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Objective: To evaluate the treatment effects of long-term growth hormone (GH) replacement therapy in adults with GH deficiency (GHD) who were followed in KIMS Germany (Pfizer International Metabolic Database), a national surveillance study., Design: The analysis was performed using baseline and long-term data (range: 4-10 years) of 440 consecutively documented patients (216 women and 224 men) with GHD, aged 20 to 49 years, enrolled in KIMS Germany. Serum insulin-like growth factor I (IGF-I), fasting blood glucose, fasting serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) as well as body mass index (BMI), waist circumference (WC) and hip circumference (HC) at baseline and at last visit were studied. Furthermore, QoL-AGHDA score was determined to assess quality-of-life (QoL)., Results: The mean dose of GH over all years was 0.41 mg per day in women and 0.37 mg per day in men. IGF-I and IGF-I SDS levels (standard deviation score) increased significantly (p<0.001) during GH treatment. The QoL-AGHDA score decreased significantly (p<0.001), indicating long-lasting improvement in QoL. In total cholesterol, LDL-C and fasting blood glucose, no significant changes were found. Only six patients developed type 2 diabetes during follow-up. Females and males similarly increased significantly in BMI, WC and HC. During GH treatment, recurrences of pituitary or central nervous system tumours or further de novo neoplasia were reported in 6 or 11 patients, respectively. The number of the most frequently reported GH treatment-associated adverse events was low., Conclusion: These observational data show long-term beneficial effects of GH replacement therapy on QoL and show no significant effects on total cholesterol, LDL-C or BMI, WC and HC. Additionally, our data indicate that GH replacement therapy in adults is well tolerated., (Copyright © 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.)

Objective: IGF1 is associated with metabolic parameters and involved in glucose metabolism. Low-IGF1 has been implicated in the etiology of glucose intolerance and subjects with pathological causes of either low- or high-IGF1 are at risk of diabetes. We hypothesized that both low- and high-IGF1 levels increase the risk of diabetes and aimed to assess the role of IGF1 in the risk of developing diabetes in a large prospective study., Design: An analysis of two prospective cohort studies, the DETECT study and SHIP., Methods: We measured IGF1 levels in 7777 nondiabetic subjects and assessed incident diabetes mellitus during follow-up., Results: There were 464 cases of incident diabetes during 32 229 person-years (time of follow-up in the DETECT study and SHIP: 4.5 and 5 years respectively). There was no heterogeneity between both studies (P > 0.4). The hazard ratios (HRs) of incident diabetes in subjects with IGF1 levels below the 10th or above the 90th age- and sex-specific percentile, compared to subjects with intermediate IGF1 levels, were 1.44 (95% confidence interval (CI) 1.07-1.94) and 1.55 (95% CI 1.06-2.06) respectively, after multiple adjustment. After further adjustment for metabolic parameters, the HR for low-IGF1 became insignificant. Analysis of IGF1 quintiles revealed a U-shaped association of IGF1 with risk of diabetes. Results remained similar after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline., Conclusions: Subjects with low- or high-IGF1 level are at increased risk of developing diabetes.

Background: Chronic kidney disease (CKD) and low serum total testosterone (TT) concentrations are independent predictors of mortality risk in the general population, but their combined potential for improved mortality risk stratification is unknown., Methods: We used data of 1,822 men from the population-based Study of Health in Pomerania followed- up for 9.9 years (median). The direct effects of kidney dysfunction (estimated glomerular filtration rate <60 ml/min/ 1.73 m(2)), albuminuria (urinary albumin-creatinine ratio ≥2.5 mg/mmol) and their combination (CKD) on all-cause and cardiovascular mortality were analyzed using multivariable Cox regression models. Serum TT concentrations below the age-specific 10th percentile (by decades) were considered low and were used for further risk stratification., Results: Kidney dysfunction (hazard ratio, HR, 1.40; 95% confidence interval, CI, 1.02-1.92), albuminuria (HR, 1.38; 95% CI, 1.06-1.79), and CKD (HR, 1.42; 95% CI, 1.09-1.84) were associated with increased all-cause mortality risk, while only kidney dysfunction (HR, 2.01; 95% CI, 1.21-3.34) was associated with increased cardiovascular mortality risk after multivariable adjustment. Men with kidney dysfunction and low TT concentrations were identified as high-risk individuals showing a more than 2-fold increased all-cause mortality risk (HR, 2.52; 95% CI, 1.08-5.85). Added to multivariable models, nonsignificant interaction terms suggest that kidney dysfunction and low TT are primarily additive rather than synergistic mortality risk factors., Conclusion: In the case of early loss of kidney function, measured TT concentrations might help to detect high-risk individuals for potential therapeutic interventions and to improve mortality risk assessment and outcome., (Copyright © 2011 S. Karger AG, Basel.)

Background: Insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) are central mediators of endocrine effects of growth hormone and there is increasing evidence for an association with muscle strength and exercise capacity. The aim of the present study was to clarify the possible association of circulating IGF-I and IGFBP-3 concentrations and exercise capacity in a general adult population., Materials and Methods: From the Study of Health in Pomerania (SHIP) 1332 subjects aged 25 to 85 years participated in a standardised symptom limited cardiopulmonary exercise test on a bicycle. Exercise capacity was characterized by oxygen uptake at anaerobic threshold (VO₂@AT), peak exercise (peakVO₂), oxygen pulse and maximum power output at peak exertion. Multivariable linear regression analyses adjusted for age, sex, body mass index, physical activity and smoking were performed., Results: At peak exercise performance, in women IGF-I showed significant associations to peakVO₂ and maximum power output, IGF-I/IGFBP-3 ratio was associated with maximum power output. In men, this association was not consistently reproducible. Neither IGF-I nor IGFBP-3 did reveal any association to VO₂@AT in both genders., Conclusion: Serum IGF-I concentrations are associated with peak exercise capacity in healthy women, but not in men over a wide range in ages, body sizes and activity scores., (Copyright © 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.)

