Donor-Recipient Matching Based on Predicted Indirectly Recognizable HLA Epitopes Independently Predicts the Incidence of De Novo Donor-Specific HLA Antibodies Following Renal Transplantation.

De novo donor-specific HLA antibodies (dnDSA) are recognized as a risk factor for premature allograft failure. Determinants of DSA specificity are generated via the indirect allorecognition pathway. Here, we present supportive data for the relevance of predicted indirectly recognizable HLA epitopes (PIRCHE) to predict dnDSA following kidney transplantation. A total of 2787 consecutive kidney transplants performed between 1995 and 2015 without preformed DSA have been analyzed. De novo DSA were detected by single antigen bead assay. HLA epitope mismatches were determined by the HLAMatchmaker and PIRCHE approach and correlated in uni- and multivariate analyses with 10-year allograft survival and incidence of dnDSA. The PIRCHE-II score moderately predicted allograft survival. However, the predictive value of elevated PIRCHE-II scores >9 for the incidence of dnDSA was statistically significant (p < 0.001). In a multivariate Cox regression analysis adjusted for antigen mismatch and HLAMatchmaker epitopes, the PIRCHE-II score could be identified as an independent risk factor for dnDSA. The PIRCHE-II score independently from the antigen mismatch and HLAMatchmaker epitopes could be revealed as being a strong predictor for dnDSA. PIRCHE may help to identify acceptable mismatches with decreased risk of dnDSA and thus improve long-term renal allograft survival.

[Epicardial fat: Imaging and implications for diseases of the cardiovascular system]. / Epikardiales Fett : Bildgebung und Bedeutung für Erkrankungen des kardiovaskulären Systems.

Since the discovery of the obese (ob) gene product leptin, fat has been considered an endocrine organ. Especially epicardial fat has gained increasing attention in recent years. The epicardial fat plays a major role in fat metabolism; however, harmful properties have also been reported. Echocardiography, computed tomography and cardiac magnetic resonance imaging are the non-invasive tools used to measure epicardial fat volume. This review briefly introduces the basic physiological and pathophysiological considerations concerning epicardial fat. The main issue of this review is the presentation of non-invasive measurement techniques of epicardial fat using various imaging modalities and a literature overview of associations between epicardial fat and common cardiovascular diseases.

[Assessment of systolic function in patients with poor echogenicity: echocardiographic methods]. / Abschätzung der linksventrikulären systolischen Funktion bei Patienten mit schlechter Bildqualität : Echokardiographische Methoden.

The visual echocardiographic evaluation of left ventricular (LV) systolic function can be cumbersome, especially in patients with poor image quality. This review describes several alternative echocardiographic methods to determine LV systolic function: endocardial border delineation by contrast agents, mitral annular plane systolic excursion, mitral annular velocity derived from tissue Doppler, myocardial performance index, mitral regurgitation derived LV dP/dtMax and estimation of cardiac output by Doppler echocardiography. The review introduces the respective methods along with the presentation of suitable measurements, clinical implications and methodological limitations.

Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications.

OBJECTIVE: The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease. METHODS: A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. RESULTS: During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. CONCLUSION: Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.

[Echocardiography in diabetic cardiomyopathy]. / Echokardiographie bei diabetischer Kardiomyopathie.

The term diabetic cardiomyopathy was initially introduced in the 1980s when evidence was found that diabetes leads to a distinct cardiomyopathy, independent of coronary artery disease or hypertension. The detection of diabetic cardiomyopathy using echocardiography is challenging because no pathognomonic signs exist; however, it is the merit especially of the newer echocardiographic techniques, such as deformation imaging, that it is now possible to describe the morphology and function of diabetic hearts. Unfortunately, no long-term echocardiography studies are available describing disease progression in detail. Therefore, staging and differential diagnosis of diabetic cardiomyopathy remains challenging. This review tries to fill this gap by presenting a possible echocardiographic staging algorithm. Early stages of diabetic cardiomyopathy are marked by a deterioration of longitudinal systolic function and a compensative elevated radial function. Diastolic dysfunction is another early sign. When the disease progresses the functional deterioration is accompanied by morphological changes, such as left ventricular concentric hypertrophy and fibrosis. End stage disease is characterized by reduced ejection fraction and ventricular dilatation. Very late stage can mimic dilative cardiomyopathy.

