Einfluss einer gesteigerten neurohumoralen Aktivierung bei chronischer Niereninsuffizienz auf die Entstehung eines atrialen arrhythmogenen Substrats

Bei Patient*innen mit einer chronischen Nierenerkrankung (CKD) ist neu auftretendes Vorhofflimmern (VHF) ein unabhängiger Risikofaktor für das Auftreten eines ischämischen Schlaganfalls und den Tod. Im Vorhof verursacht CKD ein strukturelles, biochemisches und elektrisches Remodeling des Myokards und erhöht die Anfälligkeit für atriale Arrhythmien. Eine erhöhte Aktivität des sympathischen Nervensystems, ein häufiges Kennzeichen der CKD, stellt bekanntlich einen Auslöser für VHF dar. Der Einfluss des sympathischen Nervensystems auf atriale Remodelingprozesse im Rahmen der CKD muss jedoch noch untersucht werden. Methoden: Männliche Sprague Dawley Ratten wurden über 16 Wochen mit 0.25% Adenin-haltigem Futter zur Induktion einer chronischen Nierenerkrankung gefüttert. In der fünften Woche wurde die Hälfte der Adenin-gefütterten Tiere einer renalen Denervation (Ad+RDN) zur Modulation des sympathischen Nervensystems unterzogen, die andere Hälfte wurde sham-operiert (Ad). Als Kontrolltiere (Ko) dienten Ratten, die eine normale Haltungsdiät erhielten. Die Nierenfunktion wurde über die Zeit durch Messung der Plasmakonzentrationen von Kreatinin und Harnstoff erfasst. Der Blutdruck wurde über 16 Wochen mittels Katheter-basierter Telemetrie gemessen und zur Bestimmung der P-Wellen-Dauer wurden EKG-Aufzeichnungen verwendet. Strukturelle und biochemische Veränderungen von Niere und Herz wurden mittels Immunoblot und Gewebe-Histologie untersucht. Ergebnisse: 0.25% Adenin-Futter über 16 Wochen induzierte einen ausgeprägten tubulären Nierenschaden mit signifikant erhöhten Plasmakonzentrationen von Kreatinin (Ko: 0.54±0.27 mg/dl vs. Ad: 3.0±0.22 mg/dl, p=0.0002) und Harnstoff (Ko: 52.8±3.0 mg/dl vs. Ad: 396.2±45.0 mg/dl, p=0.0001). RDN konnte die Nierenfunktion nicht verbessern (Ad+RDN Kreatinin: 2.8±0.18 mg/dl, p=0.81 vs. Ad; Ad+RDN Harnstoff: 344.5±13.7 mg/dl, p=0.45 vs. Ad). Verglichen mit den Kontrollen resultierte die Fütterung mit Adenin in einer zunehmenden Nierenfibrose mit gesteigerter Expression des oxidativen Stress-Markerproteins Hämoxygenase 1 (HO-1) und einer Reduktion von den an anti-oxidativen Abwehrmechanismen beteiligten Proteinen. RDN verbesserte die Nierenfunktion in keinem dieser Parameter. Nach 16 Wochen führte die Adenin-induzierte CKD zu einer Erhöhung des mittleren arteriellen Blutdrucks und löste die Bildung interstitieller Fibrose im linken Vorhof aus (Ko: 6.4±0.51 %, Ad: 16.8±1.3 %, p<0.0001) sowie eine prolongierte P-Wellen-Dauer (Ko: 22.6±0.92 ms, Ad: 31.2±1.3 ms, p=0.0005). RDN führte zu einer signifikant reduzierten Fibrosebildung im linken Vorhof (Ad+RDN: 8.8±0.64 %, p<0.0001 vs. Ad) und verbesserter P-Wellen-Dauer im Vergleich zu Adenin-gefütterten Tieren (Ad+RDN: 24.1±1.4 ms, p=0.001 vs. Ad). Fazit: In einem Rattenmodell der