Hypophosphatemia after high-dose iron repletion with ferric carboxymaltose and ferric derisomaltose-the randomized controlled HOMe aFers study.

BACKGROUND: In patients with iron deficiency anemia, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) allow high-dose iron repletion. While FCM is reported to induce hypophosphatemia, the frequency of hypophosphatemia after an equivalent dosage of FDI had not been assessed prospectively. METHODS: In the prospective, single-center, double-blind HOMe aFers study, 26 women with iron deficiency anemia (hemoglobin < 12 g/dL plus either plasma ferritin ≤ 100 ng/mL or a plasma ferritin ≤ 300 ng/mL and transferrin saturation (TSAT) ≤ 30%) were randomized to a single intravenous infusion of 20 mg/kg body weight (up to a maximum of 1000 mg) FCM or FDI. The primary endpoint was the incidence of hypophosphatemia (plasma phosphorus levels < 2.0 mg/dL at day 1, day 7 ± 2, and/or day 35 ± 2 after the infusion). In order to investigate potential skeletal and cardiovascular implications, we assessed changes in other components of mineral and bone metabolism, left ventricular function, and arrhythmias. RESULTS: Hypophosphatemia occurred more frequently in women treated with FCM (9 out of 12 [75%]) than in those treated with FDI (1 out of 13 [8%]; p = 0.001). Within 24 h after iron supplementation, women in the FCM group had significant higher plasma intact FGF23 (p < 0.001) and lower plasma 1.25-dihydroxyvitamin D (p < 0.001). As an indicator of urinary phosphorus losses, urinary fractional phosphorus excretion was higher in the FCM group (p = 0.021 at day 7 ± 2 after iron supplementation). We did not observe differences in skeletal and cardiovascular markers, potentially because of the limited number of participants. CONCLUSIONS: While both FCM and FDI provide efficient iron repletion in participants with iron deficiency anemia, FCM induced hypophosphatemia more often than FDI. TRIAL REGISTRATION: Clinical Trials.gov NCT02905539. Registered on 8 September 2016. 2015-004808-36 (EudraCT Number) U1111-1176-4563 (WHO Universal Trial Number) DRKS00010766 (Deutsches Register Klinischer Studien).

Impact of different intraoperative CO2 pressure levels (8 and 15 mmHg) during laparoscopic hysterectomy performed due to benign uterine pathologies on postoperative pain and arterial pCO2 : a prospective randomised controlled clinical trial.

OBJECTIVE: To compare the effects of two different intraoperative CO2 pressures (8 and 15 mmHg) during laparoscopic hysterectomy for benign uterine pathologies in terms of postoperative abdominal and shoulder pain, laparoscopy-mediated vegetative alterations, pain medication requirement, arterial CO2 pressure (pCO2 ), surgical parameters, and safety. DESIGN: Prospective randomised controlled study. SETTING: German university hospital. POPULATION: Female patients undergoing laparoscopic hysterectomy for benign uterine pathologies. METHODS: Patients were randomised to a standard pressure (SP; 15 mmHg, control) or low-pressure (LP; 8 mmHg, experimental) group. MAIN OUTCOME MEASURES: Primary outcomes were postoperative abdominal and shoulder pain intensities, measured via numeric rating scale (NRS) and vegetative parameters (fatigue, nausea, vomiting, bloating) at 3, 24, and 48 hours postoperatively. Secondary outcomes were pain medication requirement (mg) and arterial pCO2 (mmHg). Surgical parameters and intra- and postoperative complications were also recorded. RESULTS: In total, 178 patients were included. Patients in the LP group (n = 91) showed significantly lower postoperative abdominal and shoulder pain scores, fewer vegetative alterations, lower pain medication requirements, a shorter postoperative hospitalization, and lower intra- and postoperative arterial pCO2 values compared with the SP group (n = 87; P ≤ 0.01). No differences in intra- and postoperative complications were observed between groups. CONCLUSIONS: Low-pressure laparoscopy seems to be an effective and safe technique for the reduction of postoperative pain and laparoscopy-induced metabolic and vegetative alterations following laparoscopic hysterectomy for benign indications. TWEETABLE ABSTRACT: Low-pressure laparoscopy seems to be an effective and safe technique for reduction of pain following laparoscopic hysterectomy.

Safety and feasibility of electrical muscle stimulation in patients undergoing autologous and allogeneic stem cell transplantation or intensive chemotherapy.