[Assessment of diastolic heart failure. Current role of echocardiography]. / Beurteilung der diastolischen Herzinsuffizienz. Aktueller Stellenwert der Echokardiographie.

Diastolic heart failure, also known as heart failure with preserved left ventricular ejection fraction (HF-pEF), is responsible for approximately 50 % of all heart failure cases. According to current guidelines the diagnosis HF-pEF requires three criteria: (1) signs or symptoms of heart failure, (2) presence of a normal left ventricular ejection fraction and (3) evidence of diastolic dysfunction. Echocardiography is the diagnostic modality of choice, especially after ruling out other causes of dyspnea, such as pulmonary diseases, heart rhythm disturbances and volume overload. Important echocardiographic parameters for the assessment of diastolic function are atrial dimensions, myocardial mass, mitral inflow pattern, pulmonary vein flow, propagation velocity of mitral inflow and the tissue Doppler of the mitral annulus. Nevertheless, a complete echocardiographic examination should be performed in every patient with heart failure. In general, diastolic dysfunction is frequently associated with increased atrial diameter and left ventricular hypertrophy. In advanced stages pulmonary hypertension can be present. A robust method for evaluation of systolic function in patients with diastolic dysfunction is crucial. The mitral inflow pattern provides various parameters to describe diastolic function (E/A ratio, deceleration time, isovolumetric relaxation time). In case of difficulties to separate a normal from a pseudonormal mitral inflow pattern the Valsalva maneuver can be used. Another valuable parameter for this differentiation is the duration of the backward flow in the pulmonary veins in contrast to forward flow over the mitral valve. Tachycardia or atrial fibrillation is a major problem for grading of diastolic function; however, in patients with atrial fibrillation E/e' is a well-established parameter. In summary, this review provides a detailed overview and discussion of the established and newer echocardiography techniques for the evaluation of diastolic function and provides an algorithm for the assessment of diastolic dysfunction in everyday routine.

[Low flow/low gradient aortic valve stenosis : clinical and diagnostic management]. / "Low-Flow/Low-Gradient"-Aortenklappenstenose : Klinisches und diagnostisches Spektrum.

Low gradient aortic stenoses (AS) represent a special challenge for physicians with respect to an exact diagnosis and optimal therapy. The difficulty lies in the estimation of the severity of AS which is decisive for subsequent treatment and the prognosis. Low flow and low gradient can be due to systolic or diastolic dysfunction by high-grade as well as by medium-grade AS and be of non-valvular origin. The latter group is to be interpreted as pseudoaortic stenosis as long as the low flow can successfully be raised by interventional means. However, only patients in the first group can be expected to profit from valve replacement and for patients in the second group the accompanying diseases must be the focus of therapeutic treatment. Therefore, according to recent European surveys up to 30% of patients with severe AS are undertreated due to false estimation of the severity of stenosis and perioperative risk stratification. Furthermore, follow-up investigations have shown that patients with low flow/low gradient stenosis and borderline-normal ejection fraction (EF) are in an advanced stage of the disease because they have often developed a severe reduction in longitudinal myocardial function and in addition have pronounced myocardial replacement fibrosis due to cardiac remodelling despite a preserved EF. Therefore, aortic valve area, mean pressure gradient and EF alone cannot be taken into consideration for the management of patients with severe AS but a comprehensive assessment of the hemodynamics, such as stroke volume, special functional parameters as well as individual clinical appearance is essential for precise diagnostic and therapeutic decision making.

[Imaging examination procedures, navigation and minimally invasive procedures in acetabular surgery]. / Bildgebende Untersuchungsverfahren, Navigation und minimal-invasive Verfahren in der Acetabulumchirurgie.

Acetabular fractures still pose a special challenge even today. Considering the increasing case numbers, especially in the geriatric patient group, modern imaging examination procedures represent an essential pillar of the diagnostics. Especially in this vulnerable patient group, minimally invasive methods are necessary, which can be guaranteed by intraoperative navigation; however, the choice of surgical access and implants is also made based on the existing morphological characteristics of fractures, which highlights the importance of an imaging modality that is as detailed as possible. Last but not least, new developments concerning the surgical treatment of these injuries are also based on this. This article summarizes the current state of the techniques and the available literature.

Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II.

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.

[The various forms of left ventricular hypertrophy: diagnostic value of echocardiography]. / Verschiedene Formen der linksventrikulären Hypertrophie: Differenzialdiagnostischer Beitrag der Echokardiographie.

Left ventricular hypertrophy is a non-specific physiological or maladaptive cardiac response to a large array of stimuli mediated by exercise and numerous cardiac and systemic diseases. The precise characterization and quantification of left ventricular hypertrophy may allow a more timely diagnosis of the underlying condition. The clinical reference standard to assess left ventricular hypertrophy is echocardiography, but a comprehensive description of how to approach this frequent finding in clinical practice is lacking. The current review systematically describes the typical echocardiographic patterns of important types of cardiac hypertrophy using both established and advanced imaging modalities. In hypertrophic obstructive cardiomyopathy a markedly reduced regional systolic function is found in the prominent thickened septum, whereas in essential arterial hypertension a typical concentric left ventricular hypertrophy with a less prominent basal septal bulge is present. The echocardiographic characteristics of cardiac amyloidosis are ventricular hypertrophy with sparkling granular myocardial texture and a small epicardial effusion. In addition, the strain rate curve for longitudinal function shows a typically reduced function which reaches maximum already in early systole. The typical feature of Friedreich cardiomyopathy is concentric left ventricular hypertrophy and sparkling granular texture with preserved regional systolic function. In Fabry cardiomyopathy a prominent papillary muscle is presented and a typical strain rate curve can be extracted from the basal lateral wall, indicating replacement fibrosis. Prominent hypertrabecularisation (ratio of non-compacted to compacted myocardium >2) in the apical and mid left ventricular segments is typical for non-compaction cardiomyopathy. Knowledge of these typical echocardiographic features enables the cardiologist to distinguish between the different hypertrophic entities, thus paving the way to early diagnosis.

Ultra-low-vibration closed-cycle cryogenic surface-electrode ion trap apparatus.

We describe the design, commissioning, and operation of an ultra-low-vibration closed-cycle cryogenic ion trap apparatus. One hundred lines for low-frequency signals and eight microwave/radio frequency coaxial feed-lines offer the possibility of implementing a small-scale ion-trap quantum processor or simulator. With all supply cables attached, more than 1.3 W of cooling power at 5 K is still available for absorbing energy from electrical pulses introduced to control ions. The trap itself is isolated from vibrations induced by the cold head using a helium exchange gas interface. The performance of the vibration isolation system has been characterized using a Michelson interferometer, finding residual vibration amplitudes on the order of 10 nm rms. Trapping of 9Be+ ions has been demonstrated using a combination of laser ablation and photoionization.

Misleading terms in Anderson-Fabry disease.

BACKGROUND: Signs and symptoms of classic Fabry disease manifest itself on the skin (angiokeratoma), the nervous system (acroparaesthesia), the heart (restrictive cardiomyopathy) and a variety of other organs. MATERIALS AND METHODS: Diagnosis of Fabry disease was confirmed by genetic tests in a cohort of 100 patients and a standardized examination programme was performed in all patients. We were puzzled when applying well-established and textbook-anchored signs and symptoms to our patients. RESULTS: Among the 47 male and 53 female patients (mean age 41 +/- 16 years) with genetically proven disease, the Fabry-type vascular skin lesions were without hyperkeratotic aspect and keratomas were virtually absent. The peripheral neuropathic pain found in all male patients was not compatible with the wording 'acro' and 'paraesthesia', suggesting a different pathophysiological mechanism. Upon echocardiographic examination, patients mainly revealed diastolic relaxation abnormalities of the heart and only one patient had a restrictive cardiac pattern. CONCLUSIONS: Our findings suggest that some terms used to describe signs and symptoms of Fabry disease are historically derived and do not comply with state-of-the-art examination. We propose to replace the term 'angiokeratoma' with 'angioma', the term 'acroparaesthesia' with 'neuropathic pain' and the term 'restrictive cardiomyopathy' with 'cardiac hypertrophic storage disease'. As most of the physicians are not familiar with Fabry disease, terms used in the past might prevent the correct diagnosis of a potentially treatable disease.

