[Biobanks, translational research and medical informatics]. / Biobanken, translationale Forschung und Medizininformatik.

When we think of medical research, one intuitively associates it with the analysis of study data collected for a specific research question or with the secondary use of patient data from routine care. However, these are not the only sources for answering scientific questions. Especially for translational research, tissue and liquid samples such as blood, DNA or other body fluids provide essential insights into disease pathogenesis, development of new therapies and treatment decisions. Access to these biomedical materials is provided by so-called biobanks. By collecting, characterizing, documenting and, if necessary, processing human biospecimens in accordance with high quality standards, they can support research of the causes of diseases, early diagnosis and the targeted treatment of diseases, or make a significant contribution to the investigation of common diseases.

Variations in cardiovascular risk factors in people with and without migration background in Germany - Results from the STAAB cohort study.

BACKGROUND: About 20% of the German population have a migration background which might influence prevalence of preventable cardiovascular risk factors (CVRF). METHODS: We report data of the prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of inhabitants of the City of Würzburg, Germany, aged 30 to 79 years. Individuals without migration background were defined as follows: German as native language, no other native language, and/or born in Germany. All other participants were defined as individuals with migration background. RESULTS: Of 2473 subjects (51% female, mean age 54 ±â€¯12 years), 291 (12%) reported a migration background: n = 107 (37%) from a country within the EU, n = 117 (40%) from Russia, and n = 67 (23%) from other countries. Prevalence of hypertension, atherosclerotic disease, and diabetes mellitus was similar in individuals with and without migration background. By contrast, prevalence of obesity and metabolic syndrome was significantly higher in individuals with migration background, with the least favourable profile apparent in individuals from Russia (individuals without vs. with migration background: obesity 19 vs. 24%, p < 0.05; odds ratio: EU: 1.6, Russia: 2.2*, other countries: 0.6; metabolic syndrome 18 vs. 21%, p < 0.05; odds ratio: EU: 1.2, Russia: 1.7*, other countries: 1.5; *p < 0.05). CONCLUSION: Individuals with migration background in Germany might exhibit a higher CVRF burden due to a higher prevalence of obesity and metabolic syndrome. Strategies for primary prevention of heart failure may benefit from deliberately considering the migration background.

A template for broad consent in biobank research. Results and explanation of an evidence and consensus-based development process.

BACKGROUND: Biobanks increasingly presume long-term storage of biomaterials and data that shall be used for future research projects which are today unspecified. Appropriate consent documents for sample donors must therefore explain the breadth of consent and other elements of the biobank governance framework. Recent reviews demonstrated high variability in what issues these documents mention or not and how the issues are explained. This might undermine the protection of sample donors, complicate networked biobank research, create research waste and impact on public trust. METHODS: A systematic analysis of international research guidelines and existing broad consent templates was performed. Based on this information an interdisciplinary expert group from the AKMEK (Permanent Working Party of German RECs) developed a draft template and organized a comprehensive stakeholder consultation. After revision the final template was consented by all 53 German RECs. RESULTS: This paper briefly explores the spectrum of potentially relevant issues for broad consent forms. It then elaborates the template and how it was designed to be applicable in different types of biobanks. DISCUSSION: To further improve the validity and applicability of broad consent forms in biobank and other big data research, practice evaluations are needed. We hope that in this regard the presented template supports the development of new consent forms as well as the evaluation and revision of existing ones.

Antibodies to cardiac receptors.

Inflammation of cardiac tissue is generally associated with an activation of the host's immune system. On the one hand, this activation is mandatory to protect the heart by fighting the invading microbial agents or toxins and by engaging myocardial reparation and healing processes. On the other hand, uncontrolled activation of the immune defense has the risk of an arousal of auto- or cross-reactive immune cells, which in some cases bring more harm than good. Dependent on the individual genetic predisposition, such heart-directed autoimmune reactions most likely occur as a result of myocyte apoptosis or necrosis and subsequent liberation of self-antigens previously hidden to the immune system. During the past two decades, evidence for a pathogenic relevance of autoimmunity in human heart disease has substantially increased. Conformational cardiac (auto)antibodies affecting cardiac function and, in particular, (auto)antibodies that target G protein-coupled cardiac membrane receptors are thought to play a key role in the development of heart failure. Clinical pilot studies even suggest that such antibodies negatively affect survival in heart failure patients. However, the true prevalence and clinical impact of many cardiac (auto)antibodies in human heart diseases are still unclear, as are the events triggering their formation, their titer course, and their patterns of clearance and/or persistence. The present article summarizes current knowledge in the field of cardiac receptor (auto)antibodies including recent efforts to address some of the aforementioned gaps of knowledge, thereby attempting to pave the way for novel, more specific therapeutic approaches.