Intensive chemotherapy, with or without following autologous or allogeneic stem cell transplantation (HSCT), is often the only curative treatment option for patients with hematological malignancies and leave many survivors physically and psychologically impaired. Electrical muscle stimulation (EMS) is a proven tool to improve physical performance in seniors and patients with chronic diseases. We therefore investigated the safety and feasibility of EMS in 45 patients undergoing autologous HSCT (n = 13), allogeneic HSCT (n = 11) and intensive chemotherapy (n = 21). Furthermore, physical (assessed by 6-min walking distance (6MWD) and short physical performance battery (SPPB)) and psychological performance (assessed by multidimensional fatigue inventory (MFI) and the EORTC QOL-C30 questionnaire) were measured before chemotherapy (T1) and at discharge from hospital (T2). Four patients died due to septic shock, two withdrew consent before the start of EMS training and five stopped EMS training during the study because of chemotherapy-related complications, loss of motivation or loss of ability to use EMS autonomously. Thirty-four out of 45 (76%) patients used EMS throughout the study period and participated in physical and psychological tests at time points 1 and 2. EMS-related adverse events were hematoma (n = 1) and muscle pain (n = 2). No bleeding events > 1 according to the WHO bleeding scale occurred. Decline in 6MWD from T1 to T2 was 24 m. The SPPB score stayed the same with 11 points at T1 and T2. Most MFI subscales showed stable fatigue levels and quality of life (QoL) did not decrease significantly throughout therapy. EMS is feasible and safe in patients undergoing intensive chemotherapy. Trial registration: NCT03467087.

Epidural needle insertion : A large registry analysis.

BACKGROUND: Dural puncture, paraesthesia and vascular puncture are the most common complications of epidural catheter insertion. Their association with variation in midline needle insertion depth is unknown. OBJECTIVE: This study evaluated the risk of dural and vascular punctures and the unwanted events paraesthesia and multiple skin punctures related to midline needle insertion depth. MATERIAL AND METHODS: A total of 14,503 epidural catheter insertions including lumbar (L1-L5; n = 5367), low thoracic (T7-T12, n = 8234) and upper thoracic (T1-T6, n = 902) insertions, were extracted from the German Network for Regional Anaesthesia registry between 2007 and 2015. The primary outcomes were compared with logistic regression and adjusted (adj) for confounders to determine the risk of complications/events. Results are presented as odds ratios (OR, [95% confidence interval]). MAIN RESULTS: Midline insertion depth depended on body mass index, sex, and spinal level. After adjusting for confounders increased puncture depth (cm) remained an independent risk factor for vascular puncture (adjOR 1.27 [1.09-1.47], p = 0.002) and multiple skin punctures (adjOR 1.25 [1.21-1.29], p < 0.001). In contrast, dural punctures occurred at significantly shallower depths (adjOR 0.73 [0.60-0.89], p = 0.002). Paraesthesia was unrelated to insertion depth. Body mass index and sex had no influence on paraesthesia, dural and vascular punctures. Thoracic epidural insertion was associated with a lower risk of vascular puncture than at lumbar sites (adjOR 0.39 [0.18-0.84], p = 0.02). CONCLUSION: Variation in midline insertion depth is an independent risk factor for epidural complications; however, variability precludes use of depth as a reliable guide to insertion in individual patients.

High probability of comorbidities in bronchial asthma in Germany.