CKD induzierte der renal-tubuläre Schaden einen moderaten Blutdruckanstieg und initiierte strukturelle Remodelingprozesse im linken Vorhof. RDN verhinderte den Progress des atrialen Remodelings ohne Beeinflussung des Blutdrucks und ohne Verbesserung der Nierenfunktion.In patients with chronic kidney disease (CKD) new onset of atrial fibrillation (AF) is an independent risk factor for ischemic insult and death. In the atrium CKD causes structural, biochemical and electrical remodeling and increases susceptibility for atrial arrhythmias. An enhanced activation of the sympathetic nervous system, a hallmark of CKD, is a well known trigger for AF. However, the impact of the sympathetic nervous system on atrial remodeling processes in a setting of CKD needs to be elucidated. Methods: Male Sprague Dawley rats were fed with 0.25% Adenine-containing chow for 16 weeks to induce chronic kidney disease. At week five half of the adenine-fed rats were subjected to renal denervation (Ad+RDN) to modulate the sympathetic nervous system, the other half were sham-operated (Ad). Rats on normal chow served as control (Ctr). Kidney function was followed over time by assessment of plasma creatinine and urea concentrations. Blood pressure was measured for 16 weeks using catheter-based telemetry devices and ECG recordings were used for assessment of p-wave duration. Structural and biochemical alterations of the kidney and the heart were analysed by immunoblotting and histology. Results: 0.25% Adenine-chow for 16 weeks induced pronounced tubular kidney damage with significantly increased plasma concentrations of creatinine (Ctr: 0.54±0.27 mg/dl vs. Ad: 3.0±0.22 mg/dl, p=0.0002) and urea (Ctr: 52.8±3.0 mg/dl vs. Ad: 396.2±45.0 mg/dl, p=0.0001). RDN did not improve kidney function (Ad+RDN creatinine: 2.8±0.18mg/dl, p=0.81 vs. Ad; Ad+RDN urea 344.5±13.7 mg/dl, p=0.45 vs. Ad). Compared to control, adenine-chow resulted in increased kidney fibrosis with enhanced expression of oxidative stress marker protein Hemoxygenase 1 (HO-1) and a reduction in proteins involved in anti-oxidative defence mechanisms. RDN did not improve kidney function of any of these parameters. After 16 weeks adenine-induced CKD resulted in elevated mean arterial blood pressure and triggered left atrial interstitial fibrosis formation (Ctr: 6.4±0.51 %, Ad: 16.8±1.3 %, p<0.0001) and a prolonged p-wave duration (Ctr: 22.6±0.92 ms, Ad: 31.2±1.3 ms, p=0.0005). RDN significantly attenuated structural remodeling of the left atrium (Ad+RDN: 8.8±0.64 %, p<0.0001 vs. Ad) and improved p-wave duration compared to Adenine (Ad+RDN: 24.1±1.4 ms, p=0.001 vs. Ad). Conclusion: In a rat model of adenine-induced CKD, renal tubular damage induced a moderate increase in blood pressure and initiated structural remodeling processes in the left atrium. RDN inhibited progression of atrial remodeling without effecting blood pressure and without improving kidney function

