Behavior Problems and Cognitive Function in Pediatric Liver Transplant Recipients

BackgroundLiver transplant (LT) is a lifesaving treatment providing excellent clinical outcomes. However, data regarding behavioral and cognitive issues after LT are sparse in Asia. This study aimed to investigate behavior and cognitive problems among pediatric LT recipients.MethodsWe used the Child Behavior Checklist (CBCL) to evaluate behavior problems and/or the Wechsler Intelligence Scale for Children, Third Edition (WISC-III) to assess cognitive function. Participants were children aged 2 to 18 years who were treated with LT for at least 2 years.ResultsWe included 77 children with a median age of 7.8 years (interquartile range, 5.0-10.9). All children were evaluated with the CBCL, and 26 children were available for WISC-III assessment. Approximately one-third (34%) of the children had a total CBCL score above a clinical cutoff for significant behavior problems, and 29% of school-aged children had abnormal competence scores in a clinically significant range. Most of the evaluated children (17 of 26; 65%) had a normal full-scale intelligence quotient. Lower cognitive function was associated with having a single parent (P < .01). Higher behavior problems were associated with lower parental education level (P = .01) and correlated with longer post-transplant duration (Spearman’s rho = 0.443; P < .001).ConclusionsSignificant numbers of children have behavior problems after LT. Most children have normal cognitive function, although a larger sample size is required to confirm this result. Long-term support for cognitive and behavior problems after LT should be implemented, particularly in children with single parents and lower parental education level.     

Physical and biophysical effects of polysorbate 20 and 80 on darbepoetin alfa

We studied the physical and biophysical affects of the nonionic surfactants polysorbate 20 and 80 and their mechanism of interaction using darbepoetin alfa, a 4-helix bundle protein, as the exemplary protein. Differences were observed between the abilities of the polysorbates to prevent surface loss/aggregation and correlated with each polysorbates initiation of micelle formation prior to the critical micelle concentration (CMC). The biophysical properties monitored by far-UV circular dichroism (CD) and tryptophan (Trp) fluorescence showed effects due to polysorbates, but were not correlated with their CMC. At a constant protein concentration PS-80 induced α-helix in the protein with a maximal effect at 15:1 molar ratio of PS-80/protein. PS-20 initially induced α-helix with a maximal effect at 1.5:1 ratio followed by a decrease in the α-helix content. PS-80 had no effect on near-UV CD but increased Trp fluorescence only at the 150:1 polysorbate/protein ratio. PS-20 decreased the near-UV CD and Trp fluorescence. Thermodynamic studies by isothermal titration calorimetry (ITC) demonstrated that the protein interacts with monomeric polysorbate, but not with polysorbate micelles. The data suggest that the polysorbates differentially interact with the protein and that the biophysical effects are dependent on the structure of the polysorbate and the polysorbate to protein ratio. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3200–3217, 2009     

Diarrhea in pediatric recipients of solid organ or bone marrow transplants

Diarrhea is common in adults after solid organ transplantation (SOT) and bone marrow transplantation (BMT), but data in children are limited. Therefore, we aimed to determine the incidence and etiology of pediatric early-onset diarrhea in post SOT and BMT.We reviewed children aged 6 months to 18 years who underwent liver transplantation, kidney transplantation or BMT between January 2015 and December 2019 with duration of diarrhea > 72 hours within the first 6 months after transplantation. Clinical data and diarrheal course were collected. Regression analyses were performed to define factors associated with the interested outcomes.Among 252 transplanted patients, 168 patients (66.6%) had 289 documented episodes of diarrhea. A diagnosis of 68.2% of post-transplant diarrhea remained ‘indefinite’. Enteric infection in SOT and gastrointestinal acute graft-versus-host disease (GI-aGVHD) in BMT were the commonly identified etiologies. Among 182 episodes among BMT children, skin rash was more pronounced when compared the ones with diarrhea > 7 days vs ≤ 7 days (odds ratio [OR] 13.9; 95% CI 1.8, 107.6). Males were more likely to develop GI-aGVHD as compared to females (OR 8.9). We found that GI-aGVHD was more common in the ones with skin rash and the presence of white blood cells in stool examination (OR 8.4 and 3.1, respectively). Deaths occurred in 7.7%.Two-thirds of post-transplant children experienced at least one episode of early-onset diarrhea, of which the etiology mainly remains undefined. Various clinical factors of prolonged/chronic diarrhea and GI-aGVHD may help clinicians when managing these children.     