Clinical experience has shown that allergic and non-allergic respiratory, metabolic, mental, and cardiovascular disorders sometimes coexist with bronchial asthma. However, no study has been carried out that calculates the chance of manifestation of these disorders with bronchial asthma in Saarland and Rhineland-Palatinate, Germany. Using ICD10 diagnoses from health care institutions, the present study systematically analyzed the co-prevalence and odds ratios of comorbidities in the asthma population in Germany. The odds ratios were adjusted for age and sex for all comorbidities for patients with asthma vs. without asthma. Bronchial asthma was strongly associated with allergic and with a lesser extent to non-allergic comorbidities: OR 7.02 (95%CI:6.83-7.22) for allergic rhinitis; OR 4.98 (95%CI:4.67-5.32) allergic conjunctivitis; OR 2.41 (95%CI:2.33-2.52) atopic dermatitis; OR 2.47 (95%CI:2.16-2.82) food allergy, and OR 1.69 (95%CI:1.61-1.78) drug allergy. Interestingly, increased ORs were found for respiratory diseases: 2.06 (95%CI:1.64-2.58) vocal dysfunction; 1.83 (95%CI:1.74-1.92) pneumonia; 1.78 (95%CI:1.73-1.84) sinusitis; 1.71 (95%CI:1.65-1.78) rhinopharyngitis; 2.55 (95%CI:2.03-3.19) obstructive sleep apnea; 1.42 (95%CI:1.25-1.61) pulmonary embolism, and 3.75 (95%CI:1.64-8.53) bronchopulmonary aspergillosis. Asthmatics also suffer from psychiatric, metabolic, cardiac or other comorbidities. Myocardial infarction (OR 0.86, 95%CI:0.79-0.94) did not coexist with asthma. Based on the calculated chances of manifestation for these comorbidities, especially allergic and respiratory, to a lesser extent also metabolic, cardiovascular, and mental disorders should be taken into consideration in the diagnostic and treatment strategy of bronchial asthma. BRONCHIAL ASTHMA: PREVALENCE OF CO-EXISTING DISEASES IN GERMANY: Patients in Germany with bronchial asthma are highly likely to suffer from co-existing diseases and their treatments should reflect this. Quoc Thai Dinh at Saarland University Hospital in Homburg, Germany, and co-workers conducted a large-scale study of patients presenting with bronchial asthma in the Saarland region between 2009 and 2012. Patients with asthma made up 5.4% of the region's total population, with a higher prevalence occurring in females. They found that bronchial asthma was strongly associated with allergic comorbidities such as rhinitis. Indeed, asthmatic patients had a seven times higher chance to suffer from allergic rhinitis than the rest of the population, and were at higher risk of respiratory diseases like pneumonia and obstructive sleep apnea syndrome. Further associations included cardiovascular, metabolic and mental disorders. Dinh's team call for asthma treatments to take such comorbidities into account.

Tunnelling of thoracic epidural catheters is associated with fewer catheter-related infections: a retrospective registry analysis.

BACKGROUND: Catheter-related infections are a serious complication of continuous thoracic epidural analgesia. Tunnelling catheters subcutaneously may reduce infection risk. We thus tested the hypothesis that tunnelling of thoracic epidural catheters is associated with a lower risk of catheter-related infections. METHODS: Twenty-two thousand, four hundred and eleven surgical patients with continuous thoracic epidural analgesia included in the German Network for Regional Anaesthesia registry between 2007 and 2014 were grouped by whether their catheters were tunnelled (n=12 870) or not (n=9541). Catheter-related infections in each group were compared with Student's unpaired t and χ(2) tests. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with logistic regression, adjusting for potential confounding factors, including age, ASA physical status score, use of catheter for ≥4 days, multiple skin puncture, hospital, and surgical department. RESULTS: There were fewer catheter-related infections in patients with tunnelled catheters (4.5 vs 5.5%, P<0.001). Mild infections were also less common (4.0 vs 4.6%, P=0.009), as were moderate infections (0.4 vs 0.8%, P<0.001). After adjustment for potential confounding factors, tunnelling remained an independent prevention for any grade of infection (adjusted OR 0.51, 95% CI 0.42-0.61, P<0.001) and for mild infections (adjusted OR 0.54, 95% CI 0.43-0.66, P<0.001) and moderate and severe infections (adjusted OR 0.44, 95% CI 0.28-0.70, P=0.001). CONCLUSION: Tunnelling was associated with a lower risk of thoracic epidural catheter-related infections.

High-resolution manometry in patients with eosinophilic esophagitis under topical steroid therapy-a prospective observational study (HIMEOS-study).

BACKGROUND: In eosinophilic esophagitis (EoE), dysphagia, which might reflect esophageal dysmotility, is the most common symptom. High-resolution manometry (HRM) has become widely accepted for evaluating esophageal motility disorders, but to date has been sparsely examined in EoE patients, particularly under therapy. The aim of this study was to evaluate HRM in symptomatic EoE-patients under topical steroid treatment. METHODS: In this prospective observational study, symptomatic EoE patients received HRM-examinations before and after 8 weeks of topical steroid treatment with budesonide. All HRM-abnormalities were assessed and interpreted according to the Chicago classification. The primary endpoint was the influence of topical steroid treatment on the intrabolus pressure (IBP). Clinical symptoms, endoscopic findings and histological esophageal eosinophilic load were also reported. KEY RESULTS: Twenty symptomatic EoE patients were included. Overall success of budesonide therapy was 85% regarding complete histologic remission and 80% regarding complete clinical remission. High-resolution manometry showed abnormal esophageal motility in 35% of patients at baseline, which was resolved after therapy in 86% of these patients. Most frequent HRM-findings were early pan-esophageal pressurizations and weak persitalsis. There was no significant reduction of the IBP under therapy (before: 12.5 ± 4.9 mmHg, after: 10.9 ± 2.9 mmHg; p = 0.119). CONCLUSIONS & INFERENCES: Although dysphagia is the leading symptom of EoE, HRM is able to identify esophageal motility disorders in only some EoE patients. Observed motility disorders resolve after successful treatment in almost all of these patients. Intrabolus pressure does not seem an optimal parameter for the monitoring of successful treatment response in EoE patients.

