Impact of immunosuppressive therapy on therapy-neutralizing antibodies in transplanted patients with Fabry disease.

BACKGROUND: Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. METHODS: In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. RESULTS: No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. CONCLUSION: We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males.

Development of a conjunctival tissue substitute on the basis of plastic compressed collagen.

Ocular surface disorders, such as pterygium, cicatricial pemphigoid and external disruptions, can cause severe inflammation, scarring, fornix shortening as well as ankyloblepharon. Current treatments do not resolve these conditions sufficiently. The aim of this study was to evaluate clinical applicability and suitability of plastic compressed collagen to serve as a substrate for the expansion of human conjunctival epithelial cells in order to develop an epithelialized conjunctival substitute for fornix reconstruction. Human conjunctival epithelial cells were expanded on plastic compressed collagen gels. Epithelial cell characteristics were evaluated by haematoxylin and eosin staining, electron microscopy and cytokeratin expression. The expression of putative epithelial progenitor cell markers p63α, ABCG2 and CK15 was assessed by immunostaining. The proliferative capacity and clonal growth of the cells was evaluated before (P0) and after expansion (P1) on the plastic compressed collagen gels by colony forming efficiency assay. The potential clinical applicability of this gel substitutes was evaluated by assessment of their biomechanical properties as well as their surgical handling. Human conjunctival epithelial cells cultured on plastic and plastic compressed collagen gels formed a confluent cell layer and expressed CK19. The cells showed expression of the putative epithelial progenitor cell markers p63α, ABCG2 and CK15 and sustained colony forming ability. The compressed collagen gels showed a high ultimate tensile strength and elasticity and the surgical handling of gels was comparable to amniotic membrane. An epithelialized conjunctival tissue construct on the basis of compressed collagen might therefore be a promising alternative bioartificial tissue substitute for conjunctival reconstruction. Copyright © 2015 John Wiley & Sons, Ltd.

Aldosterone to active Renin ratio as screening test for primary aldosteronism: reproducibility and influence of orthostasis and salt loading.

Measurement of the aldosterone to active renin ratio (AARR) is the recommended screening test for primary aldosteronism (PA), but several sampling conditions impact on the AARR. We aimed to evaluate the reproducibility and the influence of orthostasis and salt loading on the AARR. The Graz Endocrine Causes of Hypertension (GECOH) study is a diagnostic accuracy study among hypertensive patients at a tertiary care centre in Graz, Austria. With a median interval of 4 weeks we determined the AARR under standardized sampling conditions twice in the sitting position, after 1h in the supine position, and after a salt infusion test (SIT). We identified 9 patients with PA and 151 patients with essential hypertension (EH). The Pearson correlation coefficient between both AARR measurements in the sitting position was 0.79 (p<0.001). In EH, recumbency was associated with a significant decrease of aldosterone and, to a lesser extent, of renin, thus lowering the AARR as compared to the sitting position (p<0.001 for all). In PA, recumbency had only minor effects, but it increased the rate of false negative AARR. SIT suppressed the AARR and its components in EH, whereas in PA only renin was slightly decreased. AARR has a good intra-individual reproducibility and decreases during recumbency. These results suggest that a single AARR determination in the sitting position is a reliable screening tool for PA.

Associations of homoarginine with bone metabolism and density, muscle strength and mortality: cross-sectional and prospective data from 506 female nursing home patients.

UNLABELLED: In female nursing home patients, homoarginine was associated with lower bone turnover, higher bone density, lower mortality and, by trend, with muscle strength. INTRODUCTION: Homoarginine, a cationic amino acid, may be relevant for muscusloskeletal health because it inhibits alkaline phosphatases (AP) and is involved in nitric oxide and energy metabolism. We aimed to evaluate whether homoarginine serum concentrations are associated with bone density and metabolism, muscle strength, fractures and mortality. METHODS: We examined a cohort of female nursing home patients that underwent quantitative bone ultrasound (QUS) measurements and assessments of knee extensor strength. Measurements of serum homoarginine, C-terminal telopeptide cross-links (ß-CTxs) and osteocalcin were also performed at baseline. Thereafter, patients were followed-up with respect to fractures and mortality. RESULTS: Serum homoarginine concentrations were determined in 506 female study participants (mean age: 83.9 ± 6.0 years). Homoarginine was inversely correlated with ß-CTxs (r = -0.26; p < 0.001) and osteocalcin (r = -0.21; p < 0.001), and these associations remained significant in multiple regression analyses. Multivariate regression analyses showed that homoarginine is significantly associated with calcaneus stiffness (beta coefficient = 0.11; p = 0.020) and by trend with knee extensor strength (beta coefficient = 0.09; p = 0.065). During a mean follow-up time of 27 ± 8 months, we recorded 119 deaths (23.5%) and 63 fractures (12.5%). In multivariate analyses, homoarginine was associated with significantly reduced risk of mortality and the combined endpoint of fractures and mortality. CONCLUSIONS: Whether homoarginine metabolism is critically involved into the pathogenesis of musculoskeletal diseases and fatal events warrants further studies.

Apolipoprotein A-IV concentrations and clinical outcomes in haemodialysis patients with type 2 diabetes mellitus--a post hoc analysis of the 4D Study.