Contemplative meditation reduces ambulatory blood pressure and stress-induced hypertension: a randomized pilot trial.

A total of 52 pharmacologically untreated subjects with essential hypertension were randomly allocated to either 8 weeks of contemplative meditation combined with breathing techniques (CMBT) or no intervention in this observer-blind controlled pilot trial. CMBT induced clinically relevant and consistent decreases in heart rate, systolic and diastolic blood pressure if measured during office readings, 24-h ambulatory monitoring and mental stress test. Longer-term studies should evaluate CMBT as an antihypertensive strategy.

[Hormone inactive parathyroid cyst: rare differential diagnosis in the evaluation of cervical cysts]. / Hormoninaktive Nebenschilddrüsenzyste: eine seltene Differenzialdiagnose bei zystischen Veränderungen im Halsbereich.

Parathyroid cysts are a very rare disease entity. Hormone activity is uncommon and they usually present without any clinical symptoms. The differential diagnosis of cystic neck masses should nevertheless include parathyroid cysts as surgical therapy can be very effective. We report the case of a 57-year-old patient presenting to our department with a hormone inactive parathyroid cyst. Final diagnosis was achieved eventually after histological examination of the resected specimen, which is the reason for evaluating the current data for preoperative management of this disease entity in this case report.

Exacerbation of Whipple's disease associated with infliximab treatment.

A 34-year-old man with chronic inflammatory joint disease and recurrent fever over 6 years was diagnosed as having Still's disease. Treatment with corticosteroids and azathioprine was ineffective. Therefore, infliximab/ methotrexate was started. The patient subsequently developed a wasting disease with rapid weight loss, erythema nodosum, diarrhoea, progressive lymph node enlargement, and a sigmoido-vesical fistula. Histological analysis of several enlarged lymph nodes, the margins of the fistula, and the small bowel established the diagnosis of Whipple's disease (WD). The presence of Tropheryma whipplei (Tw) DNA in the tissues was confirmed by polymerase chain reaction (PCR). Careful re-evaluation of biopsies taken from the ileum and the liver 2 years earlier, which at that time was not judged to be diagnostic for WD, retrospectively showed subtle histological signs of WD and were positive for Tw DNA. In summary, infliximab treatment seems to increase the risk of exacerbation of WD. WD should be carefully ruled out prior to application of tumour necrosis factor-alpha (TNF-alpha) blockade.

Metallic stents and plastic endoprostheses in percutaneous treatment of biliary obstruction.

BACKGROUND: In the light of the clinical controversy whether metallic stents or plastic endoprostheses should be used in the percutaneous treatment of biliary obstruction we retrospectively evaluated our experience with both drainage-systems. METHODS: 71 patients (mean age 68 +/- 12 years) underwent a total of 81 interventions and received either plastic endoprostheses (11.5 or 12 French diameter; N = 57/81) or metallic stents (N = 24/81). RESULTS: Drainage insertion was technically successful in all of the 71 patients. There was no procedure-related mortality, but a 30-day mortality of 15 % (N = 11). Overall, 27 complications occurred in 81 interventions with a statistically significant higher complication-rate in plastic endoprostheses (39 %; N = 21/54) compared to metallic stents (22 %; N = 6/27). The average patency of the drainage-systems was 166 +/- 341 days (range 1-2,705 days) and did not differ significantly between the drainage-subtypes. Incidence of complications and a further increase in serum bilirubin following intervention was associated with a higher drainage occlusion-rate and reduced survival, irrespective of the drainage-system used. CONCLUSIONS: Percutaneous transhepatic treatment of biliary obstructions with internal drainages is a reliable therapy. The overall complication-rate of metallic stents was lower compared to plastic endoprostheses; however, no significant differences were found with respect to drainage patency or success-rate.

High resolution ultrasound detects a decrease in pannus vascularisation of small finger joints in patients with rheumatoid arthritis receiving treatment with soluble tumour necrosis factor alpha receptor (etanercept).