PTH [1-34]-induced alterations of the subchondral bone provoke early osteoarthritis.

OBJECTIVE: To test the hypothesis that changes in the subchondral bone induced by parathyroid hormone (PTH [1-34]) reciprocally affect the integrity of the articular cartilage within a naïve osteochondral unit in vivo. DESIGN: Daily subcutaneous injections of 10 µg PTH [1-34]/kg were given to adult rabbits for 6 weeks, controls received saline. Blood samples were continuously collected to monitor renal function. The subchondral bone plate and subarticular spongiosa of the femoral heads were separately assessed by micro-computed tomography. Articular cartilage was evaluated by macroscopic and histological osteoarthritis scoring, polarized light microscopy, and immunohistochemical determination of type-I, type-II, type-X collagen contents, PTH [1-34] receptor and caspase-3 expression. Absolute and relative extents of hyaline and calcified articular cartilage layers were measured histomorphometrically. The correlation between PTH-induced changes in subchondral bone and articular cartilage was determined. RESULTS: PTH [1-34] enhanced volume, mineral density, and trabecular thickness within the subarticular spongiosa, and increased thickness of the calcified cartilage layer (all P < 0.05). Moreover, PTH [1-34] led to cartilage surface irregularities and reduced matrix staining (both P < 0.03). These early osteoarthritic changes correlated with and were ascribed to the increased thickness of the calcified cartilage layer (P = 0.026) and enhanced mineral density of the subarticular spongiosa (P = 0.001). CONCLUSIONS: Modifications of the subarticular spongiosa by PTH [1-34] cause broadening of the calcified cartilage layer, resulting in osteoarthritic cartilage degeneration. These findings identify a mechanism by which PTH-induced alterations of the normal subchondral bone microarchitecture may provoke early osteoarthritis.

Biomechanical effect of isolated capitate shortening in Kienbock's disease: an anatomical study.

Multiple operations have been proposed to slow the progression of osteonecrosis and secondary carpal damage in Kienböck's disease. To assess the biomechanical changes after capitate shorting, we inserted pressure-testing devices into the carpal and radiocarpal joints in an anatomical study. Pressure sensors were placed into eight thawed non-fixated human cadaver arms to measure the forces transmitted in physiological loading. Longitudinal 9.8 N and 19.6 N forces were applied before and after capitate shortening. After capitate shortening, significant load reduction on the lunate was evident in all specimens. An average decrease of 49% was seen under a 9.8 N load and 56% under a 19.6 N load. The load was transferred to the radial and ulnar intercarpal joints. More relief of pressure on the lunate after isolated capitate shortening is achieved with a shallow angle between the scaphoid and capitate in the posteroanterior radiograph.

Bispectral index monitoring of midazolam and propofol sedation during endoscopic retrograde cholangiopancreatography: a randomized clinical trial (the EndoBIS study).