BACKGROUND: Apolipoprotein A-IV (apoA-IV) is an anti-atherogenic and anti-oxidative plasma glycoprotein involved in reverse cholesterol transport. The aim of this study was to examine the association between apoA-IV and all-cause mortality, cardiovascular endpoints and parameters of protein-energy wasting and nutrition in haemodialysis patients. METHODS: This post hoc analysis was performed in the German Diabetes Dialysis Study (4D Study) evaluating atorvastatin in 1255 haemodialysis patients with type 2 diabetes mellitus, followed for a median of 4 years. The association between apoA-IV and relevant outcomes was analysed using Cox proportional hazards regression analyses. Body mass index (BMI) was used as a marker of protein-energy wasting. In addition, a definition of extended wasting was applied, combining median values of BMI, serum albumin, creatinine and sensitive C-reactive protein, to classify patients. RESULTS: Mean (±SD) apoA-IV concentration was 49.8 ± 14.2 mg dL(-1). Age- and gender-adjusted apoA-IV concentrations were strongly associated with the presence of congestive heart failure at baseline [odds ratio = 0.81, 95% confidence interval (CI) 0.74-0.88 per 10 mg dL(-1) increase; P < 0.001). During the prospective follow-up, the strongest association was found for all-cause mortality [hazard ratio (HR) = 0.89, 95% CI 0.85-0.95, P = 0.001), which was mainly because of patients with BMI > 23 kg m(-2) (HR = 0.87, 95% CI 0.82-0.94, P < 0.001) and those in the nonwasting group according to the extended definition (HR = 0.89, 95% CI 0.84-0.96, P = 0.001). This association remained significant after additionally adjusting for parameters associated with apoA-IV at baseline. Further associations were observed for sudden cardiac death. ApoA-IV was less strongly associated with atherogenic events such as myocardial infarction. CONCLUSIONS: Low apoA-IV levels seem to be a risk predictor of all-cause mortality and sudden cardiac death. This association might be modified by nutritional status.

The EQUAL study: a European study in chronic kidney disease stage 4 patients.

The timing of the start of dialysis in elderly patients is driven by the desire to optimize the quantity and quality of life. Limited data exist on how the level of renal function, and uraemic signs and symptoms can be used to determine when dialysis should be initiated in elderly patients. EQUAL, an international prospective cohort study, aims to address these issues. To this end, it will enroll 3500 patients >65 years of age with CKD of various aetiologies under the care of nephrologists. These patients will be followed until death, discharge from the nephrology clinic to primary care or until the end of the observation period after 4 years of follow-up. At the time of enrollment, patients must have an estimated glomerular filtration rate (eGFR) of 20 mL/min/1.73 m(2) or lower, but should not yet be on dialysis. Standardized data collection will include demographics, lifestyle, comorbidities, uraemic signs and symptoms, nutritional status, medication and routine blood and urine biochemistry. It will also comprise quality of life data, information on decision making including patients preferences and patients satisfaction.

[Phenotyping of type 2 diabetes mellitus by "genetic field work": are data sufficient that are based only on a questionnaire?]. / Phänotypisierung durch "genetic field work": Ist die Datenerhebung durch Fragebögen ausreichend?

BACKGROUND AND OBJECTIVE: Genetic studies of complex diseases such as diabetes mellitus (DM) require the recruitment of patients and acquisition of patient data in a time- and cost-effective manner. An effective method to do so may be genetic field work (GFW) that recruits the relatives of index cases, these relatives then replying to appropriate questionnaires. This study investigated the validity of GFW data compared with patient interviews by a physician who had examined those persons. METHODS: 122 relatives were identified through GFW among a cohort of 35 families with DM. Questionnaires with self-reported information on past medical history, cardiovascular risk factors and life style were obtained. In a second step these famiy members were interviewed and examined by a physician in an outpatient setting. RESULTS: Comparison of the two data sets of the 122 individuals yielded clear differences which favored interviews by a physician. The number of persons declaring themselves as having DM was significantly lower by GFW than direct examination (18 vs. 27). Diabetic nephropathy was reported by four individuals by GFW, while examination resulted in the identification of 16 cases. Body weight was also clearly too low when self-reported, so that significantly lower values were recorded for BMI in the questionnaire. Hypertension was reported by 25 vs. 54 participants. The amount of cigarettes smoked was significant lower in the GFW than in physicians' examination. But the numbers recorded for myocardial infarction, peripheral vascular disease and stroke were not significantly different. CONCLUSION: These data show that information obtained by GFW is less accurate than that collected in interview and examination by physicians. The latter are necessary to gain valid data for accurate phenotyping, while GFW is useful in the initial recruitment of relatives.

[Selected light microscopy and polarization optical studies of implant-bone interfaces]. / Ausgewählte durchlichtmikroskopische und polarisationsoptische Untersuchungen des Implantat-Knochen-Grenzbereiches.

Implant bone specimen of inert materials and of the material BVK Ap 40 mended histologically. The bone specimen were both decalcified and carried to the polish technique after plastics embedding. The experiments were carried out in miniature swines (type Mini-Lewe) and rabbits. Microscopical and polarisation optical investigations were carried out. A connective-tissue membrane was provable at the interface implant-bone in all cases with use of the biocompatible material titanium. With BVK Ap 40 was observed a direct compound with the bone.