Validity of interpretation criteria for standardized Western blots (immunoblots) for serodiagnosis of Lyme borreliosis based on sera collected throughout Europe

De novo criteria were developed on the basis of the reactivities of the EUCALB sera and were evaluated with the data for the samples from southern Germany. Comparison of all results led to the following recommendations: For WB for immunoglobulin G (IgG), at least two bands among p83/100, p58, p43, p39, p30, OspC, p21, p17, and p14 for PKo and at least one band among p83/100, p39, p30, OspC, p21, and p17b for PBi; for WB for IgM, at least one band among p39, OspC, and p17 or a strong p41 band for PKo and at least one band among p39 and OspC or a strong p41 band for PBi. WB with PKo was the most sensitive, and this strain is recommended for use in WB for the serodiagnosis of LB throughout Europe

Monodopsis subterranea is a source of α‐tocomonoenol, and its concentration, in contrast to α‐tocopherol, is not affected by nitrogen depletion

α‐Tomonoenols (αT1) are tocochromanols structurally related to tocopherols (T) and tocotrienols (T3), the bioactive members of the vitamin E family. However, limited evidence exists regarding the sources and biosynthesis of tocomonoenols. Nitrogen depletion increases the content of α‐tocopherol (αT), the main vitamin E congener, in microalgae, but little is known regarding its effect on other tocochromanols, such as tocomonoenols and tocotrienols. We therefore quantified the concentrations of T, T1, and T3, in freeze‐dried biomass from nitrogen‐sufficient, and nitrogen‐depleted Monodopsis subterranea (Eustigmatophyceae). The identities of isomers of αT1 were confirmed by LC-MS and GC-MS. αT was the predominant tocochromanol (82% of total tocochromanols). αT1 was present in higher quantities than the sum of all T3 (6% vs. 1% of total tocochromanols). 11′‐αT1 was the main αT1 isomer. Nitrogen depletion increased αT, but not αT1 or T3 in M. subterranea. In conclusion, nitrogen depletion increased the content of αT, the biologically most active form of vitamin E, in M. subterranea without affecting αT1 and T3 and could potentially be used as a strategy to enhance its nutritional value but not to increase αT1 content, indicating that αT1 accumulation is independent of that of αT in microalgae.Baden‐Württemberg StiftungFood Security Center (University of Hohenheim)German Academic Exchange Service (DAAD)German Federal Ministry for Economic Cooperation and Development (BMZ

Association of exposure to manganese and iron with relaxation rates R1 and R2*- magnetic resonance imaging results from the WELDOX II study

Objective Magnetic resonance imaging is a non-invasive method that allows the indirect quantification of manganese (Mn) and iron (Fe) accumulation in the brain due to their paramagnetic features. The WELDOX II study aimed to explore the influence of airborne and systemic exposure to Mn and Fe on the brain deposition using the relaxation rates R1 and R2* as biomarkers of metal accumulation in regions of interest in 161 men, including active and former welders. Material and methods We obtained data on the relaxation rates R1 and R2* in regions that included structures within the globus pallidus (GP), substantia nigra (SN), and white matter of the frontal lobe (FL) of both hemispheres, as well as Mn in whole blood (MnB), and serum ferritin (SF). The study subjects, all male, included 48 active and 20 former welders, 41 patients with Parkinson's disease (PD), 13 patients with hemochromatosis (HC), and 39 controls. Respirable Mn and Fe were measured during a working shift for welders. Mixed regression models were applied to estimate the effects of MnB and SF on R1 and R2*. Furthermore, we estimated the influence of airborne Mn and Fe on the relaxation rates in active welders. Results MnB and SF were significant predictors of R1 but not of R2* in the GP, and were marginally associated with R1 in the SN (SF) and FL (MnB). Being a welder or suffering from PD or HC elicited no additional group effect on R1 or R2* beyond the effects of MnB and SF. In active welders, shift concentrations of respirable Mn > 100 μg/m3 were associated with stronger R1 signals in the GP. In addition to the effects of MnB and SF, the welding technique had no further influence on R1. Conclusions MnB and SF were significant predictors of R1 but not of R2*, indicative of metal accumulation, especially in the GP. Also, high airborne Mn concentration was associated with higher R1 signals in this brain region. The negative results obtained for being a welder or for the techniques with higher exposure to ultrafine particles when the blood-borne concentration was included into the models indicate that airborne exposure to Mn may act mainly through MnB

Tocochromanol Profiles in <i>Chlorella sorokiniana</i>, <i>Nannochloropsis limnetica</i> and <i>Tetraselmis suecica</i> Confirm the Presence of 11′-α-Tocomonoenol in Cultured Microalgae Independently of Species and Origin