Muscle oxygen saturation increases during head-up tilt-induced (pre)syncope.

AIM: To evaluate whether muscle vasodilatation plays a role for hypotension developed during central hypovolaemia, muscle oxygenation (Sm O2 ) was examined during (pre)syncope induced by head-up tilt (HUT). Skin blood flow (SkBF) and oxygenation (Sskin O2 ) were determined because evaluation of Sm O2 may be affected by superficial tissue oxygenation. Furthermore, we evaluated cerebral oxygenation (Sc O2 ) and middle cerebral artery mean blood flow velocity (MCAvmean ). METHODS: Twenty healthy male volunteers (median age 24 years; range 19-38) were subjected to passive 50° HUT for 1 h or until (pre)syncope. Sc O2 and Sm O2 (near-infrared spectroscopy), MCAvmean (transcranial Doppler) along with mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) (Modelflow® ) were determined. RESULTS: (Pre)syncopal symptoms appeared in 17 subjects after 11 min (median; range 2-34) accompanied by a decrease in MAP, SV, CO and TPR, while HR remained elevated. During (pre)syncope, Sc O2 decreased [73% (71-76; mean and 95% CI) to 68% (65-71), P < 0.0001] along with MCAvmean [40 (37-43) to 32 (29-35) cm s-1 , P < 0.0001]. In contrast, Sm O2 increased [63 (56-69)% to 71% (65-78), P < 0.0001], while Sskin O2 [64% (58-69) to 53% (47-58), P < 0.0001] and SkBF [71 (44-98) compared to a baseline of 99 (72-125) units, P = 0.020] were reduced. CONCLUSION: We confirm that the decrease in MAP during HUT is associated with a reduction in indices of cerebral perfusion. (Pre)syncope was associated with an increase in Sm O2 despite reduced Sskin O2 and SkBF, supporting that muscle vasodilation plays an important role in the circulatory events leading to hypotension during HUT.

Quantitative comparison of 2D and 3D late gadolinium enhancement MR imaging in patients with Fabry disease and hypertrophic cardiomyopathy.

BACKGROUND: This study aims to determine whether the quantification of myocardial fibrosis in patients with Fabry disease (FD) and hypertrophic cardiomyopathy (HCM) using a late gadolinium enhancement (LGE) singlebreath-hold three-dimensional (3D) inversion recovery magnetic resonance (MR) imaging sequence is comparable with a clinically established two-dimensional (2D) multi-breath-hold sequence. METHODS: In this retrospective, IRB-approved study, 40 consecutive patients (18 male; mean age 50±17years) with Fabry disease (n=18) and HCM (n=22) underwent MR imaging at 1.5T. Spatial resolution was the same for 3D and 2D images (field-of-view, 350×350mm(2); in-plane-resolution, 1.2×1.2mm(2); section-thickness, 8mm). Datasets were analyzed for subjective image quality; myocardial and fibrotic mass, and total fibrotic tissue percentage were quantified. RESULTS: There was no significant difference in subjective image quality between 3D and 2D acquisitions (P=0.1 and P=0.3) for either disease. In patients with Fabry disease there were no significant differences between 3D and 2D acquisitions for myocardial mass (P=0.55), fibrous tissue mass (P=0.89), and total fibrous percentage (P=0.67), with good agreement between acquisitions according to Bland-Altman analyses. In patients with HCM there were also no significant differences between acquisitions for myocardial mass (P=0.48), fibrous tissue mass (P=0.56), and total fibrous percentage (P=0.67), with good agreement according to Bland-Altman analyses. Acquisition time was significantly shorter for 3D (25±5s) as compared to the 2D sequence (349±62s, P<0.001). CONCLUSIONS: In patients with Fabry disease and HCM, 3D LGE imaging provides equivalent diagnostic information in regard to quantification of myocardial fibrosis as compared with a standard 2D sequence, but at superior acquisition speed.

Thymidine catabolism and the reutilization of its degradative products in Tetrahymena pyriformis. Metabolism of [2,6-14C2]thymidine and [2-14C]methylmalonic acid.

