Plasma exchange as a treatment for hyperbilirubinemia in 2 foals with neonatal isoerythrolysis

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The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, mediated by the hydrophobic pocket of PCNA and perturbed in naturally-occurring ALKBH2 variants

Human AlkB homolog 2 (ALKBH2) is a DNA repair enzyme that catalyzes the direct reversal of DNA methylation damage through oxidative demethylation. While ALKBH2 colocalizes with proliferating cell nuclear antigen (PCNA) in DNA replication foci, it remains unknown whether these two proteins alone form a complex or require additional components for interaction. Here, we demonstrate that ALKBH2 can directly interact with PCNA independent from other cellular factors, and we identify the hydrophobic pocket of PCNA as the key domain mediating this interaction. Moreover, we find that PCNA association with ALKBH2 increases significantly during DNA replication, suggesting that ALKBH2 forms a cell-cycle dependent complex with PCNA. Intriguingly, we show that an ALKBH2 germline variant, as well as a variant found in cancer, display altered interaction with PCNA. Our studies reveal the ALKBH2 binding interface of PCNA and indicate that both germline and somatic ALKBH2 variants could have cellular effects on ALKBH2 function in DNA repair.Swiss National Science Foundation (31003A_133100/1)National Institutes of Health (U.S.) (grant CA055042)National Institutes of Health (U.S.) (grant ES002109)Universität Züric

Handling the 3-methylcytosine lesion by six human DNA polymerases members of the B-, X- and Y-families

Alkylating agents often generate 3-methylcytosine (3meC) lesions that are efficiently repaired by AlkB homologues. If AlkB homologue proteins are not functional, or the number of 3meC lesions exceeds the cellular repair capacity, the damage will persist in the genome and become substrate of DNA polymerases (Pols). Though alkylating agents are present in our environment and used in the clinics, currently nothing is known about the impact of 3meC on the accuracy and efficiency of human Pols. Here we compared the 3meC bypass properties of six human Pols belonging to the three families: B (Pol δ), X (Pols β and λ) and Y (Pols κ, ι and η). We show that under replicative conditions 3meC impairs B-family, blocks X-family, but not Y-family Pols, in particular Pols η and ι. These Pols successfully synthesize opposite 3meC; Pol ι preferentially misincorporates dTTP and Pol η dATP. The most efficient extenders from 3meC base-paired primers are Pols κ and η. Finally, using xeroderma pigmentosum variant patient cell extracts, we provide evidence that the presence of functional Pol η is mandatory to efficiently overcome 3meC by mediating complete bypass or extension. Our data suggest that Pol η is crucial for efficient 3meC bypass

Atypische myopathie bij het paard

Atypical myopathy (AM) is a frequently fatal pasture myopathy that emerges in Europe. Outbreaks are of an acute and unexpected nature and practitioners and owners should be prepared to handle the critically ill patients of this disease. Different hypotheses concerning the etiology and pathogenesis have been described. In this review, the most important hypotheses are summarized, and treatment plans and preventive measures are suggested. At this moment, maple seeds are thought to be the cause of AM. These seeds contain a toxin, hypoglycin A, which may lead to multiple acyl-CoA dehydrogenase deficiency (MADD). Treatment is often limited to supportive care. Since treatment is often unsuccessful, the main emphasis is currently still on prevention

Measurement variability of right atrial and ventricular monophasic action potential and refractory period measurements in the standing non-sedated horse

Background: In human and veterinary medicine, monophasic action potential (MAP) analysis and determination of local refractory periods by contact electrode technique gives valuable information about local cardiac electrophysiological properties. It is used to investigate dysrhythmias and the impact of drugs on the myocardium. Precise measurement of total MAP duration is difficult, therefore the MAP duration is usually determined at a repolarization level of 90% (APD90). Until now, no studies are published about the feasibility of this technique in the standing non-sedated horse. In 6 healthy Warmblood horses, on two different days, an 8F quadripolar contact catheter was passed through a jugular introducer sheath and placed under ultrasound guidance at the level of the intervenous tubercle or right atrial free wall (RA), and in the right ventricular apex (RV) to record the MAP. The MAP amplitude and APD90 were measured at a resting sinus rhythm (heart rate of 30-42 bpm) and at pacing cycle lengths (PCL) of 1000 and 600 ms. The effective refractory period (ERP) was determined at PCL of 1000 and 600 ms. Results: The overall mean (+/- SD) APD90 (rest), APD90 (1000) and APD90 (600) were 263 +/- 39 ms, 262 +/- 41 ms, 236 +/- 47 ms for the RA and 467 +/- 23 ms, 412 +/- 38 ms, 322 +/- 29 ms for the RV. The mean ERP1000 and ERP600 were 273 +/- 24 ms and 256 +/- 22 ms for the RA and 386 +/- 40 ms and 293 +/- 30 ms for the RV. The measurement variability for the amplitude, APD90 and ERP measurements in the RA ranged between 36 and 44, 9-22 and 7-8%, respectively. The measurement variability for the amplitude, APD90 and ERP measurements in the RV ranged between 49 and 66, 6-7 and 10-12%, respectively. Conclusions: RA and RV MAP duration and ERP can be obtained by a contact electrode in standing non-sedated horses. The measurement variability varies with catheter location

Can heart rate variability parameters derived by a heart rate monitor differentiate between atrial fibrillation and sinus rhythm?