INTRODUCTION: Bispectral index (BIS) monitoring provides a non-invasive measure of the level of sedation. The purpose of this randomized, single-blind clinical trial was to evaluate whether BIS monitoring of sedation would lead to improved oxygenation and a reduced rate of cardiopulmonary complications during endoscopy. PATIENTS AND METHODS: Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) under procedural sedation with a combination of low dose midazolam and propofol were randomly assigned to either standard monitoring of sedation only (BIS-blinded arm) or an open arm in which additional BIS monitoring was available (BIS-open arm). In the BIS-open arm, propofol administration was to be withheld if BIS values were <55. The primary study end point was the mean oxygen saturation per patient. Secondary end points were the rates of cardiopulmonary complications, propofol dose, quality of sedation (patient cooperation as rated by the endoscopist and patient satisfaction), and recovery. RESULTS: A total of 144 patients were enrolled and included in the intention-to-treat analysis. Mean oxygen saturation per patient was 97.7% in the BIS-open arm and 97.6% in the BIS-blinded arm (P=0.71). Total rates of cardiopulmonary complications, single numbers of hypoxemic, bradycardic, and hypotensive events, mean propofol doses, and quality of sedation also showed no statistically significant differences between the groups. However, BIS monitoring did result in faster recovery of patients as reflected by shorter times to eye opening (P=0.001), first verbal response (P=0.02), and leaving the procedure room (P<0.001). CONCLUSIONS: The use of additional BIS monitoring did not lead to improved oxygenation or a reduced rate of cardiopulmonary complications. Recovery times after the procedure were shorter than with standard monitoring alone, but the clinical benefit for daily practice may be limited.

Head circumference, apolipoprotein E genotype and cognition in the Bavarian School Sisters Study.

BACKGROUND: The apolipoprotein E (APOE) ɛ4 allele is correlated with an earlier onset of Alzheimer's disease symptoms; larger head circumference has been associated with an individual resilience against cognitive impairment. METHODS: We explored if larger head circumference attenuates the effect of the APOE ɛ4 allele on cognition in 380 Catholic sisters covering the spectrum from normal cognitive performance to severe dementia. RESULTS: Linear regression analysis, adjusting for risk factors for cognitive decline, revealed that APOE ɛ4 was correlated with worse cognition and that larger head circumference attenuated the negative effect of the ɛ4 allele on cognitive performance. CONCLUSION: Larger head circumference (i.e. larger brain size) seems to be associated with greater resilience against genetic determinants of cognitive impairment, possibly due to enhanced brain or cognitive reserve.

Disturbances of basal and postprandial insulin secretion and clearance in obese patients with type 2 diabetes mellitus.

Hyperinsulinemia of nondiabetic overweight and obese subjects is associated with weight-dependent increased insulin secretion and decreased insulin clearance. The present analysis examines whether similar effects can be observed in overweight and obese patients with type 2 diabetes mellitus (DM2). Additionally basal and postprandial insulin secretion and clearance were analyzed in relation to duration of disease. In a random sample of 348 DM2 patients basal plasma insulin concentrations were significantly higher in most BMI groups compared to matched nondiabetic (ND) controls. The weight-dependent increase of basal insulin in DM2 was primarily the result of reduced clearance rather than augmented secretion. Postprandial insulin concentrations were lower in DM2 patients and did not show any BMI-related increase. The weight-dependent reduction of postprandial insulin clearance was absent in DM2. At the time of diagnosis basal insulin concentration was higher and secretion was comparable to ND subjects and this did not change with duration of diabetes. The early postprandial insulin response was still comparable between DM2 and ND subjects at the time of diagnosis but deteriorated with longer duration of disease. The later postprandial response at diagnosis (AUC 90-180) was characterized by significantly greater insulin secretion and concentration while later on the 3-fold higher secretion was paralleled by comparable peripheral plasma concentrations due to a significantly greater postprandial insulin clearance in DM2. In conclusion, the present data indicate that apart from disturbances of insulin secretion substantial changes of insulin clearance contribute to inadequate peripheral insulin concentrations in obese DM2 patients.

ARFI-based tissue elasticity quantification and kidney graft dysfunction: first clinical experiences.