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Objective: IGF1 mediates multiple physiological and pathophysiological responses in the cardiovascular system. The aim of this study was to analyze the association between serum IGF1 as well as IGF-binding protein 3 (IGFBP3) levels and endothelial function measured by flow-mediated dilation (FMD)., Design: Cross-sectional population-based observational study., Methods: The study population comprised 1482 subjects (736 women) aged 25-85 years from the Study of Health in Pomerania. Serum IGF1 and IGFBP3 levels were determined by chemiluminescence immunoassays. FMD measurements were performed using standardized ultrasound techniques. FMD values below the sex-specific median were considered low., Results: In males, logistic regression analyses revealed an odds ratio (OR) of 1.27 (95% confidence interval (CI) 1.07-1.51; P=0.008) for decreased FMD for each decrement of IGF1 s.d. after adjustment for major cardiovascular confounders. In females, no significant relationship between serum IGF1 and FMD was found (OR 0.88, CI 0.74-1.05; P=0.147). After exclusion of subjects with the current use of antihypertensive medication, these findings were similar (males: OR 1.40, CI 1.12-1.75; P=0.003; females: OR 0.95, CI 0.77-1.16; P=0.595). There was no association between serum IGFBP3 levels and FMD in both sexes., Conclusions: Low serum IGF1 levels are associated with impaired endothelial function in males. In women, serum IGF1 is not associated with endothelial function.

Background: Studies from iodine-sufficient areas have shown that a high proportion of patients taking medication for thyroid diseases have thyroid stimulating hormone (TSH) levels outside the reference range. Next to patient compliance, inadequate dosing adjustment resulting in under- and over-treatment of thyroid disease is a major cause of poor therapy outcomes. Using thyroid function tests, we aim to measure the proportions of subjects, who are under- or over-treated with thyroid medication in a previously iodine-deficient area., Findings: Data from 266 subjects participating in the population-based Study of Health in Pomerania (SHIP) were analysed. All subjects were taking thyroid medication. Serum TSH levels were measured using immunochemiluminescent procedures. TSH levels of < 0.27 or > 2.15 mIU/L in subjects younger than 50 years and < 0.19 or > 2.09 mIU/L in subjects 50 years and older, were defined as decreased or elevated, according to the established reference range for the specific study area. Our analysis revealed that 56 of 190 (29.5%) subjects treated with thyroxine had TSH levels outside the reference range (10.0% elevated, 19.5% decreased). Of the 31 subjects taking antithyroid drugs, 12 (38.7%) had TSH levels outside the reference range (9.7% elevated, 29.0% decreased). These proportions were lower in the 45 subjects receiving iodine supplementation (2.2% elevated, 8.9% decreased). Among the 3,974 SHIP participants not taking thyroid medication, TSH levels outside the reference range (2.8% elevated, 5.9% decreased) were less frequent., Conclusion: In concordance with previous studies in iodine-sufficient areas, our results indicate that a considerable number of patients taking thyroid medication are either under- or over-treated. Improved monitoring of these patients' TSH levels, compared to the local reference range, is recommended.

Sialic acids are ubiquitously found on the surface of all vertebrate cells at the extremities of glycan chains and widely exploited by viruses and bacteria to enter host cells. Carbohydrate-bearing receptors are equally important for host cell invasion by the obligate intracellular protozoan parasites of the phylum Apicomplexa. Host cell entry is an active process relying crucially on proteins that engage with receptors on the host cell surface and promote adhesion and internalisation. Assembly into complexes, proteolytic processing and oligomerization are important requirements for the functionality of these adhesins. The combination of adhesive proteins with varying stringency in specificity confers some flexibility to the parasite in face of receptor heterogeneity and immune pressure. Sialic acids are now recognised to critically contribute to selective host cell recognition by various species of the phylum., (Copyright 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.)

Host cell invasion by the Apicomplexa critically relies on regulated secretion of transmembrane micronemal proteins (TM-MICs). Toxoplasma gondii possesses functionally non-redundant MIC complexes that participate in gliding motility, host cell attachment, moving junction formation, rhoptry secretion and invasion. The TM-MICs are released onto the parasite's surface as complexes capable of interacting with host cell receptors. Additionally, TgMIC2 simultaneously connects to the actomyosin system via binding to aldolase. During invasion these adhesive complexes are shed from the surface notably via intramembrane cleavage of the TM-MICs by a rhomboid protease. Some TM-MICs act as escorters and assure trafficking of the complexes to the micronemes. We have investigated the properties of TgMIC6, TgMIC8, TgMIC8.2, TgAMA1 and the new micronemal protein TgMIC16 with respect to interaction with aldolase, susceptibility to rhomboid cleavage and presence of trafficking signals. We conclude that several TM-MICs lack targeting information within their C-terminal domains, indicating that trafficking depends on yet unidentified proteins interacting with their ectodomains. Most TM-MICs serve as substrates for a rhomboid protease and some of them are able to bind to aldolase. We also show that the residues responsible for binding to aldolase are essential for TgAMA1 but dispensable for TgMIC6 function during invasion., (© 2010 Blackwell Publishing Ltd.)

There is increasing evidence that urinary albumin excretion, even when below the accepted threshold values for normal excretion, may have significant impact on future cardiovascular risks. To further define this, a total of 1086 patients, aged 45 years and older from the population-based, longitudinal 'Study of Health in Pomerania' were evaluated. Patients had echocardiographic analysis at baseline and 5-year follow-up, and were grouped into quartiles according to their baseline urinary albumin-to-creatinine ratio. At baseline, left ventricular mass in the first three quartiles was similar; however, the fourth quartile was significantly elevated and further increased over the 5-year follow-up. In the first quartile, the albumin-to-creatinine ratio and left ventricular mass did not significantly change over 5 years. In the second and third quartiles, the left ventricular mass progressively increased and was significantly correlated with the albumin-to-creatinine ratio. In multivariable analysis, this association was independent of other common cardiovascular risk factors and applicable to both genders. Our study found that the urinary albumin-to-creatinine ratio, even below the current threshold for definition of microalbuminuria, is significantly associated with increased left ventricular mass.