OBJECTIVE: High resolution ultrasound (HRUS) was used to investigate the effects of tumour necrosis factor alpha (TNFalpha) blockade on pannus formation and vascularisation of small finger joints in patients with active rheumatoid arthritis (RA). METHODS: Five patients with active RA were treated with etanercept, a soluble TNFalpha receptor protein, for one month. Before, during, and after treatment the patients were followed up by clinical rheumatological examination, determination of their subjective pain score, blood chemistry, and by HRUS of the second metacarpophalangeal (MCP) joint of the right hand. RESULTS: One month after treatment with etanercept, rheumatological examination showed a significant decrease in a modified single joint rheumatic disease activity index (from 2.9 (SD 0.2) to 1.2 (0.7); p<0.05) in all patients. Moreover, a significant decrease in the general pain score (from 4.7 (0.4) to 1.8 (0.6); p<0.05) and in C reactive protein (CRP) levels was seen (from 3.02 (0.9) to 0.24 (0.1); p<0.05). Concordantly, HRUS showed a significant reduction in pannus vascularisation of the MCPII joints (from 23,602 (5339) to 2907 (1609) colour signals/region of interest, CS/ROI; p<0.001). Pearson's correlation coefficient between the results obtained by HRUS and the clinical response was 0.85. CONCLUSION: HRUS is promising as an additional useful method in the assessment of RA activity, and probably also in monitoring therapeutic responses.

Comparison of axial reconstructed ultrasonographic images from three-dimensional data volumes and computed tomographic scans in the documentation and detection of liver lesions.

OBJECTIVE: To compare axial reconstructed ultrasonographic images from three-dimensional data volumes and conventional computed tomographic scans in documentation and detection of liver lesions. METHODS: The livers of 23 patients were examined by a multifrequency curved array transducer to acquire three-dimensional data volumes and by conventional computed tomography The ultrasonographic device was equipped with three-dimensional ultrasonographic technology allowing for real-time parallel movement in every plane within an acquired data volume. Axial ultrasonographic images reconstructed from three-dimensional data volumes were compared with conventional computed tomographic scans. RESULTS: When both methods were taken together, a total of 51 different liver lesions could be detected. Reconstructed ultrasonographic images depicted 44 (86%) of 51 lesions, and computed tomographic scans showed 46 (90%) of 51 lesions. Compared with computed tomography, ultrasonography depicted 5 additional lesions in 3 of the patients (4 hemagiomas and 1 unspecified lesion), whereas 7 lesions were missed in another 4 patients (4 metastases, 2 calcifications, and 1 cyst). The Pearson correlation coefficient between ultrasonography and computed tomography was r = 0.84 (P < .001). CONCLUSIONS: Our study shows that ultrasonographic images can be effectively reconstructed from three-dimensional data volumes. With respect to documentation and detection of liver lesions, the results obtained by three-dimensional ultrasonography appear comparable with those obtained by conventional computed tomography. However, several technical and procedural limitations have to be respected.

Immunofluorescent imaging of beta 1- and beta 2-adrenergic receptors in rat kidney.

BACKGROUND: beta-Adrenergic receptors (beta-ARs) are known to participate in the regulation of glomerular filtration, NaCl reabsorption, acid-base balance, and renin secretion; however, the precise histologic localization of beta-AR at putative signaling sites involved in these processes remains an open issue. METHODS: We used a set of subtype-specific rabbit antibodies to visualize beta(1)- and beta(2)-AR in rat kidney by immunohistochemistry and specified cells and segments of the nephron thought to be regulated by catecholamines. In addition, the relative proportion of beta-AR subtypes in cortical and medullary portions of rat kidney was determined by Western blotting and by competing [(125)I]-cyanopindolol binding with the beta(1)- or beta(2)-selective antagonists bisoprolol or ICI 118,551, respectively. RESULTS: Immunoreactivity for beta(1)-AR was found in mesangial cells, juxtaglomerular granular cells, the macula densa epithelium, proximal and distal tubular segments, and acid-secreting type A intercalated cells of the cortical and medullary collecting ducts. Immunoreactivity for beta(2)-AR was predominantly localized in the apical and subapical compartment of proximal and, to a lesser extent, distal tubular epithelia (suggesting interactions with luminal fluid catecholamines). Both subtypes were dense in the membranes of smooth muscle cells from renal arteries. Concordant data were obtained by radioligand binding and immunoblotting of membranes prepared from cortical and medullary portions of the kidney. CONCLUSION: Our data provide an immunohistochemical basis for the cellular targets of beta-adrenergic regulation of renal function. Moreover, they could help to devise therapeutic strategies directed at renal beta-ARs.

Assessment of microvascular changes in Raynaud's phenomenon and connective tissue disease using colour doppler ultrasound.

