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This is the case report of a 58-year-old male patient who presented with recurring abdominal pain of 4 months duration. He had undergone multiple investigations including upper and lower gastrointestinal tract endoscopies and diagnostic laparoscopy, but there were no significant findings detected.
Capsule endoscopy revealed a submucosal small bowel tumor that was suspected to originate from the distal third of the small bowel. Surgery was indicated and a highly differentiated neuroendocrine tumor was found at laparotomy at the distal ileum. An ileocecal resection was performed confirming a neuroendocrine tumor of the small bowel (G2T2N1M1). This article is part of an expert video encyclopedia.
Background: Balloon pulmonary angioplasty is an evolving, interventional treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension at rest as well as exercise capacity is considered to be relevant outcome parameters. The aim of the present study was to determine whether measurement of pulmonary hemodynamics during exercise before and six months after balloon pulmonary angioplasty have an added value.
Methods: From March 2014 to July 2018, 172 consecutive patients underwent balloon pulmonary angioplasty. Of these, 64 consecutive patients with inoperable CTEPH underwent a comprehensive diagnostic workup that included right heart catheterization at rest and during exercise before balloon pulmonary angioplasty treatments and six months after the last intervention.
Results: Improvements in pulmonary hemodynamics at rest and during exercise, in quality of life, and in exercise capacity were observed six months after balloon pulmonary angioplasty: WHO functional class improved in 78% of patients. The mean pulmonary arterial pressure (mPAP) at rest was reduced from 41 ± 9 to 31 ± 9 mmHg (p < 0.0001). The mPAP/cardiac output slope decreased after balloon pulmonary angioplasty (11.2 ± 25.6 WU to 7.7 ± 4.1 WU; p < 0.0001), and correlated with N-terminal fragment of pro-brain natriuretic peptide (p = 0.035) and 6-minute walking distance (p = 0.01).
Conclusions: Exercise right heart catheterization provides valuable information on the changes of pulmonary hemodynamics after balloon pulmonary angioplasty in inoperable CTEPH patients that are not obtainable by measuring resting hemodynamics.
Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSPs) that lead to muscle weakness. Here, we identify METTL21C as a skeletal muscle-specific lysine methyltransferase. Insertion of a β-galactosidase cassette into the Mettl21c mouse locus revealed that METTL21C is specifically expressed in MYH7-positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to age-dependent accumulation of autophagic vacuoles in skeletal muscle. Denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins, in Mettl21c−/− muscles. In addition, we demonstrate that METTL21C interacts with the ATPase p97 (VCP), which is mutated in various human MSP conditions. We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. We conclude that the methyltransferase METTL21C is an important modulator of protein degradation in skeletal muscle under both normal and enhanced protein breakdown conditions.
Calcification, Collagen Membrane, Ca/P Ratio Dependence Spontaneous calcification of a membrane made of native collagen has been investigated. The method permits independent variation of calcium and phosphate concentrations. With increasing phosphate concentration the precipitation of calcium-phosphate on the collogen occurs at a conspicuously lower calcium concentration as with a number of other membranes.
Background: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3.
Methods: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631).
Results: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%).
Conclusion: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.
Background_ Postural control is associated with fall risk. Patients with rheumatoid arthritis (RA) have a higher risk to fall than healthy subjects. The objective of this study was to identify associations between variables of postural control with prospective falls in patients with RA.
Methods: For the baseline, the balance performance of 289 men and women with RA, ages 24–85 years, was evaluated by SPPB, FICSIT-4 and Romberg tests. Postural sway for Romberg, semitandem, tandem and one-leg stands were measured with the Leonardo Mechanograph®. Self-reported disability was assessed using the Health Assessment Questionnaire (HAQ) and the Activity-specific Balance Confidence Scale (ABC-scale). Falls were reported in quarterly reports over a year. Univariate and multiple logistic regression analysis were used to explore any associations with falling. Receiver-operating characteristics were determined, and the area under the curve is reported.
Results`A total of 238 subjects completed the 1-year follow-up, 48 (20.2%) experienced at least one fall during the observational period. Age (OR = 1.04, CI 1.01–1.07), HAQ (OR = 1.62, 1.1–2.38), FICSIT-4 scoring 0–4 (OR = 2.38, 1.13–5.0), and one-leg standing (OR = 2.14, 1.06–4.31) showed significant associations with falls. With regard to the SPPB and ABC-scale, no statistically significant associations with falls were found. The quartiles containing the worst results of medio-lateral sway of Romberg (OR = 2.63, CI 1.03–6.69), total sway of semitandem (OR = 3.07, CI 1.10–8.57) and tandem (OR = 2.86, CI 1.06–7.69), and area of sway of semitandem (OR = 2.80, CI 1.11–7.08) stands were associated with falls.
Conclusions: The assessment of a one-leg stand seems to be a good screening tool to discriminate between high and low risk of falls in RA patients in clinical practice. A low FICSIT-4 score and several sway parameters are important predictors of falls.
Biophysical parameters can accelerate drug development; e.g., rigid ligands may reduce entropic penalty and improve binding affinity. We studied systematically the impact of ligand rigidification on thermodynamics using a series of fasudil derivatives inhibiting protein kinase A by crystallography, isothermal titration calorimetry, nuclear magnetic resonance, and molecular dynamics simulations. The ligands varied in their internal degrees of freedom but conserve the number of heteroatoms. Counterintuitively, the most flexible ligand displays the entropically most favored binding. As experiment shows, this cannot be explained by higher residual flexibility of ligand, protein, or formed complex nor by a deviating or increased release of water molecules upon complex formation. NMR and crystal structures show no differences in flexibility and water release, although strong ligand-induced adaptations are observed. Instead, the flexible ligand entraps more efficiently water molecules in solution prior to protein binding, and by release of these waters, the favored entropic binding is observed.