Obesity is a major risk factor for chronic diseases including cardiovascular disorders. Divergent associations between obesity and hormonal changes have been reported. The objective of the present study was to analyse the associations between anthropometric measurements and hormone levels including serum thyroid stimulating hormone (TSH), prolactin, insulin-like growth factor (IGF) I, and testosterone. Form the cross-sectional Study of Health in Pomerania 1 women and 1 864 men aged 20-79 years were included in the analyses. Serum TSH, prolactin, IGF-I, and testosterone levels were determined by immunochemiluminescent procedures. Body height, weight as well as waist and hip circumferences were measured. Body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were calculated. Our analyses revealed inverse linear associations of waist and hip circumferences, BMI and WHtR with serum TSH levels and linear associations between waist circumference as well as WHtR and serum prolactin levels in women. In men, inverse linear and quadratic associations between anthropometric parameters and serum IGF-I as well as serum testosterone levels were found. Additionally, men with high waist circumference had more often low serum IGF-I or testosterone levels and less often high serum IGF-I or testosterone levels compared to men with low waist circumference. These sex-specific differences should be noted in studies regarding hormones and obesity., ((c) J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart. New York.)

Context: To date, it is unclear which measure of obesity is the most appropriate for risk stratification., Objective: The aim of the study was to compare the associations of various measures of obesity with incident cardiovascular events and mortality., Design and Setting: We analyzed two German cohort studies, the DETECT study and SHIP, including primary care and general population., Participants: A total of 6355 (mean follow-up, 3.3 yr) and 4297 (mean follow-up, 8.5 yr) individuals participated in DETECT and SHIP, respectively., Interventions: We measured body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and waist-to-hip ratio (WHR) and assessed cardiovascular and all-cause mortality and the composite endpoint of incident stroke, myocardial infarction, or cardiovascular death., Results: In both studies, we found a positive association of the composite endpoint with WHtR but not with BMI. There was no heterogeneity among studies. The relative risks in the highest versus the lowest sex- and age-specific quartile of WHtR, WC, WHR, and BMI after adjustment for multiple confounders were as follows in the pooled data: cardiovascular mortality, 2.75 (95% confidence interval, 1.31-5.77), 1.74 (0.84-3.6), 1.71 (0.91-3.22), and 0.74 (0.35-1.57), respectively; all-cause mortality, 1.86 (1.25-2.76), 1.62 (1.22-2.38), 1.36 (0.93-1.69), and 0.77 (0.53-1.13), respectively; and composite endpoint, 2.16 (1.39-3.35), 1.59 (1.04-2.44), 1.49 (1.07-2.07), and 0.57 (0.37-0.89), respectively. Separate analyses of sex and age groups yielded comparable results. Receiver operating characteristics analysis yielded the highest areas under the curve for WHtR for predicting these endpoints., Conclusions: WHtR represents the best predictor of cardiovascular risk and mortality, followed by WC and WHR. Our results discourage the use of the BMI.

Numerous intracellular pathogens exploit cell surface glycoconjugates for host cell recognition and entry. Unlike bacteria and viruses, Toxoplasma gondii and other parasites of the phylum Apicomplexa actively invade host cells, and this process critically depends on adhesins (microneme proteins) released onto the parasite surface from intracellular organelles called micronemes (MIC). The microneme adhesive repeat (MAR) domain of T. gondii MIC1 (TgMIC1) recognizes sialic acid (Sia), a key determinant on the host cell surface for invasion by this pathogen. By complementation and invasion assays, we demonstrate that TgMIC1 is one important player in Sia-dependent invasion and that another novel Sia-binding lectin, designated TgMIC13, is also involved. Using BLAST searches, we identify a family of MAR-containing proteins in enteroparasitic coccidians, a subclass of apicomplexans, including T. gondii, suggesting that all these parasites exploit sialylated glycoconjugates on host cells as determinants for enteric invasion. Furthermore, this protein family might provide a basis for the broad host cell range observed for coccidians that form tissue cysts during chronic infection. Carbohydrate microarray analyses, corroborated by structural considerations, show that TgMIC13, TgMIC1, and its homologue Neospora caninum MIC1 (NcMIC1) share a preference for alpha2-3- over alpha2-6-linked sialyl-N-acetyllactosamine sequences. However, the three lectins also display differences in binding preferences. Intense binding of TgMIC13 to alpha2-9-linked disialyl sequence reported on embryonal cells and relatively strong binding to 4-O-acetylated-Sia found on gut epithelium and binding of NcMIC1 to 6'sulfo-sialyl Lewis(x) might have implications for tissue tropism.

Background: The objective of the present study was to calculate age- and gender-specific reference ranges for serum insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) concentrations using quantile regression., Methods: From the Study of Health in Pomerania (SHIP), 1798 men and women aged 25-85 years were recruited. Serum IGF-I and IGFBP-3 concentrations were determined using a chemiluminescent immunometric assay on an Immulite 2500 analyzer. Quantile regressions were performed to calculate the 2.5th and 97.5th percentiles., Results: The reference ranges identified 43 (4.6%) women and 41 (4.8%) men with serum IGF-I concentrations, and 47 (5.0%) women and 42 (5.0%) men with serum IGFBP-3 concentrations outside the reference range., Conclusions: The use of quantile regression results in accurate calculation of age- and gender-specific reference ranges for serum IGF-I and IGFBP-3.

In some ascomycete fungi, ribosomal protein S3 (Rps3) is encoded within a group I intron (mL2449) that is inserted in the U11 region of the mitochondrial large subunit rDNA (rnl) gene. Previous characterization of the mL2449 intron in strains of Ophiostoma novo-ulmi subspecies americana (Dutch Elm Disease) revealed a complex genes-within-genes arrangement whereby a LAGLIDADG homing endonuclease gene (HEG) is inserted into the RPS3 gene near the 3' terminus, creating a hybrid Rps3-LAGLIDADG fusion protein. Here, we examined 119 additional strains of Ophiostoma and related taxa representing 85 different species by a polymerase chain reaction- based survey and detected both short (approximately 1.6 kb) and long (>2.2 kb) versions of the mL2449 intron in 88 and 31 strains, respectively. Among the long versions encountered, 21 were sequenced, revealing the presence of either intact or degenerated HEG-coding regions inserted within the RPS3 gene. Surprisingly, we identified two new HEG insertion sites in RPS3; one near the original C-terminal insertion site and one near the N-terminus of RPS3. In all instances, the HEGs are fused in-frame with the RPS3-coding sequences to create fusion proteins. However, comparative sequence analysis showed that upon insertion, the HEGs displaced a portion of the RPS3-coding region. Remarkably, the displaced RPS3-coding segments are duplicated and fused in-frame to the 3' end of RPS3, restoring a full-length RPS3 gene. We cloned and expressed the LAGLIDADG portion of two Rps3-HEG fusions, and showed that I-OnuI and I-LtrI generate 4 nucleotide (nt), 3' overhangs, and cleave at or 1 nt upstream of the HEG insertion site, respectively. Collectively, our data indicate that RPS3 genes are a refuge for distinct types of LAGLIDADG HEGs that are defined by the presence of duplicated segments of the host gene that restore the RPS3 gene, thus minimizing the impact of the HEG insertion on Rps3 function.

