0.34, P<0.05) and IGFBP-4 (r=-0.3, P<0.05) but positively with IGFBP-5 (r=0.37, P<0. 05), which was independent of age, diabetes duration, height, weight and body mass index, as assessed by partial correlation analysis. Furthermore, biochemical markers indicating bone loss (ICTP) and increased bone turnover (PTH, OSC) correlated positively with IGFBP-1 and IGFBP-4 but negatively with IGF-I, IGFBP-3 and IGFBP-5, while the opposite was observed with bone formation markers (PICP, B-ALP) and vitamin D3 metabolites. In 20 Type 2 patients in whom immunoreactive proinsulin could be detected, significant positive correlations were found between proinsulin and BMD of hip (r=0.63, P<0.005), IGF-I (r=0.59, P<0.01) as well as IGFBP-3 (r=0.49, P<0.05). Type 1 and Type 2 patients with macroalbuminuria showed a lower BMD of hip, lower IGFBP-5 but higher IGFBP-4 levels, suggesting that diabetic nephropathy may contribute to bone loss by a disturbed IGF system. In conclusion, the findings of this study support the hypothesis that the imbalance between individual IGF system components and the lack of endogenous proinsulin may contribute to the lower BMD in Type 1 diabetics.

Identification of HLA-DR and -DQ alleles conferring susceptibility to pollen allergy and pollen associated food allergy.

BACKGROUND: Allergenic crossreactivity of pollen and foods due to the antigeneic similarity of oligopeptides is a well established clinical phenomenon. OBJECTIVE: To determine the immunopathological relevance of antigen presentation, we analysed the HLA class-II genotype of patients with either pollen allergy or pollen associated food allergy. METHODS: One hundred and twenty patients with pollen allergy and 80 patients with pollen associated food allergy were evaluated by skin- prick tests, RAST, and HLA class-II genotyping. The control population comprised 4251 healthy blood and bone marrow donors. RESULTS: Monovalent pollen allergy was observed in 57% (n=68) of patients with pollinosis (57x grass pollen, 11x birch pollen), but only in 15% (n=12) of patients with food allergy (9x grass pollen, 3x birch pollen). Hazelnut (71%), almond (65%), walnut (44%) and apple (41%) were the most common food allergens and frequently associated with birch pollen allergy. Grass pollen allergy was associated with an increased frequency of HLA-DQB1*0301 (RR=2.3; EF=0.4; P=0.0016) when compared with the control population. HLA-DRB *08 conferred a sixfold higher risk for peanut allergy (EF=0.3; P=0.0013) and -DRB1*12 a 13-fold higher risk for carrot allergy (EF=0.3; P<0.000001). The differences on allele frequencies detected among patients with food allergies diminished or turned statistically insignificant when their genotypes were directly compared to those of patients with the corresponding pollen allergies. This was found in the case of birch pollen associated hazel nut allergy for the extended haplotype HLA-DRB1*01, -DQA1*0101, -DQB1*0501 as well as in grass pollen associated peanut allergy for HLA-DRB1*08 (from RR=6, P=0.0013 to insignificant) and in birch pollen associated carrot allergy for HLA-DRB1*12 (from RR=13, P < 0.000001 to insignificant). CONCLUSION: We were able to identify HLA class-II alleles associated with some allergies thus indicating that these alleles might confer susceptibility to the respective allergens. Similarities at the level of the HLA class-II genotype parallel the empirical finding of distinct cross-reactivity patterns thus complementing investigations of IgE specificities. Our observations provide evidence for the major importance of antigen presentation on the manifestation of distinct crossreactivity patterns.

Combined analysis and single-step detection of GAD65 and IA2 autoantibodies in IDDM can replace the histochemical islet cell antibody test.

Cytoplasmic islet cell antibodies (ICAs) are the classical serological markers for diagnosis and prediction of IDDM, but high technical demands have limited the widespread use of the histochemical ICA test. To investigate whether combined analysis of autoantibodies to two defined islet antigens can replace the histochemical ICA test, we established quantitative radioimmunoassays for autoantibodies to glutamate decarboxylase (GAD65-A), the tyrosine phosphatase IA2/ICA512 (IA2-A), and the cytoplasmic part of IA2 (IA2c-A). The GAD65-A and IA2c-A profiles of 920 sera from healthy individuals and from patients with IDDM, other organ-specific autoimmune diseases, and polyendocrine autoimmune syndrome were compared with the ICA profiles from these same individuals. Combined analysis of GAD65-A and IA2c-A detected 93-100% of the ICA+ sera, and, at equal specificity, improved the diagnostic sensitivity (85%) for IDDM compared with that of ICA (74%). This effect was especially pronounced in children with disease onset before 16 years of age (91% sensitivity). To replace ICA testing in risk assessment for IDDM, we designed a strategy adapted to study groups with low antibody prevalence. A combined radioimmunoassay for single-step detection of GAD65-A and IA2c-A was developed, and positive sera were reanalyzed to define their single autoantibody specificity. We identified 93% of the ICA+ sera from 204 first-degree relatives of IDDM patients. Single-step detection reduced costs and effort by more than 40% compared with separate testing, allowing an efficient large-scale screening of sera for GAD65-A and IA2c-A in IDDM. In sum, GAD65-A and IA2c-A detected much ICA reactivity, and their combined evaluation and detection is suitable to replace the histochemical ICA test.

Alopecia areata but not androgenetic alopecia is characterized by a restricted and oligoclonal T-cell receptor-repertoire among infiltrating lymphocytes.

Although the etiology of alopecia areata is still unknown, evidence has accumulated to support an autoimmune pathogenesis for this disease. To evaluate the role of T cells in alopecia areata the T-cell receptor VB-repertoire was investigated in lesional skin and blood of 5 patients by means of a semiquantitative technique based on the reverse transcriptase polymerase chain reaction. Three patients with androgenetic alopecia served as controls. Amplification products were screened for clonality by temperature gradient gel electrophoresis. Four of 5 patients with alopecia areata exhibited a lesional T-cell receptor-repertoire characterized by an almost exclusive utilization of variable regions beta 2, 4, and 13. Temperature gradient gel electrophoresis revealed the oligoclonal constitution of the infiltrate. The restricted nature of the lesional T-lymphocytic infiltrate in alopecia areata strongly suggests that an antigen-specific T-cell response plays an important role in the pathogenesis of this disease.

[Results of pan-retinal argon laser coagulation in proliferative diabetic retinopathy]. / Ergebnisse nach panretinaler Argonlaserkoagulation bei proliferativer diabetischer Retinopathie.

To minimize the risk of visual loss and to stop the progression of diabetic retinopathy argon laser treatment is the therapy of choice in proliferative diabetic retinopathy (PDR). The results after panretinal argon laser coagulation (ALC) were studied retrospectively considering visual outcome and frequencies of diabetic ocular complications. In all 95 patients were included in whom laser treatment had been performed due to clinically and angiographically diagnosed proliferative diabetic retinopathy at the Department of Ophthalmology between 1990 and 1994 with a follow-up of at least 1 year. The most frequent diabetic complications observed were vitreous haemorrhage in 9 (or 9.5%) and iris neovascularization in 10 cases (or 10.5%). Rare complications were neovascular glaucoma in 3 patients (or 3.2%) and tractional retinal detachment in 4 patients (or 4.2%). Nearly 70% of the patients maintained or improved visual acuity after laser treatment. The frequency of diabetic complications of PDR after ALC was significantly associated with older age, diabetes type II, longer duration of diabetes and elevated blood pressure.