BACKGROUND AND PURPOSE: Beyond the medical history, the clinical exam and lab findings, non-invasive ultrasound parameters such as kidney size and Doppler values (e.g. the resistive index) are important tools assisting clinical decision making in the monitoring of renal allografts. The gold standard for the diagnosis of renal allograft dysfunction remains the renal biopsy; while an invasive procedure, the justifiable necessity for this derives from its definitive nature a requirement beyond the synopses of all non-invasive tools. "Acoustic Radiation Force Impulse Imaging"(ARFI)-quantification is a novel ultrasound-based technology measuring tissue elasticity properties. So far experience related to this new method has not been reported in renal transplant follow-up. The purpose of this study was to evaluate changes in ARFI-measurements between clinically stable renal allografts and biopsy-proven transplant dysfunction. METHODS: We employed "Virtual Touch™ tissue quantification" (Siemens Acuson, S2000) for the quantitative measurement of tissue stiffness in the cortex of transplant kidneys. We performed initial baseline and later disease-evaluative ultrasound examinations in 8 renal transplant patients in a prospective study design. Patients were first examined during stable allograft function with a routine post-transplant renal ultrasound protocol. A second follow-up examination was carried out on subsequent presentation with transplant dysfunction prior to allograft biopsy and histological evaluation. All patiens were examined using ARFI-quantification (15 measurements/kidney). Resistive indices (RI) were calculated using pulsed-wave Doppler ultrasound, and transplant kidney size was measured on B-mode ultrasound images. All biopsies were evaluated histologically by a reference nephropathologist unaware of the results of the ultrasound studies. Histopathological diagnoses were based on biopsy results, taking clinical and laboratory findings into account. Finally we calculated the relative changes in ARFI-quantification, resistive indices and the absolute change of kidney size on a percentage basis at these defined assessment times and compared the results with the final pathologic diagnosis. RESULTS: Histological results enumerated five cases of acute T-cell-mediated rejection, one case of calcineurin inhibitor toxicity and two cases of acute tubular necrosis. Calcineurin inhibitor toxicity and acute tubular necrosis were subsumed as "other pathologies". Mean ARFI-values showed an average increase of more than 15% percent in transplants with histologically proven acute rejection whereas no increase was seen in transplants with other pathologies. Mean RI-values showed no increase either in the diagnostic group of acute rejection, nor in the group with other pathologies. Kidney size showed a mean absolute increase of 0.5 centimetres in allografts with acute rejection, whereas a mean decrease of 0.17 centimetres was seen in the group with other pathologies. CONCLUSION: As shown before in other studies, RI values and kidney size are of doubtful utility in the evaluation of kidney allograft dysfunction. ARFI-based elasticity measurement shows promise as a complementary non-invasive parameter in follow-on diagnosis of renal allograft rejection.

Head circumference, atrophy, and cognition: implications for brain reserve in Alzheimer disease.

BACKGROUND: Clinical and epidemiologic studies suggest that patients with Alzheimer disease (AD) with larger head circumference have better cognitive performance at the same level of brain pathology than subjects with smaller head circumference. METHODS: A total of 270 patients with AD participating in the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study underwent cognitive testing, APOE genotyping, and MRI of the brain in a cross-sectional study. Linear regression analysis was used to examine the association between cerebral atrophy, as a proxy for AD pathology, and level of cognitive function, adjusting for age, duration of AD symptoms, gender, head circumference, APOE genotype, diabetes mellitus, hypertension, major depression, and ethnicity. An interaction term between atrophy and head circumference was introduced to explore if head circumference modified the association between cerebral atrophy and cognition. RESULTS: There was a significant inverse association between atrophy and cognitive function, and a significant interaction between atrophy and head circumference. With greater levels of atrophy, cognition was higher for individuals with greater head circumference. CONCLUSION: This study suggests that larger head circumference is associated with less cognitive impairment in the face of cerebral atrophy. This finding supports the notion that head circumference (and presumably brain size) offers protection against AD symptoms through enhanced brain reserve.

Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants on eczema risk.

BACKGROUND: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. METHODS: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls. RESULTS: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected. CONCLUSIONS: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk.

Examination of the current top candidate genes for AD in a genome-wide association study.

With the advent of technologies that allow simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the 'Top Results' list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case-control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with AD.

Relation of plasma obestatin levels to bmi, gender, age and insulin.

Obestatin is supposed to be involved in nutrient homeostasis. Therefore, basal plasma obestatin levels were investigated in 321 normal weight and obese subjects in relation to body mass index, gender, age, insulin concentrations, and type 2 diabetes mellitus. Additionally, postprandial obestatin levels were determined in 20 normal weight subjects. Basal obestatin levels in females were higher compared to males (193.6+/-5.8 vs. 140.6+/-5.1 pg/ml). Obestatin levels correlated inversely and significantly with body mass index (f: r=-0.632, p<0.001; m: r=-0.487, p<0.001) and basal insulin levels (f: r=-0.536, p<0.001; m: r=-0.320, p=0.008) in females and males. However, in a multiple regression analysis as well as in a matched comparison of a low and high insulin group no significant relationship between insulin and obestatin levels was observed in nondiabetics. On the other hand, inclusion of type 2 diabetics with higher insulin levels resulted in a significant inverse correlation. Obestatin levels were independent of age in both sexes. In patients with type 2 diabetes mellitus basal obestatin levels were not different compared to nondiabetic subjects when matched for gender, body mass index, and insulin. In normal weight subjects, postprandial obestatin levels showed a significant decrease between 60 and 90 minutes rising to basal levels thereafter. The present data demonstrate a relation of plasma obestatin levels to body weight, gender and food intake, but not to age. The inverse relationship with insulin might depend on the level of hyperinsulinemia. The present data are compatible with a potential role of obestatin in nutrient regulation.