The intracellular protozoan Toxoplasma gondii is among the most widespread parasites. The broad host cell range of the parasite can be explained by carbohydrate microarray screening analyses that have demonstrated the ability of the T. gondii adhesive protein, TgMIC1, to bind to a wide spectrum of sialyl oligosaccharide ligands. Here, we investigate by further microarray analyses in a dose-response format the differential binding of TgMIC1 to 2-3- and 2-6-linked sialyl carbohydrates. Interestingly, two novel synthetic fluorinated analogs of 3'SiaLacNAc(1-4) and 3'SiaLacNAc(1-3) were identified as highly potent ligands. To understand the structural basis of the carbohydrate binding specificity of TgMIC1, we have determined the crystal structures of TgMIC1 micronemal adhesive repeat (MAR)-region (TgMIC1-MARR) in complex with five sialyl-N-acetyllactosamine analogs. These crystal structures have revealed a specific, water-mediated hydrogen bond network that accounts for the preferential binding of TgMIC1-MARR to arrayed 2-3-linked sialyl oligosaccharides and the high potency of the fluorinated analogs. Furthermore, we provide strong evidence for the first observation of a C--F...H--O hydrogen bond within a lectin-carbohydrate complex. Finally, detailed comparison with other oligosaccharide-protein complexes in the Protein Data Bank (PDB) reveals a new family of sialic-acid binding sites from lectins in parasites, bacteria, and viruses.

The 'iron hypothesis' claims that Fe depletion protects against IHD. The objective of the present study was to investigate the associations between serum ferritin levels and the risk of CVD and IHD in a population-based sample. A total of 2874 subjects with serum ferritin levels between 15 and 300 microg/l from the Danish part of the 'Monitoring of Trends and Determinants in Cardiovascular Disease' (DAN-MONICA) I study and the 1914 Cohort survey were followed for 10 years. Information on behavioural and socio-demographic characteristics were collected and serum ferritin levels measured. Non-fatal and fatal CVD and IHD were identified by the International Classification of Diseases diagnoses numbers. Multivariable Cox proportional hazard regression models with restricted cubic splines were performed. During the follow-up period, 310 subjects (201 men; 109 women) and 161 subjects (117 men; forty-four women) experienced CVD and IHD, respectively. Our analyses revealed no statistically significant associations between serum ferritin levels and the risk of CVD or IHD in both sexes. However, in women, the results argue for a U-shaped relationship between serum ferritin levels and CVD as well as IHD. In concordance with former prospective studies, the present results do not support the hypothesis that normal body Fe stores should play a significant role in the development of CVD.

Context: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease., Objective: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples., Design, Setting, and Participants: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort., Main Outcome Measures: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size., Results: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance)., Conclusions: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

Background: There is strong evidence that IGF-I and IGF binding protein 3 (IGFBP-3), as central mediators of endocrine and finally metabolic or anabolic effects of GH, were associated with increased lung size in acromegaly or a decrease of respiratory muscle pressures in patients with GH deficiency. The aim of the present study was to further clarify the impact of IGF-I and IGFBP-3 levels on lung volumes and respiratory pressures in a general adult population., Material and Methods: From the Study of Health in Pomerania, 1326 subjects aged 25 to 85 yr participated in standardized pulmonary function testing. IGF-I and IGFBP-3 levels were measured with the Immulite 2500 system. Multivariable linear regression analyses adjusted for age, sex, body mass index, physical activity, and smoking were performed., Results: In men, positive linear associations between IGF-I and IGF-I/IGFBP-3 ratio with forced expiratory volume in 1 sec (FEV1) as well as with forced vital capacity (FVC) were detected across all ages, whereas in women this positive association was only detectable above 50 yr. Furthermore, the analyses indicated positive linear relations of IGF-I/IGFBP-3 ratio with FEV1 and FVC, respectively. No significant relations between IGF-I or IGFBP-3 and maximal inspiratory pressure was detectable in both sexes., Conclusion: In conclusion, higher IGF-I levels were associated with higher lung volumes in men, whereas in women this association was only detectable in subjects older than 50 yr. Higher IGF-I values were not associated with increased respiratory muscle strength measured as maximal inspiratory pressure.

Background: Previous studies provided conflicting results regarding the association of serum IGF-I or IGF-binding protein-3 (IGFBP-3) and mortality. The aim of this study was to assess the relation of IGF-I and IGFBP-3 levels with mortality from all causes, cardiovascular disease (CVD), and cancer in a prospective population-based study., Methods: From the Study of Health in Pomerania (SHIP) 1988 men and 2069 women aged 20-79 yr were followed up on average 8.5 yr. Causes of deaths were coded according to the International Classification of Diseases, 10th revision. Serum IGF-I and IGFBP-3 levels were determined by chemiluminescence immunoassays and categorized into three groups (low, normal, high) according to the sex- and age-specific 10th and 90th percentiles., Results: Adjusted analyses revealed that men with low but not high IGF-I levels had an almost 2-fold higher risk of all-cause mortality [hazard ratio (HR) 1.92 (95% confidence interval [CI] 1.35; 2.73)], CVD mortality [HR 1.92 (95% CI 1.00; 3.71)], and cancer mortality [HR 1.85 (95% CI 1.00; 3.45)] compared with men with normal IGF-I levels. In women, no association between IGF-I and mortality was found. Moreover, low IGFBP-3 levels were associated with higher all-cause mortality in men [HR 1.87 (95% CI 1.31; 2.64)] and women [HR 1.63 (95% CI 0.96; 2.76)]., Conclusions: The present study found inverse associations between IGF-I or IGFBP-3 levels and mortality from all causes, CVD, or cancer in men and between IGFBP-3 and all-cause mortality in women.