Background: Because of limitations of transportation imposed by the COVID-19 pandemic, current recommendation calls for cryopreservation of allogeneic stem cell transplants before patient conditioning. A single cell therapy laboratory was selected to function as the central cryopreservation hub for all European registry donor transplants intended for the Australian-Pacific region. We examined properties of these transplants to ascertain how quality is maintained.
Methods: We analyzed 100 pandemic-related allogeneic mobilized blood-derived stem cell apheresis products generated at 30 collection sites throughout Europe, shipped to and cryopreserved at our center between April and November of 2020. Products were shipped in the cool, subsequently frozen with DMSO as cryoprotectant. Irrespective of origin, all products were frozen within the prescribed shelf-life of 72 h.
Results: Prior to cryopreservation, viable stem cell and leukocyte count according to the collection site and our reference laboratory were highly concordant (r2 = 0.96 and 0.93, respectively) and viability was > 90% in all instances. Median nominal post-thaw recovery of viable CD34+ cells was 42%. Weakly associated with poorer CD34+ cell recovery was higher leukocyte concentration, but not time lag between apheresis or addition of cryopreservant, respectively, and start of freezing. The correlation between pre- and post-thaw CD34+ cell dose was high (r2 = 0.85), hence predictable. Neutrophil and platelet engraftment were prompt with no evidence of dose dependency within the range of administered cell doses (1.31–15.56 × 106 CD34+ cells/kg).
Conclusions: General cryopreservation of allogeneic stem cell transplants is feasible. While more than half of the CD34+ cell content is lost, the remaining stem cells ensure timely engraftment.
An accurate quantification of low viremic HCV RNA plasma samples has gained importance since the approval of direct acting antivirals and since only one single measurement predicts the necessity of a prolonged or shortened therapy. As reported previously, HCV quantification assays such as Abbott RealTime HCV and Roche COBAS AmpliPrep/COBAS TaqMan HCV version 2 (CTM v2) may vary in sensitivity and precision particularly in low-level viremia. Importantly, substantial variations were previously demonstrated between some of these assays compared to the Roche High Pure System/COBAS TaqMan assay (HPS) reference assay, which was used to establish the clinical decision points in clinical studies. In this study, the reproducibility of assay performances across several laboratories was assessed by analysing quantification results generated by six independent laboratories (3× RealTime, 3× CTM v2) in comparison with one HPS reference laboratory. The 4th WHO Standard was diluted to 100, 25 and 10 IU/ml, and aliquots were tested in triplicates in 5 independent runs by each assay in the different laboratories to assess assay precision and detection rates. In a second approach, 2 clinical samples (GT 1a & GT 1b) were diluted to 100 and 25 IU/ml and tested as described above. While the result range for WHO 100 IU/ml replicates across all laboratories was similar in this analysis, the CVs of each laboratory ranged from 19.3 to 25.6 % for RealTime laboratories and were lower than CVs of CTM v2 laboratories with a range of 26.1–47.3 %, respectively, and also in comparison with the CV of the HPS reference laboratory (34.9 %). At WHO standard dilution of 25 IU/ml, 24 replicates were quantified by RealTime compared to 8 replicates with CTM v2. Results of clinical samples again revealed a higher variation of CTM v2 results as compared to RealTime values. (CVs at 100 IU/ml: RealTime: 13.1–21.0 % and CTM v2: 15.0–32.3 %; CVs at 25 IU/ml: RealTime 17.6–34.9 % and CTM v2 28.2–54.9 %). These findings confirm the superior precision of RealTime versus CTM v2 at low-level viremia even across different laboratories including the new clinical decision point at 25 IU/ml. A highly precise monitoring of HCV viral load during therapy will remain crucial for patient management with regard to futility rules, therapy efficacy and SVR.
Background: Although being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V. Beside an enhancement of resistance, L76V is also discussed to confer hypersusceptibility to the drugs Atazanavir and Saquinavir which might enable new treatment strategies by trying to take advantage of particular mutations. Results: Based on a cohort of 47 L76V-positive patients, we examined if there might exist a clinical advantage for L76V-positive patients concerning long-term success of PI-containing regimens in patients with limited therapy options. Genotypic- and phenotypic HIV-resistance tests from 47 mostly multi-resistant, L76V-positive patients throughout Germany were accomplished retrospectively 1999-2009. Five genotype-based drug-susceptibility predictions received from online interpretation-tools for Atazanavir, Saquinavir, Amprenavir and Lopinavir, were compared to phenotype-based predictions that were determined by using a recombinant virus assay along with a Virtual Phenotype™(Virco). The clinical outcome of the L76V-adapted follow-up therapy was determined by monitoring viral load for 96 weeks. Conclusions: In this analysis, the mostly used interpretation systems overestimated the L76V-mutation concerning Atazanavir- and SQV resistance. In fact, a clear benefit in drug susceptibility for these drugs was observed in phenotype analysis after establishment of L76V. More importantly, long-term therapy success was significantly higher in patients receiving Atazanavir and/or Saquinavir plus one L76V-selecting drug compared to patients without L76V-selecting agents (p = 0.002). In case of L76V-occurrence ATV and/or SQV may represent encouraging options for patients in deep salvage situations.