Moritz Hahn

Effects of Inhibition of Interleukin-6 Signalling on Insulin Sensitivity and Lipoprotein (A) Levels in Human Subjects with Rheumatoid Diseases

Background Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has been found to be increased in type 2 diabetic subjects. However, it still remains unclear if these elevated IL-6 levels are co-incidental or if this cytokine is causally related to the development of insulin resistance and type 2 diabetes in humans. Therefore, in the present study we examined insulin sensitivity, serum adipokine levels and lipid parameters in human subjects before and after treatment with the IL-6 receptor antibody Tocilizumab. Methodology/Principal Findings 11 non-diabetic patients with rheumatoid disease were included in the study. HOMA-IR was calculated and serum levels for leptin, adiponectin, triglycerides, LDL-cholesterol, HDL-cholesterol and lipoprotein (a) (Lp (a)) were measured before as well as one and three months after Tocilizumab treatment. The HOMA index for insulin resistance decreased significantly. While leptin concentrations were not altered by inhibition of IL-6 signalling, adiponectin concentrations significantly increased. Thus the leptin to adiponectin ratio, a novel marker for insulin resistance, exhibited a significant decrease. Serum triglycerides, LDL-cholesterol and HDL-cholesterol tended to be increased whereas Lp (a) levels significantly decreased. Conclusions/Significance Inhibition of IL-6 signalling improves insulin sensitivity in humans with immunological disease suggesting that elevated IL-6 levels in type 2 diabetic subjects might be causally involved in the pathogenesis of insulin resistance. Furthermore, our data indicate that inhibition of IL-6 signalling decreases Lp (a) serum levels, which might reduce the cardiovascular risk of human subjects.

Impact of the Common Genetic Associations of Age-Related Macular Degeneration upon Systemic Complement Component C3d Levels

Age-related macular degeneration (AMD) is a common condition that leads to severe vision loss and dysregulation of the complement system is thought to be associated with the disease. To investigate associations of polymorphisms in AMD susceptibility genes with systemic complement activation, 2655 individuals were genotyped for 32 single nucleotide polymorphisms (SNPs) in or near 23 AMD associated risk genes. Component 3 (C3) and its catabolic fragment C3d were measured in serum and AMD staging was performed using multimodal imaging. The C3d/C3 ratio was calculated and associations with environmental factors, SNPs and various haplotypes of complement factor H (CFH) genes and complement factor B (CFB) genes were analyzed. Linear models were built to measure the influence of genetic variants on the C3d/C3 ratio. The study cohort included 1387 patients with AMD and 1268 controls. Higher C3d/C3 ratios were found for current smoker (p = 0.002), higher age (p = 1.56×10−7), AMD phenotype (p = 1.15×10−11) and the two SNPs in the C3 gene rs6795735 (p = 0.04) and rs2230199 (p = 0.04). Lower C3d/C3 ratios were found for diabetes (p = 2.87×10−6), higher body mass index (p = 1.00×10−13), the SNPs rs1410996 (p = 0.0001), rs800292 (p = 0.003), rs12144939 (p = 4.60×10−6) in CFH, rs4151667 (p = 1.01×10−5) in CFB and individual haplotypes in CFH and CFB. The linear model revealed a corrected R-square of 0.063 including age, smoking status, gender, and genetic polymorphisms explaining 6.3% of the C3d/C3 ratio. After adding the AMD status the corrected R-square was 0.067. In conclusion, none of the evaluated genetic polymorphisms showed an association with increased systemic complement activation apart from two SNPs in the C3 gene. Major genetic and non-genetic factors for AMD were not associated with systemic complement activation.

Allergy Is a Protective Factor Against Age-Related Macular Degeneration

PURPOSE To investigate the role of allergy on AMD. METHODS Age-related macular degeneration staging was performed for 3585 individuals (1878 from Cologne, Germany, and 1707 from Nijmegen, The Netherlands). Interviewer-assisted questionnaires were evaluated for the factors smoking, use of corticosteroids, and history of allergy, including causative allergens. Serum complement component C3d and C3 levels were measured and the C3d:C3 ratio was calculated. Associations of allergy with AMD/late AMD were assessed by logistic regression analysis; C3d:C3 ratio was compared between groups. RESULTS The discovery cohort from Cologne included 864 AMD patients and 1014 controls; 495 patients had late AMD. Positive history of allergy showed strong protective effects on the phenotype AMD (OR 0.52; P = 3.42 × 10(-9)) and late AMD (OR 0.32; P = 2.57 × 10(-13)). Subclassification in allergy-provoking agents showed significant protective effects in all groups. After adjustment for age, sex, smoking, and corticosteroid use, protective effects for AMD (OR 0.75; P = 0.018) and late AMD (OR 0.49; P = 2.87 × 10(-5)) were confirmed. Although the C3d:C3 ratio was higher in AMD/late AMD patients (both P < 0.001), there was no association with allergy in AMD (P = 0.22). The protective effect of allergy on AMD was confirmed in the replication cohort from Nijmegen (P = 0.002 for AMD; P = 0.0001 for late AMD). CONCLUSIONS Allergy has a protective effect on the development of AMD independent of the provoking allergen, which cannot be explained by complement activation. Further investigations are necessary to elucidate the molecular mechanisms underlying the protective effect of allergy on AMD.