Objectives: Gallstones are a common disease worldwide, with disparities in the prevalence of the disease in different settings. The aim of the present study was to assess if different distributions of risk factors could explain the disparities in the prevalence of gallstone disease between Denmark and northeast Germany., Methods: Data of 5,559 subjects from the Danish MONICA survey and of 3,647 subjects of the German Study of Health in Pomerania were investigated. Gallstone disease was defined as a prior history of cholecystectomy or the presence of sonographically diagnosed gallstones. Logistic regression models were performed to assess the confounding effect of selected risk factors on regional disparities in gallstone disease., Results: After adjustment for age and vocational training, German subjects (women: Odds ratio, OR, 2.46 (95% confidence interval, CI: 2.07-2.91); men: OR, 1.89 (95% CI: 1.52-2.36)) had approximatively twice the odds of gallstones than Danes. Inclusion of lifestyle factors (smoking, alcohol intake, coffee use) did not affect this result, whereas adjustment for body mass index (BMI), lipids, diabetes, and use of oral contraceptives, menopausal hormone therapy (MHT) and parity (women only) changed the estimates considerable, but still Germans (women: OR, 1.65 (95% CI: 1.36-2.00); men: OR, 1.61 (95% CI: 1.27-2.04)) had higher odds than Danes., Conclusions: German individuals had a higher prevalence of gallstones than Danes. This difference was partly explained by a higher BMI, unfavorable lipid levels, higher prevalence of diabetes, and a more frequent use of OR and MHT in German subjects. Further research is needed to evaluate the impact of unmeasured predictors, including genetic components, on the population-related risk of gallstones.

Objective: To analyse 12-month response to GH treatment in a single-country cohort of hypopituitary adult patients with GH deficiency (GHD) in regards to health-related quality of life (HRQoL) and insulin-like growth factor-1 (IGF-1) compared with values from general population sample. Moreover, association between the response in HRQoL and the IGF-1 values in patients and in the background population was investigated., Design: HRQoL was assessed by quality of life assessment of GH deficiency in adults (QoL-AGHDA) in 651 patients retrieved from the German KIMS (Pfizer International Metabolic Database) before and after 12 months of GH replacement and in a sample drawn from a cross-sectional study in Germany (n=2734). IGF-1 was measured in KIMS patients and in the population-based study with the same assay technique., Results: In KIMS patients, mean QoL-AGHDA scores before GH replacement were 9.2+/-6.8 (8.7+/-6.8) in women (men) and in the general population sample 4.5+/-5.3 (4.3+/-5.0) in women (men). Mean differences in QoL-AGHDA scores were statistically significant for all age categories (P<0.05). The mean IGF-1 SDS of KIMS patients before GH replacement was -1.1+/-1.4 (-0.8+/-1.4) in women (men). After GH replacement, a significant increase of IGF-1 concentration and a significant decrease of QoL-AGHDA scores near to age- and gender-specific population-based values were observed., Conclusions: This study confirms an improvement in HRQoL and an increase of IGF-1 SDS in GH-replaced adults, which approximated the values of general population. However, there was no association between IGF-1 values and HRQoL assessment as one of the important treatment outcomes.

The obligate intracellular parasite Toxoplasma gondii, a member of the phylum Apicomplexa that includes Plasmodium spp., is one of the most widespread parasites and the causative agent of toxoplasmosis. Adhesive complexes composed of microneme proteins (MICs) are secreted onto the parasite surface from intracellular stores and fulfil crucial roles in host-cell recognition, attachment and penetration. Here, we report the high-resolution solution structure of a complex between two crucial MICs, TgMIC6 and TgMIC1. Furthermore, we identify two analogous interaction sites within separate epidermal growth factor-like (EGF) domains of TgMIC6-EGF2 and EGF3-and confirm that both interactions are functional for the recognition of host cell receptor in the parasite, using immunofluorescence and invasion assays. The nature of this new mode of recognition of the EGF domain and its abundance in apicomplexan surface proteins suggest a more generalized means of constructing functional assemblies by using EGF domains with highly specific receptor-binding properties.

The eukaryotic mismatch repair (MMR) protein MSH6 exhibits a core region structurally and functionally similar to bacterial MutS. However, it possesses an additional N-terminal region (NTR), comprising a PCNA binding motif, a large region of unknown function and a nonspecific DNA binding fragment. Yeast NTR was recently described as an extended tether between PCNA and the core of MSH6 . In contrast, we show that human NTR presents a globular PWWP domain in the region of unknown function. We demonstrate that this PWWP domain binds double-stranded DNA, without any preference for mismatches or nicks, whereas its apparent affinity for single-stranded DNA is about 20 times lower. The S144I mutation, which in human MSH6 causes inherited somatic defects in MMR resulting in increased development of hereditary non polyposis colorectal cancer , is located in the DNA binding surface of the PWWP domain. However, it only moderately affects domain stability, and it does not perturb DNA binding in vitro.

Objective: Insulin-like growth factor I (IGF-1), which is mostly carried by IGF binding protein 3 (IGFBP-3), mediates endocrine actions of growth hormone and represents an important prognostic factor for systemic diseases. The main objectives of the present study were (1) to calculate age- and sex-specific reference values for serum IGF-1 and IGFBP-3 levels using the Gaussian mean+/-1.96 *standard deviation method and the quantile regression method and (2) to perform a comparison of the results from both statistical methods., Design: Cross-sectional study (Study of Health in Pomerania). The study population included 2499 men and women aged 20-79 years., Methods: Serum IGF-1 and IGFBP-3 levels were determined by chemiluminescence immunoassays. Linear and quantile regressions were performed to calculate age- and sex-related reference ranges., Results: Both statistical methods generated different results: The reference ranges based on linear regression identified 43 (1.7%) subjects with serum IGF-1 levels and 99 (4.0%) subjects with serum IGFBP-3 levels outside the reference range. Using quantile regression, 117 (4.7%) or 118 subjects (4.7%) with serum IGF-1 or IGFBP-3 levels outside the range were detected, respectively., Conclusion: The present study established age- and sex-specific reference ranges for serum IGF-1 and IGFBP-3 levels. Quantile regression should be preferred to calculate reference ranges because a better concordance to original data is possible due to no distribution assumption are required and the robustness against outliers is given.

