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Proton-translocating NADH:ubiquinone oxidoreductase (complex I) is the largest and least understood enzyme of the respiratory chain. Complex I from bovine mitochondria consists of more than forty different polypeptides. Subunit PSST has been suggested to carry iron-sulfur center N-2 and has more recently been shown to be involved in inhibitor binding. Due to its pH-dependent midpoint potential, N-2 has been proposed to play a central role both in ubiquinone reduction and proton pumping. To obtain more insight into the functional role of PSST, we have analyzed site-directed mutants of conserved acidic residues in the PSST homologous subunit of the obligate aerobic yeast Yarrowia lipolytica. Mutations D136N and E140Q provided functional evidence that conserved acidic residues in PSST play a central role in the proton translocating mechanism of complex I and also in the interaction with the substrate ubiquinone. When Glu89, the residue that has been suggested to be the fourth ligand of iron-sulfur center N-2 was changed to glutamine, alanine, or cysteine, the EPR spectrum revealed an unchanged amount of this redox center but was shifted and broadened in the gzregion. This indicates that Glu89 is not a ligand of N-2. The results are discussedin the light of structural similarities to the homologous [NiFe] hydrogenases.
Purpose: To evaluate the potential impact of rebubbling on the anterior segment parameters and refractive outcomes in patients with graft detachment following uneventful DMEK for Fuchs endothelial dystrophy (FED).
Methods: Retrospective institutional cohort study of comparing 34 eyes of 31 patients with rebubbling for graft detachment following Descemet membrane endothelial keratoplasty (DMEK) to 33 eyes of 28 patients with uneventful DMEK. Main outcome parameters were various corneal parameters obtained by Scheimpflug imaging, refractive outcome, corrected distance visual acuity (CDVA), and endothelial cell density (ECD).
Results: Anterior and posterior corneal astigmatism, corneal densitometry, central corneal thickness, and anterior chamber depth and volume showed no significant differences. Preoperative distribution of astigmatism axis orientations showed a high proportion of anterior corneal with-the-rule astigmatism (71%) in eyes requiring rebubbling. Mean postoperative cylinder in the rebubbling group (1.21 ± 0.85 D) was significantly higher compared to the controls (p = 0.04), while differences in spherical equivalent (SE) were insignificant (p = 0.24). Postoperative CDVA was 0.11 ± 0.11 in the control group compared to 0.21 ± 0.17 in the rebubbling group (p = 0.03). Eyes with subsequent rebubbling demonstrated a significantly higher endothelial cell loss (56% versus 37%) (p < 0.001).
Conclusion: Apart from higher cylinder values, refractive outcome and corneal parameters assessed by Scheimpflug imaging were comparable in eyes with rebubbling and controls. However, a reduced visual acuity and an increased endothelial cell loss should be taken into consideration prior to rebubbling especially in eyes with circumscribed graft detachment.
Purpose: To analyze refractive and topographic changes secondary to Descemet membrane endothelial keratoplasty (DMEK) in pseudophakic eyes with Fuchs’ endothelial dystrophy (FED). Methods: Eighty-seven pseudophakic eyes of 74 patients who underwent subsequent DMEK surgery for corneal endothelial decompensation and associated visual impairment were included. Median post-operative follow-up time was 12 months (range: 3–26 months). Main outcome measures were pre- and post-operative manifest refraction, anterior and posterior corneal astigmatism, simulated keratometry (CASimK) and Q value obtained by Scheimpflug imaging. Secondary outcome measures included corrected distance visual acuity (CDVA), central corneal densitometry, central corneal thickness, corneal volume (CV), anterior chamber volume (ACV) and anterior chamber depth (ACD). Results: After DMEK surgery, mean pre-operative spherical equivalent (± SD) changed from + 0.04 ± 1.73 D to + 0.37 ± 1.30 D post-operatively (p = 0.06). CDVA, proportion of emmetropic eyes, ACV and ACD increased significantly during follow-up. There was also a significant decrease in posterior corneal astigmatism, central corneal densitometry, central corneal thickness and corneal volume over time (p = 0.001). Only anterior corneal astigmatism and simulated keratometry (CASimK) remained fairly stable after DMEK. Conclusion: Despite tendencies toward a hyperopic shift, changes in SE were not significant and refraction remained overall stable in pseudophakic patients undergoing DMEK for FED. Analysis of corneal parameters by Scheimpflug imaging mainly revealed changes in posterior corneal astigmatism pointing out the relevance of posterior corneal profile changes during edema resolution after DMEK.