The operation of reductive pyrimidine catabolic and reutilization pathway in Tetrahymena pyriformis was investigated. Consistent with the proposed catabolic interconversions, radioactivity from [2,6-14C2]thymidine was recovered in respired CO2 30 min after its addition to the culture, whereas, consistent with the proposed anabolic interconversions, over 50% of the incorporated label was recovered in cellular macromolecules other than DNA 12 h after its addition. The chromatographic recovery of 14C radioactivity in monosaccharides from [2,6-14C2]thymidine as well as from [2-14C]methylmalonic acid, a key reutilization intermediate in this proposed pathway, further substantiated the operation of the required anabolic interconversions in this organism.

Inhibition of human serine proteases by SPAAT, the C-terminal 44-residue peptide from alpha1-antitrypsin.

SPAAT has previously been shown to be a competitive inhibitor of the model serine protease, chymotrypsin. We now present evidence that SPAAT is likewise a competitive inhibitor of human neutrophil elastase and cathepsin G with Ki's of 15-20 and 40 microM, respectively. The mechanism of this inhibition was investigated by comparing the relative effectiveness of the 23-residue N-terminal fragment of SPAAT (N-SPAAT) to inhibit chymotrypsin and human neutrophil elastase. N-SPAAT, which does not contain the primary chymotrypsin cleavage site, was approximately 10-fold less effective as an inhibitor of chymotrypsin than SPAAT (Ki of 65 microM versus 7.5 microM). In contrast, this fragment, which contains the primary human neutrophil elastase cleavage site, was found to competitively inhibit human neutrophil elastase with a Ki of 24 microM which was comparable to that of SPAAT (Ki = 15-20 microM). Thus it appears that SPAAT is a reversible inhibitor of these enzymes rather than an irreversible, stoichiometric one like its parent protein, AAT. Such fragmentation of AAT, however, might provide a mechanism whereby a cascade of decreasingly potent, but increasingly specific SPAAT-related inhibitory peptides could be generated. These results further substantiate the view that SPAAT may play a role in vivo in the protection of extracellular proteins from inappropriate attack by proteases which are elevated during various pathophysiological conditions.

Carbohydrate composition of the second, third and fifth components and factors B and D of human complement.

The carbohydrate composition of the second, third and fifth components of human complement (C2, C3 and C5) and of factors B and D was determined employing gas-chromatographic and mass-spectrometric methods. C2 was found to contain 15.9% carbohydrate composed of fucose, galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (approximate molar ratio 1:4:9:9:4). N-acetylglucosamine and mannose (approximate molar ratio 1:4), amounting to 1.7% of the mass of the molecule, were the only monosaccharides detected in C3. C5 contained 3.8% carbohydrate composed of galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (approximate molar ratio 2:4:4-5:2). The carbohydrate moiety of B consisted of fucose, galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (molar ratio 1:2:3:4:2). The total carbohydrate content of B was estimated at 8.6%. In addition to these monosaccharides, glucose (0.4-0.9%) was also detected in all preparations analysed. Glucose was the only sugar detected in D.

Quantitation of complement factor D in human serum by a solid-phase radioimmunoassay.

A sensitive solid-phase radioimmunoassay is described which quantitates human D to 1-2 ng/ml. The assay was used to measure the concentration of D in normal and acute-phase sera and sera from individuals with systemic lupus erythematosus. All 3 groups of sera had comparable levels of D with mean values of 1.8, 2.3 and 2.5 micrograms/ml, respectively. Also tested were sera decomplemented in vitro by activators of the classical and alternative pathways. The results indicated that D is not depleted by alternative or classical pathway activation. However, heat inactivation (56 degrees C, 30 min) of serum resulted in almost complete loss of antigenic D.

Carnot process with a single particle.

We determine the statistics of work in isothermal volume changes of a classical ideal gas consisting of a single particle. Combining our results with the findings of Lua and Grosberg [J. Chem. Phys. B 109, 6805 (2005)] on adiabatic expansions and compressions we then analyze the joint probability distribution of heat and work for a microscopic, nonequilibrium Carnot cycle. In the quasistatic limit we recover Carnot efficiency, however, combined with nontrivial distributions of work and heat. With increasing piston speed the efficiency decreases. The efficiency at maximum power stays within recently derived bounds.