Background: A number of studies have shown that self-reported alcohol intake is positively associated with total serum immunoglobin E (IgE) levels. The purpose of the present study was to investigate the association of self-reported alcohol consumption and different biomarkers of alcohol exposure to total serum IgE levels in a general adult population., Methods: A total of 3,443 subjects aged 20 to 79 years from the population-based cross-sectional Study of Health in Pomerania (SHIP) were included in the analyses. Information on alcohol consumption and serum carbohydrate-deficient transferrin (CDT), gamma-glutamyl transferase (GGT), aspartate-amino transferase (ASAT), andalanine-amino transferase (ALAT) levels were measured. Multivariable linear regression models were performed separately in atopic and nonatopic subjects., Results: In nonatopic subjects positive associations between self-reported alcohol consumption as well as all considered biomarkers of alcohol exposure and total serum IgE levels were found. Further the results also suggested positive associations between alcohol consumption as well as alcohol biomarkers and total serum IgE level in atopic subjects, even though not all tests for linear trend reached statistical significance., Conclusions: In conclusion, biomarkers of alcohol exposure were positively associated with total serum IgE levels supporting that the positive association between self-reported alcohol intake and IgE levels observed in previous studies is real and not due to misclassification of alcohol intake or confounding by other factors that may be linked to both alcohol intake and total serum IgE levels.

Aim: In a general adult population, we have demonstrated an inverse association between periodontitis and respiratory allergies that is in line with the hygiene hypothesis suggesting a protective effect of infections against the development of allergies. The objective of the present study was to investigate the association between periodontitis and respiratory allergies in a type 1 diabetes mellitus population., Material and Methods: The study population comprised 170 patients with type 1 diabetes mellitus aged 17-80 years. Respiratory allergies were present in 22 subjects. The attachment loss (AL) was measured. Periodontitis was defined according to the percentage of surfaces that exceeded 3 mm AL (healthy, mild, moderate, severe periodontal conditions)., Results: Our adjusted analyses revealed an inverse association between periodontitis and respiratory allergies. For increasing AL, a trend towards a decreasing risk was present for respiratory allergies (p(trend)<0.05). Compared with subjects with healthy periodontal conditions, individuals with severe periodontal conditions had the lowest risk of respiratory allergies [odds ratios (OR) 0.06 (95% confidence interval (CI) 0.01-0.39)], followed by subjects with moderate AL [OR 0.14 (95% CI 0.03-0.63)] and mild AL [OR 0.32 (95% CI 0.09-1.08)]., Conclusion: There is a strong inverse association between periodontitis and respiratory allergies in patients with type 1 diabetes mellitus. These findings further support the hygiene hypothesis.

Background: Autoimmune thyroid disease (AIT) is more common in females than in males. Furthermore, it is well documented that the risk of thyroid autoimmunity increases during pregnancy and in the postpartum period. The objective of the present study was to analyse the association between parity and AIT by using ultrasound and serological data., Methods: The study population included 2156 women, aged 20-79 years. Serum thyroperoxidase antibodies (anti-TPO) and thyrotropin levels were measured and thyroid ultrasonography was performed. AIT was defined according to the combined presence of a hypoechogenic thyroid pattern and positive anti-TPO levels (>200 IU/ml). Odds ratios (OR) and 95% confidence intervals (CI) were calculated., Results: The analyses revealed an association between parity and AIT. Women with at least one pregnancy had increased odds for AIT (OR 4.6 [95%-CI 1.4-15.1], p < 0.05) compared to women who have never been pregnant. Similar results were observed using hypoechogenic thyroid pattern (OR 1.7 [95%-CI 1.0-2.9], p < 0.05) and positive anti-TPO levels (OR 1.8 [95%-CI 1.0-3.3], p = 0.05) as separate dependent variables or using number of births as alternate independent variable., Conclusion: In this female population we found an association between parity and AIT and conclude that parity appears to be a potential risk factor for AIT.

Background: The goal of this study was to evaluate the prevalence of chronic tympanic membrane perforation in the adult population., Materials and Method: The study population included 1,000 subjects (453 males, 547 females) aged 18-93 years. In addition to interview data, ear examinations were performed., Results: There were eight subjects with unilateral chronic tympanic membrane perforation and a single subject with a bilateral perforation. The age adjusted prevalence of chronic tympanic membrane perforation was 0.45% (95% confidence interval: 0.03-0.87). Eight out of nine subjects disliked tympanoplasty., Conclusion: The high proportion of subjects with chronic tympanic membrane perforations who do not want to be operated suggests that there is a considerable need for novel therapeutic procedures.

Several studies have reported associations between reduced humoral immune response to vaccine antigens and diseases with modified reactions of the immune system. We have investigated the influence of atopic diseases on specific IgG levels to tetanus, diphtheria and hepatitis B (HB), following immunisation, in a general adult population. From the Study of Health in Pomerania, a total number of 3,920 subjects aged 20 to 79 years were included in the analyses. Information on immunisation history, as well as behavioural and socio-demographic characteristics were collected. Anti-tetanus IgG, anti-diphtheria IgG and anti-HBs IgG were measured by indirect enzyme-linked immunosorbent assay (ELISA). Odds ratios and 95% confidence intervals were calculated using logistic regression. Atopic diseases were reported by 14% of participants. Proportions of 67%, 34% and 10% had been vaccinated against tetanus, diphtheria and hepatitis B within the past ten years, respectively. Multi-variable analyses revealed no associations between the presence of atopic diseases and all of the three vaccine-specific antibody titres. We conclude that there is no reduced immune response related to antibody production following immunisations against tetanus, diphtheria and hepatitis B in adults with atopic diseases.

Objective: There is current debate on whether serum IGF-I levels are associated with thyroid disorders. The aims of the present study were: 1) to investigate possible associations between serum IGF-I levels and thyroid disorders and 2) to analyze the role of serum IGF binding protein (IGFBP)-3 and TSH levels for these associations., Design: This was a cross-sectional Study of Health in Pomerania., Setting: The study was conducted in the general population of northeast Germany., Subjects: The study population comprised 3662 subjects (1746 women) without history of thyroid disorders., Interventions: No interventions have been performed., Main Outcome Measures: Goiter and thyroid nodules were determined by ultrasound. Serum TSH levels less than 0.25 mIU/liter were considered decreased., Results: Adjusted for major confounders and risk factors for thyroid disorders, subjects with serum IGF-I levels above the upper tertile had higher odds for goiter relative to subjects with serum IGF-I levels below the lower tertile [odds ratio (OR) 1.67; 95% confidence interval (CI) 1.24-2.26 in women; OR 2.04; 95% CI 1.55-2.68 in men]. A similar association was present for thyroid nodules in men (OR 1.64; 95% CI 1.17-2.32) and for decreased serum TSH levels in women (OR 1.65; 95% CI 1.00-2.69). Serum IGFBP-3 levels were not associated with thyroid disorders and did not represent effect modifiers for the association between serum IGF-I levels and the endpoints., Conclusions: We conclude that high serum IGF-I levels are associated with goiter. Whereas high serum IGF-I levels are also related to thyroid nodules in men, they are related to decreased serum TSH levels in women. Serum IGFBP-3 and TSH levels did not modulate these associations.