Health-Related Quality of Life in Pediatric Liver Transplant Recipients

BackgroundHealth-related quality of life (HRQoL) of liver transplantation (LT) recipients has been widely studied because of increased patient longevity. However, studies in developing countries are scanty. We aimed to evaluate psychometric properties of the Thai version of the PedsQL Transplant Module and used it to determine the HRQoL in LT children.MethodsWe included children aged 2 to 18 years who underwent LT more than 1 year previously. The phase 1 study included a cognitive interview with 20 LT children and their parents using the Thai version of PedsQL Transplant Module and revised the module accordingly. Then, the finalized version was evaluated for psychometric properties in 50 LT children. In phase 2, HRQoL was evaluated in 52 LT children who did not participate in the phase 1 study.ResultsIn the Thai PedsQL Transplant Module, both parent report and child self-report had good internal consistency (α = 0.94 and 0.93, respectively) and substantial reliability (interclass correlation coefficient = 0.82 and 0.77, respectively). Median HRQoL scores from the parent report and child self-report were 80 (interquartile range [IQR], 70, 88) and 77 (IQR, 71, 88), respectively. From the parent report, lower HRQoL was associated with opportunistic viral infection (P = .004) and correlated with a greater number of immunosuppressive agents (ρ = –0.346, P = .014). However, none of these factors were significant according to the child self-report.ConclusionsThe Thai PedsQL Transplant Module has satisfactory psychometric properties. Post-LT children have good HRQoL. To improve their HRQoL, specific attention should be focused on managing viral infection and optimizing immunosuppressive therapy.     

Biophysical comparability of the same protein from different manufacturers: a case study using Epoetin alfa from Epogen and Eprex

This study focuses on the development and application of biophysical methodology to characterize conformations of Epogen and Eprex, the injectable formulations of recombinant human Epoetin alfa produced by different manufacturers and commonly used for the treatment of renal anemia. In these studies Eprex, from prefilled syringes, and Epogen bulk product formulated in a buffer similar to the Eprex formulation, were purified by anion-exchange chromatography. Analytical ultracentrifugation studies of the purified main peak from each sample demonstrated that Epogen contains a single component with an s value of 2.51 while Eprex contains a single component with the same molecular weight but with an s value of 2.44 suggesting a slight difference in hydrodynamic structure. The degree of alpha-helicity was compared by far-UV circular dichroism and shown to contain slight differences. Intrinsic tryptophan fluorescence and near-UV circular dichroism were assessed and demonstrated additional differences between the proteins. Finally, the global stability of the proteins was monitored using thermal unfolding monitored by far-UV circular dichroism. The Epoetin alfa of Epogen demonstrated complete reversibility while the Epoetin alfa purified from Eprex demonstrated only 80%-85% thermal reversibility when heated to 100 degrees C. Together the data indicate that the proteins are not structurally identical.     

Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture

The transthyretin (TTR) amyloidoses are human diseases in which the misfolded TTR protein aggregates in tissues with subsequent visceral, peripheral, and autonomic nerve dysfunction. Recent reports have stressed the importance of oligomeric intermediates as major cytotoxic species in various forms of amyloidogenesis. We have examined the cytotoxic effects of several quaternary structural states of wild-type and variant TTR proteins on cells of neural lineage. TTR amyloid fibrils and soluble aggregates >100 kDa were not toxic. Incubation of TTR under the conditions of the cell assay and analysis by size-exclusion chromatography and SDS/PAGE reveal that monomeric TTR or relatively small, rapidly formed aggregates of a maximum size of six subunits were the major cytotoxic species. Small molecules that stabilize the native tetrameric state were shown to prevent toxicity. The studies are consistent with a model in which the misfolded TTR monomer rapidly aggregates to form transient low molecular mass assemblies (<100 kDa) that are highly cytotoxic in tissue culture.