OBJECTIVE: We used colour Doppler ultrasound (CDU) to differentiate primary from secondary Raynaud's phenomenon (pRP and sRP, respectively) and to assess digital vascular damage in patients with connective tissue disease (CTD). METHODS: Vascularity in the nailbeds of 15 healthy controls and 35 patients with CTD (systemic sclerosis or systemic lupus erythematosus) was quantified using a multi-D array transducer before and after cold and warm challenge, respectively. The results were compared with the clinically evaluated initial skin lesions. Vascularity was compared similarly between 10 pRP and 22 sRP patients. RESULTS: Vascularity at ambient temperature differed between healthy subjects and sRP patients as well as between healthy subjects and CTD patients without initial skin lesions. Patients with pRP had normal vascularity at ambient temperature but differed from healthy controls in response to a dynamic temperature challenge. CDU confirmed the clinical evaluation in 89.4% of the patients with RP and in 78.0% of the skin lesions. CONCLUSION: The novel CDU technique presented here makes it possible to discriminate between pRP and sRP and to quantify vascular changes in CTD patients.

Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies.

OBJECTIVES: Our study attempted to gain further understanding of the allosteric effects of human autoantibodies on beta1-adrenergic receptor (beta1-AR) function. BACKGROUND: Recently, we reported on the existence of activating anti-beta1-AR antibodies in patients with dilated cardiomyopathy (DCM 26% prevalence) or ischemic cardiomyopathy (ICM, 10% prevalence); however, their functional effects have not yet been thoroughly characterized. METHODS: In this study we detected functionally active receptor-antibodies in 8 out of 30 DCM patients. Their immunological and functional properties were analyzed using both synthetic receptor-peptides and intact recombinant human beta1-AR, and were compared with those of heterologous antibodies to selected beta1-AR domains generated in rabbits and mice. RESULTS: Rabbit, mouse, and human anti-beta1-AR against the second extracellular domain preferentially bound to a native receptor conformation and impaired radioligand binding to the receptor. However, their functional effects differed considerably: Rabbit and mouse antibodies decreased both basal and agonist-stimulated cAMP production, whereas the patient antibodies (n = 8) increased basal, and six of them also increased agonist-stimulated receptor activity (i.e., acted as receptor-sensitizing agents). Two out of eight human anti-beta1-AR increased basal but decreased agonist-stimulated receptor activity (i.e., acted as partial agonists). CONCLUSIONS: Antibodies against the same small beta1-AR domain can have very divergent allosteric effects, ranging from inhibitory to agonist-promoting activities. Activating autoantibodies were associated with severe cardiac dysfunction and thus might be involved in the development and/or course of human cardiomyopathy.

Three-dimensional power Doppler sonography in screening for carotid artery disease.

PURPOSE: Color Doppler sonography has gained considerable recognition as a noninvasive method to detect carotid artery disease and to assess the degree of carotid artery stenosis. However, results are highly operator-dependent and cannot be presented as survey images. The purpose of this study was to evaluate real-time 3-dimensional (3D) power Doppler sonography as a method for screening for atherosclerosis in the carotid arteries. METHODS: We prospectively screened 75 patients for carotid artery disease using both conventional color Doppler sonography and 3D power Doppler sonography, and the results from the 2 modalities were compared. A total of 150 common carotid arteries, 150 internal carotid arteries, and 150 external carotid arteries were examined utilizing a 7.5-MHz linear-array transducer combined with tissue harmonic imaging. RESULTS: Color Doppler sonography detected 297 normal or atherosclerotic arteries without stenosis, 57 arteries with mild (1-49%) stenosis, 41 with moderate (50-69%) stenosis, 32 with severe (70-99%) stenosis, and 9 with occlusions. The degree of stenosis determined by color Doppler sonography correlated with that determined by 3D power Doppler sonography (r = 0.982-0.998). Moreover, there was a good correlation between the measurements for both the length of the lesion and its distance from the bulb as determined by the 3D volume surveys and by color Doppler sonography (r = 0.986). The interobserver variability rate was 3.7% +/- 0.5%. Generally, the acquisition and reconstruction of the 3D data took less than 5 minutes. CONCLUSIONS: 3D power Doppler sonography is easy to perform and is an accurate method in screening for atherosclerotic lesions of the carotid arteries. Moreover, it provides excellent 3D volume surveys that may be helpful in the planning of surgical treatment.

Rest and exercise hemodynamics before and after valve replacement--a combined Doppler/catheter study.