The obligate intracellular parasite Toxoplasma gondii, a member of the phylum Apicomplexa that includes Plasmodium spp., is one of the most widespread parasites and the causative agent of toxoplasmosis. Micronemal proteins (MICs) are released onto the parasite surface just before invasion of host cells and play important roles in host cell recognition, attachment and penetration. Here, we report the atomic structure for a key MIC, TgMIC1, and reveal a novel cell-binding motif called the microneme adhesive repeat (MAR). Using glycoarray analyses, we identified a novel interaction with sialylated oligosaccharides that resolves several prevailing misconceptions concerning TgMIC1. Structural studies of various complexes between TgMIC1 and sialylated oligosaccharides provide high-resolution insights into the recognition of sialylated oligosaccharides by a parasite surface protein. We observe that MAR domains exist in tandem repeats, which provide a highly specialized structure for glycan discrimination. Our work uncovers new features of parasite-receptor interactions at the early stages of host cell invasion, which will assist the design of new therapeutic strategies.

Aims: Previous studies have found that abstainers utilize out-patient health services more than alcohol consumers. The aim of this study was to investigate this relationship further by including several confounding variables and effect modifiers. It was hypothesized that abstainers utilize more health services because they have less social resources, practice more risky health behaviours, have poorer self-reported health and suffer more from chronic diseases., Design and Participants: Cross-sectional health survey of a random sample of adults aged 20-64 in Pomerania, Germany. The response rate was 68.8%. Alcohol consumption was assessed using a quantity-frequency measure and categorized into past-year abstainers, low-risk, medium-risk and high-risk drinkers. Confounders and effect modifiers included socio-demographic and health-related variables., Findings: Abstainers had a 43% higher rate (rate ratio = 1.43, 95% CI = 1.24, 1.63) of physician visits compared to low-risk drinkers, adjusting for age and gender. Medium-risk and high-risk drinkers did not differ from low-risk drinkers in terms of out-patient visits. Further regression adjustment for socio-economic covariates, self-reported health status and chronic diseases suggested that abstainers used more out-patient services because they were more ill than drinkers. The effect of mental health status and the number of chronic diseases on out-patient visits was greater for abstainers than drinkers., Conclusions: The relation between alcohol consumption and out-patient services is explained partly by poorer health among the abstainers. Further research is needed to affirm these results, such as transferring this evidence to the utilization of in-patient health services.

Background: Periodontitis is an infection with systemic effects and a high prevalence among adults. In the aetiology of allergic diseases the hygiene hypothesis claims that infections in early infancy may protect against allergic diseases., Objective: The aim of the present analyses was to investigate the independent relation between periodontitis and respiratory allergies such as hayfever, house dust mite (HDM) allergy and asthma., Methods: From the Study of Health in Pomerania (SHIP) a total number of 2837 subjects aged 20 to 59 years were included in the analysis. In our study population 326, 111 and 114 subjects were classified as suffering from hayfever, HDM allergy or asthma, respectively. The attachment loss (AL) were measured. Periodontitis was defined according to the percentage of surfaces which exceeded 3 mm AL [healthy: 0-7.7%, mild: 7.8-28.6%, moderate: 28.7-63.9%, severe: >63.9%]. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression., Results: After adjustment for confounding factors these analyses revealed inverse associations between periodontitis and hayfever as well as periodontitis and HDM allergy. For increasing AL, a trend of decreasing risk could be observed for hayfever (healthy: reference; mild AL: OR 0.87 [95%-CI 0.6-1.2]; moderate AL: OR 0.80 [95% CI 0.6-1.2]; server AL: OR 0.53 [95% CI 0.3-0.9]; P(trend)=0.01) and for HDM allergy (healthy: reference; mild AL: OR 0.80 [95% CI 0.5-1.3]; moderate AL: OR 0.64 [95% CI 0.3-1.2]; server AL: OR 0.39 [95% CI 0.2-0.9]; P(trend)=0.02). Furthermore, for asthma were observed a slightly inverse association in the full-adjusted model (healthy: reference; mild AL: OR 1.10 [95% CI 0.6-2.0]; moderate AL: OR 0.96 [95% CI 0.5-1.8]; server AL: OR 0.48 [95% CI 0.2-1.0]; P(trend)=0.11)., Conclusion: There is an inverse association between periodontitis and respiratory allergies. Our results might support the hygiene hypothesis.

Context: The thyroid gland is a potential target organ for radiation-related damage., Objective: The aim of the analysis was to investigate the association between occupational exposure to ionizing radiation and autoimmune thyroid disease (AITD)., Design: Our design was the cross-sectional Study of Health in Pomerania., Setting: The setting was the general community., Subjects: Analyses were performed in a population-based sample of 4299 subjects. Among them, 160 persons reported a history of occupational exposure to ionizing radiation., Main Outcome Measure: AITD was defined as the combined presence of hypoechogenicity in thyroid ultrasound and antithyroxiperoxidase antibodies greater than 200 IU/ml., Results: Females with occupational exposure to ionizing radiation had more often AITD than nonexposed females (10.0 vs. 3.4%; P < 0.05). This association persisted after adjustment for relevant confounders (odds ratio, 3.46; 95% confidence interval, 1.16-10.31; P < 0.05). In males, there were too few subjects who fulfilled the criteria of AITD, but the association between the exposure to radiation and hypoechogenicity of the thyroid gland barely missed statistical significance (odds ratio, 2.20; 95% confidence interval, 0.92-5.26; P = 0.08). In both females and males, subjects who reported a length of exposure of more than 5 yr exhibited the highest risk of the endpoints., Conclusions: We conclude that occupational exposure to ionizing radiation is related to the risk of AITD. The usage of thyroid protection shields by radiation workers is strongly recommended.