Putative association of a TLR9 promoter polymorphism with atopic eczema.

BACKGROUND: Toll-like receptors (TLR) play a pivotal role in the induction of first-line defense mechanisms of the innate immune system and trigger adaptive immune responses to microbial pathogens. Genetic variations in innate immunity genes have been reported to be associated with a range of inflammatory disorders. Deficiencies on the level of immunity receptors such as pathogen-recognition receptors are suspected to affect the maturation of our immune system and to avail thereby the high prevalence of atopic diseases and susceptibility of atopic patients to microbial infections. AIMS OF THE STUDY: We evaluated TLR9 as susceptibility gene for atopic eczema (AE). METHODS: Analyses of four tag single-nucleotide polymorphisms in two panels of families containing a total of 483 parent-affected offspring trios as well as a cohort of 274 unrelated adult AE cases and 252 hypernormal population-based controls have been performed. RESULTS: In both family cohorts, polymorphism C-1237T, which is located within the promoter region of the TLR9 gene, was significantly associated with AE, in particular the intrinsic subtype of AE. No associations were seen in the case-control cohort. Luciferase reporter gene assays revealed significantly higher promoter activity of the TT allelic variant at this single nucleotide polymorphism site. CONCLUSION: These observations suggest that the TLR9 promoter polymorphism C-1237T might affect AE susceptibility in particular in patients with the intrinsic variant of AE.

[Cholinesterase inhibitors and Alzheimer's disease: meta-analysis of the verification of effectiveness, origin and bias of results in published studies]. / Cholinesterase-Inhibitoren und Alzheimer-Demenz: Metaanalyse zu Wirksamkeitsnachweis, Ursprung und Ergebnisverzerrung in publizierten Studien.

BACKGROUND AND OBJECTIVE: The cholinesterase-inhibitors (AChE-I) donepezil, galantamine and rivastigmine are currently used in the symptomatic treatment of patients with Alzheimer's dementia (AD) and the associated cholinergic deficits as well as those with other forms of dementia. Three aspects were analysed: (1) data on their clinical efficacy, (2) differences between North-American and international studies, and (3) potential publication biases. METHODS: Included were data from randomized, placebo-controlled, double-blind parallel group trials on more than 100 patients who had been treated for > or =12 weeks for AD, VaD, dementia with Lewy bodies, dementia with Parkinson's disease or with mild cognitive impairment. RESULTS: These large published trials support the clinical efficacy of AChE-I in patients with mild to moderate AD and other forms of dementia with regard to cognition and global impression. there was a trend towards greater beneficial cognitive effects in North-American studies, but this was non-significant. There was no evidence of a publication bias. CONCLUSIONS: Published data provide evidence for the clinical efficacy of donepezil, galantamine and rivastigmine in patients with mild to moderate AD. There is no indication that these results are critically influenced by the origin or a bias of the publication.

Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography.

BACKGROUND: Functional imaging studies report that higher education is associated with more severe pathology in patients with Alzheimer's disease, controlling for disease severity. Therefore, schooling seems to provide brain reserve against neurodegeneration. OBJECTIVE: To provide further evidence for brain reserve in a large sample, using a sensitive technique for the indirect assessment of brain abnormality (18F-fluoro-deoxy-glucose-positron emission tomography (FDG-PET)), a comprehensive measure of global cognitive impairment to control for disease severity (total score of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery) and an approach unbiased by predefined regions of interest for the statistical analysis (statistical parametric mapping (SPM)). METHODS: 93 patients with mild Alzheimer's disease and 16 healthy controls underwent 18F-FDG-PET imaging of the brain. A linear regression analysis with education as independent and glucose utilisation as dependent variables, adjusted for global cognitive status and demographic variables, was conducted in SPM2. RESULTS: The regression analysis showed a marked inverse association between years of schooling and glucose metabolism in the posterior temporo-occipital association cortex and the precuneus in the left hemisphere. CONCLUSIONS: In line with previous reports, the findings suggest that education is associated with brain reserve and that people with higher education can cope with brain damage for a longer time.