11′-α-Tocomonoenol (11′-αT1) is structurally related to vitamin E and has been quantified in the microalgae Tetraselmis sp. and Nannochloropsis oceanica. However, it is not known whether 11′-αT1 is present in other microalgae independent of species and origin. The aim of this study was to analyze the tocochromanol profiles of Chlorella sorokiniana, Nannochloropsis limnetica, and Tetraselmis suecica and to determine if 11′-αT1 is present in these microalgae. Cultured microalgae were freeze-dried and the presence and identity of α-tocomonoenols were confirmed by LC-MSn (liquid chromatography coupled to mass spectroscopy) and GC-MS (gas chromatography coupled to mass spectroscopy). Tocochromanol profiles were determined by HPLC-FLD (liquid chromatography with fluorescence detection) and fatty acid profiles (as fatty acid methyl esters; FAME) by GC-MS. As confirmed by LC-MSn and GC-MS, 11′-αT1 was the dominant αT1 isomer in cultured microalgae instead of 12′-αT1, the isomer also known as marine-derived tocopherol. αT1 represented less than 1% of total tocochromanols in all analyzed samples and tended to be more abundant in microalgae with higher proportions of polyunsaturated fatty acids. In conclusion, our findings confirm that αT1 is not restricted to terrestrial photosynthetic organisms, but can also accumulate in microalgae of different species, with 11′-αT1—and not the marine-derived tocopherol (12′-αT1)—as the predominant αT1 isomer

Monodopsis subterranea is a source of α-tocomonoenol, and its concentration, in contrast to α-tocopherol, is not affected by nitrogen depletion

α-Tomonoenols (αT1) are tocochromanols structurally related to tocopherols (T) and tocotrienols (T3), the bioactive members of the vitamin E family. However, limited evidence exists regarding the sources and biosynthesis of tocomonoenols. Nitrogen depletion increases the content of α-tocopherol (αT), the main vitamin E congener, in microalgae, but little is known regarding its effect on other tocochromanols, such as tocomonoenols and tocotrienols. We therefore quantified the concentrations of T, T1, and T3, in freeze-dried biomass from nitrogen-sufficient, and nitrogen-depleted Monodopsis subterranea (Eustigmatophyceae). The identities of isomers of αT1 were confirmed by LC–MS and GC–MS. αT was the predominant tocochromanol (82% of total tocochromanols). αT1 was present in higher quantities than the sum of all T3 (6% vs. 1% of total tocochromanols). 11′-αT1 was the main αT1 isomer. Nitrogen depletion increased αT, but not αT1 or T3 in M. subterranea. In conclusion, nitrogen depletion increased the content of αT, the biologically most active form of vitamin E, in M. subterranea without affecting αT1 and T3 and could potentially be used as a strategy to enhance its nutritional value but not to increase αT1 content, indicating that αT1 accumulation is independent of that of αT in microalgae

Significant Improvement of the Recombinant Borrelia-Specific Immunoglobulin G Immunoblot Test by Addition of VlsE and a DbpA Homologue Derived from Borrelia garinii for Diagnosis of Early Neuroborreliosis

We investigated whether the recombinant Borrelia Western blot test previously described (B. Wilske, C. Habermann, V. Fingerle, B. Hillenbrand, S. Jauris-Heipke, G. Lehnert, I. Pradel, D. Rössler, and U. Schulte-Spechtel, Med. Microbiol. Immunol. 188:139-144, 1999) can be improved by the addition of VlsE and additional DbpA and OspC homologues. By using a panel of sera from 36 neuroborreliosis patients and 67 control patients, the diagnostic sensitivity of the recombinant immunoblot test was significantly increased (86.1% versus 52.7%) without loss of specificity and was higher (86.1% versus 63.8%) than that of the conventional whole-cell lysate immunoblot test (U. Hauser, G. Lehnert, R. Lobentanzer, and B. Wilske, J. Clin. Microbiol. 35:1433-1444, 1997). Improvement was mainly due to the presence of VlsE and DbpA