Background: Mycophenolate mofetil (MMF) is a routinely used immunosuppressive agent that selectively blocks T- and B-lymphocyte proliferation. The present study was designed to investigate the effects of this drug on human leukocyte(HLA) antibody production in general and donor-specific antibody (DSA) formation in particular in 154 recipients of renal allografts., Patients and Methods: Renal allograft recipients were subdivided into three groups. Group 1 patients (n = 60) had received MMF since transplantation in combination with either cyclosporin A or tacrolimus and steroids. Group 2 patients (n = 29) had received an MMF-free immunosuppressive regimen initially followed by addition of MMF some time later. Group 3 patients (n = 65) had received no MMF. Cyclosporin A or tacrolimus in combination with azathioprine and/or steroids were used for immunosuppression. DSA were demonstrated by enzyme-linked immunosorbent assay (ELISA) for detection of panel-reactive antibodies of HLA class I and II specificity., Results: The HLA antibodies were found in 16.7%, 27.6% and 30.8% of transplant recipients in groups 1, 2 and 3, respectively. DSA were found in 8.3%, 17.2% and 20.0%, and non-DSA in 10.0%, 20.7% and 24.6%, of patients in groups 1, 2 and 3, respectively., Conclusion: The MMF reduces anti-HLA class I and II antibody production and consequently DSA production in renal allograft recipients. Our data indicate this effect to be more pronounced in patients given MMF immediately after transplantation than in those in whom MMF is introduced some time later. The presence of DSA in the serum of renal allograft recipients is associated with poorer graft function (higher serum creatinine and more rejection episodes).

Background: The CD40-CD40L (CD154) costimulatory pathway plays a critical role in the pathogenesis of kidney allograft rejection. In renal transplant biopsies, CD4+CD40L+ graft-infiltrating cells were detected during chronic rejection in contrast to acute rejection episodes. Using a rapid noninvasive FACS procedure, we were able to demonstrate CD40L upregulation in peripheral blood of patients with chronic renal allograft dysfunction., Materials and Methods: Whole blood from recipients of renal allografts was stimulated with PMA and ionomycin and measured by flow cytometry. Patients were assigned to three groups based on transplant function. Group 1: 26 patients with excellent renal transplant function; group 2: 28 patients with impaired transplant function; group 3: 14 patients with chronic allograft dysfunction and group 4: 8 healthy controls., Results: The median percentage +/- SEM of CD4+/CD40L+ cells stimulated ex vivo at 10 ng/ml PMA was as follows: group 1: 28.3 +/- 4.1%; group 2: 18.4 +/- 2.4%; group 3: 50.1 +/- 5.0% and group 4: 40.4 +/- 3.4%. Subdivisions of groups 2 and 3 resulted in different CD40L expression patterns. Patients with increased serum creatinine since the initial phase after transplantation (groups 2a and 3a) revealed a higher percentage of CD4+CD40L+ cells than patients showing a gradual increase over time (groups 2b and 3b). Consequently, patients of group 3a exhibited a significantly reduced transplant function compared with those of group 3b., Conclusion: After PMA + ionomycin stimulation, patients with excellent kidney graft function displayed significantly reduced expression of CD40L surface molecules on CD4+ cells early after transplantation. Those with a chronic dysfunction of the renal graft showed significantly more CD4+ cells expressing CD40L compared to the other transplanted groups. These results demonstrate that the percentage of CD4+CD40L+ cells stimulated ex vivo in peripheral blood may be a valuable marker for chronic allograft nephropathy., (Copyright 2004 S. Karger AG, Basel)

Background: The number of inducible adhesion molecules known to be involved in cell-mediated allograft rejection is still increasing. In addition, recent data describe complement activation during acute humoral allograft rejection. The aim of this study was to assess whether specific molecules from either pathway are excreted into urine and whether they can provide useful diagnostic tools for the monitoring of renal transplant recipients., Methods: Urinary concentrations of soluble adhesion molecules (sICAM-1, sVCAM-1) and of the complement degradation product C4d were determined by standardized ELISA technique in 75 recipients of renal allografts and 29 healthy controls. Patient samples were assigned to four categories according to clinical criteria: GROUP 1: acute steroid-sensitive rejection (ASSR, n = 14), GROUP 2: acute steroid-resistant rejection (ASRR, n = 12), GROUP 3: chronic allograft dysfunction (CAD, n = 20) and GROUP 4: stable graft function (SGF, n = 29)., Results: All patients with rejection episodes (groups 1-3) had significantly higher values of urinary sC4d compared with healthy controls and patients with stable graft function (p < 0.05). The urinary levels of sVCAM-1 were significantly higher in group 2 (ASRR) compared with all other groups (p < 0.001). Uniformly low amounts of s-VCAM-1 and complement-split product C4d were excreted by healthy controls (group 0). In contrast, urinary sICAM-1 concentration in healthy controls was almost as high as in group 2 (ASRR) whereas patients with a stable functioning graft (group 4) excreted significantly less sICAM-1 (p < 0.05)., Conclusion: The evaluation of sVCAM-1 and sC4d excretion in urine can provide a valuable tool with regard to the severity and type of allograft rejection. With respect to long-term allograft survival, serial measurements of these markers should have the potential to detect rejection episodes and prompt immediate treatment., (Copyright 2003 S. Karger AG, Basel)

Tibial osteotomy is a well-established procedure for treatment of the varus osteoarthritic knee. A special new technique of oblique tibial osteotomy at the level of the tibial tubercle, preserving the medical cortex and iliotibial band, is presented which allows partial weight bearing the first postoperative day. Postoperatively the femorotibial alignment should be 5 degrees to 7 degrees of valgus in elderly patients. Because in younger individuals the intact iliotibial band is a strong restraint against varus deformity, we seek to correct to 3 degrees to 5 degrees of valgus in these patients. Of 172 cases treated with this technique between 1982 and 1986, 50 patients were retrospectively reviewed. After a follow-up period of 6 months to 3 years, pain was relieved in 46 patients. Complications consisted of 5 secondary wound healings, including 2 superficial infections, 1 tibial plateau fracture, and 3 varus recurrences.

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