Background: Heart rate variability (HRV) parameters, and especially RMSSD (root mean squared successive differences in RR interval), could distinguish atrial fibrillation (AF) from sinus rhythm(SR) in horses, as was demonstrated in a previous study. If heart rate monitors (HRM) automatically calculating RMSSD could also distinguish AF from SR, they would be useful for the monitoring of AF recurrence. The objective of the study was to assess whether RMSSD values obtained from a HRM can differentiate AF from SR in horses. Furthermore, the impact of artifact correction algorithms, integrated in the analyses software for HRV analyses was evaluated. Fourteen horses presented for AF treatment were simultaneously equipped with a HRM and an electrocardiogram (ECG). A two-minute recording at rest, walk and trot, before and after cardioversion, was obtained. RR intervals used were those determined automatically by the HRM and by the equine ECG analysis software, and those obtained after manual correction of QRS detection within the ECG software. RMSSD was calculated by the HRM software and by dedicated HRV software, using six different artifact filters. Statistical analysis was performed using the Wilcoxon signed-rank test and receiver operating curves. Results: The HRM, which applies a low level filter, produced high area under the curve (AUC) (>0.9) and cut off values with high sensitivity and specificity. Similar results were obtained for the ECG, when low level artifact filtering was applied. When no artifact correction was used during trotting, an important decrease in AUC (0.75) occurred. Conclusion: In horses treated for AF, HRMs with automatic RMSSD calculations distinguish between AF and SR. Such devices might be a useful aid to monitor for AF recurrence in horses

Reconstruction of sediment provenance and transport processes from the surface textures of quartz grains from Late Pleistocene sandurs and an ice-marginal valley in NW Poland

During the Pomeranian phase of the Weichselian glaciation (~17–16 ka), the Toruń-Eberswalde ice-marginal valley (NW Poland and easternmost Germany) drained water from the Pomeranian ice sheet, while intensive aeolian process -es took place across Europe in the foreland of the Scandinavian ice sheet (‘European Sand Belt’). The micromorphology of the quartz grains in the Toruń-Eberswalde ice-marginal valley shows no traces of these aeolian processes, or only vague signs of aeolian abrasion. This is unique among the aeolian sediments in other Pleistocene ice-marginal valleys in this part of Europe. The study of the surfaces of the quartz grains shows that the supply of grains by streams from the south was minimal, which must be ascribed to the climate deterioration during the Last Glacial Maximum, which resulted in a decrease of the discharge of these extraglacial rivers to the ice-marginal valley

Atrial premature depolarization-induced changes in QRS and T wave morphology on resting electrocardiograms in horses

Background : The electrocardiographic differentiation between atrial (APDs) and ventricular (VPDs) premature depolarizations is important. P wave prematurity and normal QRS and T wave morphology generally are used as discriminating criteria for APDs. Hypothesis/Objectives : The aim of this study was to determine whether P, Q, R, S, and T wave amplitude, PQ interval, QRS and P wave duration and P and T wave morphology differ between APDs and sinus beats. To determine the relationship between the RR coupling interval and the change in S wave amplitude between sinus beats and APDs. Methods : Case-control study. From a modified base-apex configuration of 30 horses with APDs at rest, sinus beat and APD associated preceding RR interval, P, PQ and QRS duration and P, R, S, and T wave amplitudes were measured. Linear mixed models and logistic regression were used to determine the effect of APDs on the ECG variables studied. Results : In comparison to sinus beats, APDs were associated with a significant (P < .001) change in P amplitude (-0.03 0.01 mV) and increase in S (0.20 +/- 0.02 mV) and T (0.08 +/- 0.03 mV) amplitude. PQ (-20.3 +/- 5.2 ms) and RR (-519 +/- 14 ms) interval and P duration (-21.1 +/- 3.0 ms) decreased (P < .001). APDs were significantly associated with a singular positive P wave (OR: 11.0, P < .001) and were more likely to have a monophasic positive T wave (OR: 9.2, P < .001). A smaller RR coupling interval was associated with an increased relative difference in S amplitude (P < .01). Conclusions : Atrial premature depolarizations may lead to changes in QRS and T wave morphology. Knowledge of these changes is important to avoid interpreting certain APDs as VPDs