Anterior chamber aqueous flare is a strong predictor for proliferative vitreoretinopathy in patients with rhegmatogenous retinal detachment.

Purpose: To investigate preoperative aqueous flare as a predictive factor for proliferative vitreoretinopathy (PVR) redetachment in patients with rhegmatogenous retinal detachment. Methods: Preoperatively, the aqueous flare of 116 consecutive patients with retinal detachment was measured quantitatively with a laser flare-cell meter (Kowa FM-500; Kowa Company, Ltd, Tokyo, Japan). Seventy-four healthy partner eyes and 41 eyes of healthy age-matched patients served as controls. At least 6 months after surgery, patients were reevaluated, whether surgery was performed again because of PVR redetachment. Results: Eyes with retinal detachment that developed PVR redetachment later on (n = 12) had higher flare values than eyes with uncomplicated retinal detachment (n = 104) (median, 27.63 vs. 8.83 photon counts per millisecond; P < 0.0001). No eye with PVR redetachment had a flare value <10.8 photon counts per millisecond. In eyes with flare values exceeding 15 photon counts per millisecond, the odds of PVR redetachment development increases 16-fold. Conclusion: Our study shows that the breakdown of the blood–ocular barrier as determined by aqueous flare is a major risk factor for PVR redetachment. The laser flare-cell meter is a fast, noninvasive, and safe tool that allows predicting the PVR redetachment risk preoperatively. It provides the surgeon with an estimate to choose those patients who could benefit from intravitreal drugs to prevent PVR.

Nutritional Risk Factors for Age-Related Macular Degeneration

Purpose. To evaluate the role of nutritional factors, serum lipids, and lipoproteins in late age-related macular degeneration (late AMD). Methods. Intake of red meat, fruit, fish, vegetables, and alcohol, smoking status, and body mass index (BMI) were ascertained questionnaire-based in 1147 late AMD cases and 1773 controls from the European Genetic Database. Serum levels of lipids and lipoproteins were determined. The relationship between nutritional factors and late AMD was assessed using logistic regression. Based on multivariate analysis, area-under-the-curve (AUC) was calculated by receiver-operating-characteristics (ROC). Results. In a multivariate analysis, besides age and smoking, obesity (odds ratio (OR): 1.44, P = 0.014) and red meat intake (daily: OR: 2.34, P = 8.22 × 10−6; 2–6x/week: OR: 1.67, P = 7.98 × 10−5) were identified as risk factors for developing late AMD. Fruit intake showed a protective effect (daily: OR: 0.52, P = 0.005; 2–6x/week: OR: 0.58, P = 0.035). Serum lipid and lipoprotein levels showed no significant association with late AMD. ROC for nutritional factors, smoking, age, and BMI revealed an AUC of 0.781. Conclusion. Red meat intake and obesity were independently associated with increased risk for late AMD, whereas fruit intake was protective. A better understanding of nutritional risk factors is necessary for the prevention of AMD.

Genetic and Environmental Risk Factors for Age-Related Macular Degeneration in Persons 90 Years and Older

PURPOSE We studied associations of genetic polymorphisms in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) in nonagenarians with age-related macular degeneration (AMD). METHODS This case-control study comprised 2737 persons (1204 controls, 1433 AMD cases), including 166 nonagenarians (52 controls, 114 AMD cases). Single nucleotide polymorphisms (SNPs) in the genes ARMS2 and CFH were determined. Risk scores were computed by multiple logistic regression analysis, including genetic and environmental risk factors (smoking, hypertension, body mass index, diabetes) for different age groups (<70, 70-79, 80-89, ≥ 90 years [nonagenarians]). RESULTS In nonagenarians, ARMS2 showed the weakest associations with AMD (odds ratio [OR] = 1.52, P = 0.127) compared to the other groups (OR, 70 years = 2.23, P = 1.03 × 10(-13); OR, 70-79 years = 2.70, P = 1.00 × 10(-13); OR, 80-89 years = 3.11, P = 6.56 × 10(-8)). For CFH, ORs for AMD increased with age (<70 years OR = 1.96, P = 1.80 × 10(-11); 70-79 years OR = 1.89, P = 4.48 × 10(-13); 80-89 years OR = 2.71, P = 1.28 × 10(-7)), but decreased again in the nonagenarians (OR = 2.21, P = 0.005). Compared to the group <70 years, reduced minor allele frequencies (MAFs) for AMD patients were observed in the nonagenarians (CFH 0.54 vs. 0.43, P = 0.009; ARMS2 0.44 vs. 0.29, P = 2.97 × 10(-5)), while the MAFs in controls were not significantly different. The genetic risk score revealed the lowest discriminative power in the nonagenarians with an area-under-curve (AUC) of 0.658 for receiver-operating characteristics (AUC 80-89 years = 0.768, 70-79 years = 0.704, <70 years = 0.682), while no significant difference was seen for the environmental risk score (AUC < 70 years = 0.579, 70-79 years = 0.567, 80-89 years = 0.600, >90 years = 0.608). CONCLUSIONS Risk alleles in CFH and ARMS2 have a significantly smaller effect on AMD development in nonagenarians, while environmental factors retain a similar effect.