Aggensteiner, Pascal ; Albrecht, Björn ; Strehl, Ute ; Wörz, Sonja ; Ruckes, Christian Rainer ; Freitag, Christine M. ; Rothenberger, Aribert ; Gevensleben, Holger ; Millenet, Sabina ; Hohmann, Sarah ; Banaschewski, Tobias ; Legenbauer, Tanja ; Holtmann, Martin ; Brandeis, Daniel
Abstract: Neurophysiological measures of preparation and attention are often atypical in ADHD. Still, replicated findings that these measures predict which patients improve after Neurofeedback (NF), reveal neurophysiological specificity, and reflect ADHD-severity are limited. Methods: We analyzed children’s preparatory (CNV) and attentional (Cue-P3) brain activity and behavioral performance during a cued Continuous Performance Task (CPT) before and after slow cortical potential (SCP)-NF or semi-active control treatment (electromyogram biofeedback). Mixed-effects models were performed with 103 participants at baseline and 77 were assessed for pre-post comparisons focusing on clinical outcome prediction, specific neurophysiological effects of NF, and associations with ADHD-severity. Results: Attentional and preparatory brain activity and performance were non-specifically reduced after treatment. Preparatory activity in the SCP-NF group increased with clinical improvement. Several performance and brain activity measures predicted non-specific treatment outcome. Conclusion: Specific neurophysiological effects after SCP-NF were limited to increased neural preparation associated with improvement on ADHD-subscales, but several performance and neurophysiological measures of attention predicted treatment outcome and reflected symptom severity in ADHD. The results may help to optimize treatment.
The purpose of this study is to compare the efficacy and safety of microwave ablation (MWA) versus laser-induced thermotherapy (LITT) as a local treatment for hepatocellular carcinoma (HCC,) with regard to therapy response, survival rates, and complication rates as measurable outcomes. This retrospective study included 250 patients (52 females and 198 males; mean age: 66 ± 10 years) with 435 tumors that were treated by MWA and 53 patients (12 females and 41 males; mean age: 67.5 ± 8 years) with 75 tumors that were treated by LITT. Tumor response was evaluated using CEMRI (contrast-enhanced magnetic resonance imaging). Overall, 445 MWA sessions and 76 LITT sessions were performed. The rate of local tumor progression (LTP) and the rate of intrahepatic distant recurrence (IDR) were 6% (15/250) and 46% (115/250) in the MWA-group and 3.8% (2/53) and 64.2% (34/53) in the LITT-group, respectively. The 1-, 3-, and 5-year overall survival (OS) rates calculated from the date of diagnosis were 94.3%, 65.4%, and 49.1% in the MWA-group and 96.2%, 54.7%, and 30.2% in the LITT-group, respectively (p-value: 0.002). The 1-, 2-, and 3-year disease-free survival (DFS) rates were 45.9%, 30.6%, and 24.8% in the MWA-group and 54.7%, 30.2%, and 17% in the LITT-group, respectively (p-value: 0.719). Initial complete ablation rate was 97.7% (425/435) in the MWA-group and 98.7% (74/75) in the LITT-group (p-value > 0.99). The overall complication rate was 2.9% (13/445) in the MWA-group and 7.9% (6/76) in the LITT-group (p-value: 0.045). Based on the results, MWA and LITT thermal ablation techniques are well-tolerated, effective, and safe for the local treatment of HCC. However, MWA is recommended over LITT for the treatment of HCC, since the patients in the MWA-group had higher survival rates.
Purpose: To investigate short-term (3 months follow-up) changes in visual quality following Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy (FED). Methods: In this prospective institutional case series, 51 patients that underwent DMEK for FED were included. Assessment included the Quality of Vision (QoV) questionnaire preoperatively, at 1 month, and 3 months after surgery. Secondary outcome measures were anterior segment parameters acquired by Scheimpflug imaging, corrected distance visual acuity (CDVA), and endothelial cell density (ECD). Results: Glare, hazy vision, blurred vision, and daily fluctuation in vision were the symptoms mostly reported preoperatively. All symptoms demonstrated a significant reduction of item scores for severity, frequency, and bothersome in the course after DMEK (P < 0.01). Glare and fluctuation in vision remained to some extent during the follow-up period (median score = 1). Preoperatively, corneal densitometry correlated moderately to weakly with severity of hazy vision (rs = 0.39; P = 0.03) and frequency (rs = 0.26; P = 0.02) as well as severity (rs = 0.27; P = 0.03) of blurry vision. CDVA and central corneal thickness (CCT) did not correlate with visual complains. Conclusions: Following DMEK for FED, patient-reported visual symptoms assessed by the QoV questionnaire represent a useful tool providing valuable information on the impact of DMEK on visual quality that cannot be directly estimated by morphological parameters and visual acuity only.
Adam, Pia ; Kircher, Stefan Josef ; Sbiera, Iuliu ; Köhler, Viktoria Florentine ; Berg, Elke ; Knösel, Thomas ; Sandner, Benjamin ; Fenske, Wiebke Kristin ; Bläker, Hendrik ; Smaxwil, Constantin ; Zielke, Andreas ; Sipos, Bence ; Allelein, Stephanie ; Schott, Matthias ; Dierks, Christine ; Spitzweg, Christine ; Faßnacht, Martin ; Kroiß, Matthias
Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.