BACKGROUND: Hemodynamic improvement is a common finding following valve replacement. However, despite a normally functioning prosthesis and normal left ventricular ejection fraction, some patients may show an abnormal hemodynamic response to exercise. METHODS: In a combined catheter/Doppler study, rest and exercise hemodynamics were evaluated in 23 patients following aortic (n = 12) (Group 1) or mitral valve (n = 11) (Group 2) replacement and compared with preoperative findings. Patient selection was based on absence of coronary artery disease and left ventricular failure as shown by preoperative angiography. Cardiac output, pulmonary artery pressure, pulmonary capillary pressure, and pulmonary resistance were measured by right heart catheterization, whereas the gradient across the valve prosthesis was determined by Doppler echocardiography. Postoperative evaluation was done at rest and during exercise. The mean follow-up was 8.2 +/- 2.2 years in Group 1 and 4.2 +/- 1 years in Group 2. RESULTS: With exercise, there was a significant rise in cardiac output in both groups. In Group 1, mean pulmonary pressure/capillary pressure decreased from 24 +/- 9/18 +/- 9 mmHg preoperatively to 18 +/- 2/12 +/- 4 mmHg postoperatively (p < 0.05), and increased to 43 +/- 12/30 +/- 8 mmHg with exercise (p < 0.05). The corresponding values for Group 2 were 36 +/- 12/24 +/- 6 mmHg preoperatively, 24 +/- 7/17 +/- 6 mmHg postoperatively (p < 0.05), and 51 +/- 2/38 +/- 4 mmHg with exercise (p < 0.05). Pulmonary vascular resistance was 109 +/- 56 dyne.s.cm-5 preoperatively, 70 +/- 39 dyne.s.cm-5 postoperatively (p < 0.05), and 70 +/- 36 dyne.s.cm-5 with exercise in Group 1. The corresponding values for Group 2 were 241 +/- 155 dyne.s.cm-5, 116 +/- 39 dyne.s.cm-5 (p < 0.05), and 104 +/- 47 dyne.s.cm-5. There was a significant increase in the gradients across the valve prosthesis in both groups, showing a significant correlation between the gradient at rest and exercise. No correlation was found between valve prosthesis gradient and pulmonary pressures. CONCLUSION: Exercise-induced pulmonary hypertension and abnormal left ventricular filling pressures seem to be a frequent finding following aortic or mitral valve replacement. Both hemodynamic abnormalities seem not to be determined by obstruction to flow across the valve prosthesis and may be concealed, showing nearly normal values at rest but a pathologic response to physical stress.

Liposomal amphotericin B (AmBisome) application and hepatic microsomal enzyme function in the rat.

In the present study we investigated the influence of AmBisome, a lyophilized liposomal amphotericin B formulation on various hepatic cytochrome P450-dependent mixed function oxidases, antipyrine clearance and hepatic glucose-6-phosphatase activity in rats. Animals were treated intravenously for 6 days with AmBisome (15 mg kg-1 body weight). Subsequently, the enzyme activities and cytochrome P450 concentrations were measured ex vivo in hepatic microsomes. Following AmBisome the activity of the microsomal ethoxycoumarin-O-deethylase increased significantly from 333 +/- 77 pmol mg-1 to 459 +/- 125 pmol mg-1, whereas benzpyrenhydroxylase and glucose-6-phosphatase did not change compared with the controls. Accordingly, antipyrine clearance was not affected by AmBisome treatment. Microsomal cytochrome P450 concentrations as well as total microsomal protein concentrations were not changed following treatment with AmBisome and it did not affect either serum levels of liver transaminases or bilirubin. The results show that the application of a high AmBisome dose had no adverse effects on a variety of microsomal hepatic enzymes and the antipyrine clearance in rats. Thus, it seems likely that AmBisome does not seriously impair metabolic liver function.

Evaluation of pannus and vascularization of the metacarpophalangeal and proximal interphalangeal joints in rheumatoid arthritis by high-resolution ultrasound (multidimensional linear array).

OBJECTIVE: To evaluate the extent of intraarticular vascularization and pannus formation in metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of patients with rheumatoid arthritis (RA) by high-resolution ultrasound (US). METHODS: A newly developed, high-resolution multidimensional linear array US was utilized to obtain longitudinal and transverse scans of joints with active RA (n = 21), moderately active RA (n = 39), or inactive RA (n = 93), and of joints from healthy controls (n = 120). RESULTS: Healthy joints had no detectable pannus, whereas pannus could be detected in 52% of the joints with active RA, 82% of the joints with moderately active RA, and 67% of the joints with inactive RA. There was a significant difference in vascularization in the joints of all subgroups of RA patients and those of healthy subjects (P < 0.001). Moreover, vascularization differed significantly among the RA subgroups: inactive versus moderately active RA (P < 0.02) and inactive versus active RA (P < 0.05). Both pannus and vascularization appeared to be localized preferentially on the radial side of the joints. CONCLUSION: Evaluation of pannus and the extent of vascularization within the joints of patients with RA by high-resolution US might be helpful in the assessment of disease activity, and thus influence therapeutic strategies.