Hypoadiponectinemia in Extremely Low Gestational Age Newborns with Severe Hyperglycemia - A Matched- Paired Analysis

Background Hyperglycemia is commonly observed in extremely low gestational age newborns (ELGANs) and is associated with both increased morbidity and mortality. The objective of this study was to examine the relationship between neonatal hyperglycemia and adiponectin levels in ELGANs. Methodology/Principal Findings Ten preterm infants between 22+6/7 and 27+3/7 weeks’ gestation with neonatal hyperglycemia (defined as pre-feeding blood glucose levels above 200mg/dl on two consecutive measurements with a maximum parenteral glucose infusion of 4mg/kg*min−1) formed the case cohort of this study. To every single patient of this case cohort a patient with normal fasting ( = pre-feeding) blood glucose levels was matched in terms of gestational age and gender. Adiponectin ELISAs were performed both at onset of hyperglycemia and at term-equivalent age. In the case cohort 9/10 patients had to be treated with insulin for 1–26 days (range 0.01–0.4 IU/kg*h−1). Compared to matched-paired controls, significant hypoadiponectinemia was observed at onset of hyperglycemia in these affected patients (6.9µg/ml versus 15.1µg/ml, p = 0.009). At term equivalent age, normoglycemia without any insulin treatment was found in both groups. Moreover, adiponectin levels at that time were no longer significantly different (12.3µg/ml versus 20.0µg/ml; p = 0.051) possibly indicating a mechanistic relevance of this adipokine in regulating insulin sensitivity in ELGANs. Conclusions/Significance Decreased circulating adiponectin levels are correlated with hyperglycemia in ELGANs and may contribute to the pathogenesis of impaired glucose homeostasis in these infants. These findings suggest that adiponectin might be a potential future drug target for the potentially save treatment of hyperglycemia in pre-term infants.

No advanced retinopathy of prematurity stages 4 or 5 in a large high-risk German cohort.

Background Retinopathy of prematurity (ROP) remains a major cause of juvenile blindness. As screening recommendations are refined, decreasing gestational age (GA) and birth weight (BW) constitute an increasing risk for ROP. This retrospective case series reviews the screening results of a very immature cohort in Germany. Methods We conducted ROP screening according to the German guidelines of 1999: all preterm infants with a GA of <32 weeks and/or a BW of <1501 g, or with GA ≥32 weeks and postnatal oxygen treatment for >3 days, were assigned for screening. Dense laser coagulation was performed according to the current treatment criteria. Results All 767 consecutive inborn (patients born at the Department of Neonatology, University Hospital of Cologne, Germany) preterm infants of a tertiary medical centre of maximum care underwent complete screening from 2001 to 2009. The treatment incidence was 7.0%. No preterm infant developed stage 4/5 ROP. Mean GA and BW of untreated/treated preterm infants were 28.4/24.6 weeks and 1109/635 g, respectively. Increasing treatment incidence was associated with lower GA, but not with lower BW in logistic regression analysis. Conclusion In this very immature high-risk cohort, advanced stages 4 and 5 were avoided throughout 9 years of screening. We suggest three factors that contributed to this outcome: (1) strict adherence to current ROP screening and treatment guidelines; (2) prompt and very dense laser coagulation if necessary; and (3) a specialised neonatal intensive care unit with experience of very immature babies.

Nongenetic Risk Factors for Neovascular Age-Related Macular Degeneration

PURPOSE To create a risk model for neovascular age-related macular degeneration (nAMD) based on nongenetic factors. METHODS In this case-control study, 1459 individuals were included, 445 patients showed nAMD and 1014 were healthy controls. Participants were randomly assigned into a training set (containing two-thirds of individuals) and a validation set. Stepwise logistic regression analysis was performed for 25 environmental risk factors in the training set. The risk model with the remaining factors was then validated in the validation set using receiver operating characteristics (ROC) curve and Hosmer-Lemeshow-Test. Additionally, a genetic risk model including variants in the complement factor H gene (CFH, rs1061170) and the age-related maculopathy susceptibility 2 gene (ARMS2, rs10490924) was generated. RESULTS The environmental risk model with the factors age, alcohol use, allergy, education, sunlight exposure, fish consumption, and physical exercise showed an AUC of 0.80 (95% confidence interval [CI] 0.76-0.84) in the training set. Validation of the model showed adequate calibration (Hosmer-Lemeshow P = 0.81). The AUC for the genetic model was 0.77 (95% CI 0.730-0.808), for the combined environmental and genetic model 0.92 (95% CI 0.887-0.947). CONCLUSIONS Seven nongenetic factors are able to provide equivalent discrimination between nAMD patients and controls to genetic risk models. Most of them are modifiable and give the opportunity for counseling patients.

Corrigendum to “Nutritional Risk Factors for Age-Related Macular Degeneration”

[This corrects the article DOI: 10.1155/2014/413150.].