Predicting the Strength of Cohesive and Adhesive Interparticle Interactions for Dry Powder Inhalation Blends of Terbutaline Sulfate with α-Lactose Monohydrate.

Grid-based systematic search methods are used to investigate molecule-molecule, molecule-surface, and surface-surface contributions to interparticle interactions in order to identify the crystal faces that most strongly affect particle behavior during powder blend formulation and delivery processes. The model system comprises terbutaline sulfate (TBS) as an active pharmaceutical ingredient (API) and α-form lactose monohydrate (LMH). A combination of systematic molecular modeling and X-ray computed tomography (XCT) is used to determine not only the adhesive and cohesive interparticle energies but, also the agglomeration behavior during manufacturing and de-agglomeration behavior during delivery after inhalation. This is achieved through a detailed examination of the balance between the adhesive and cohesive energies with the XCT results confirming the blend segregation tendencies, through the particle-particle de-agglomeration process. The results reveal that the cohesive interaction energies of TBS-TBS are higher than the adhesive energies between TBS and LMH, but that the cohesive energies of LMH-LMH are the smallest between molecule and molecule, molecule and surface, and surface and surface. This shows how systematic grid-search molecular modeling along with XCT can guide the digital formulation design of inhalation powders in order to achieve optimum aerosolization and efficacy for inhaled medicines. This will lead to faster pharmaceutical design with less variability, higher quality, and enhanced performance.

The psychometric properties of the Vietnamese Version of the Five Facet Mindfulness Questionnaire.

BACKGROUND: Although recent decades have witnessed a growing interest in mindfulness with the development of many mindfulness scales and their adaptation to different cultures, there has been no attempt at developing or adapting a mindfulness scale for Vietnamese people. To fill this gap and encourage the study of mindfulness in Vietnam, we adapted a 20-item short-form of the Five Facet Mindfulness Questionnaire (FFMQ-20) into Vietnamese, which we called the FFMQ-V, and examined its psychometric properties in a series of three independent studies. METHODS: In Study 1, using a college sample (N = 412) we conducted several exploratory factor analyses to elucidate the factor structure of the FFMQ-V. In Study 2, using an independent college sample (N = 344) we performed a confirmatory factor analysis (CFA) to test the goodness-of-fit for all obtained factor models from Study 1. In this study, we also examined the discriminant validities of the FFMQ-V by correlating mindfulness and other related psychological constructs, including acceptance, nonattachment, depression, anxiety, and stress. In Study 3, we replicated all data analyses in Study 2 using a community sample of young adults (N = 574). RESULTS: Across all Studies, our results indicated that the hierarchical five-factor model with method factors best captured the latent structure of the FFMQ-V. Our results also showed that the mindfulness facets met our expectations as they correlated positively with the acceptance and nonattachment and negatively with the depression, anxiety, and stress. CONCLUSIONS: In aggregate, our EFA and CFA results provided strong evidence for the hierarchical five-factor model with method factors in both community and college samples, suggesting that the FFMQ-V can be used to measure trait mindfulness of the Vietnamese young adults.

Allogeneic administration of human umbilical cord-derived mesenchymal stem/stromal cells for bronchopulmonary dysplasia: preliminary outcomes in four Vietnamese infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a severe condition in premature infants that compromises lung function and necessitates oxygen support. Despite major improvements in perinatal care minimizing the devastating effects, BPD remains the most frequent complication of extreme preterm birth. Our study reports the safety of the allogeneic administration of umbilical cord-derived mesenchymal stem/stromal cells (allo-UC-MSCs) and the progression of lung development in four infants with established BPD. METHODS: UC tissue was collected from a healthy donor, followed by propagation at the Stem Cell Core Facility at Vinmec Research Institute of Stem Cell and Gene Technology. UC-MSC culture was conducted under xeno- and serum-free conditions. Four patients with established BPD were enrolled in this study between May 25, 2018, and December 31, 2018. All four patients received two intravenous doses of allo-UC-MSCs (1 million cells/kg patient body weight (PBW) per dose) with an intervening interval of 7 days. Safety and patient conditions were evaluated during hospitalization and at 7 days and 1, 6 and 12 months postdischarge. RESULTS: No intervention-associated severe adverse events or prespecified adverse events were observed in the four patients throughout the study period. At the time of this report, all patients had recovered from BPD and were weaned off of oxygen support. Chest X-rays and CT scans confirmed the progressive reductions in fibrosis. CONCLUSIONS: Allo-UC-MSC administration is safe in preterm infants with established BPD. Trial registration This preliminary study was approved by the Vinmec International Hospital Ethics Board (approval number: 88/2019/QD-VMEC; retrospectively registered March 12, 2019).

Effect of Imidazole on the Electrochemistry of Zinc Porphyrins: An Electrochemical and Computational Study.

In this study, the electrochemical behavior of zinc meso-substituted porphyrins in the presence of imidazole is examined by using both cyclic voltammetry (CV) and density functional theory (DFT) methods. The results show that the first half-wave oxidation potentials (1st E1/2) of zinc porphyrins complexed with imidazole all move to the negative side, while the second ones (2nd E1/2) move to the positive side, resulting in larger half-wave oxidation potential splittings of the two oxidation states (ΔE = second E1/2 - first E1/2) comparing with the zinc porphyrins. By employing DFT calculations, we have found that both sterically controlled inter π-conjugation between porphyrin rings and meso-substituted phenyl groups and deformation of porphyrin rings do play important roles in contributing to the half-wave oxidation potentials. Imidazole exhibits strong effects on the deformation of porphyrin rings which is dominant in determining the first E1/2 while the inter π-conjugation between porphyrin rings and meso-substituted phenyl groups mainly contributes to the second E1/2. Without imidazole, the inter π-conjugation between porphyrin rings and meso-substituted phenyl groups is the only important criterion which effects both first E1/2 and second E1/2 of zinc porphyrins.

Electrochemical Behavior of meso-Substituted Porphyrins: The Role of Cation Radicals to the Half-Wave Oxidation Potential Splitting.

In this study, the electrochemical behavior of free base and zinc meso-substituted porphyrins is examined by cyclic voltammetry (CV) and density functional theory (DFT). The results show that the half-wave oxidation potential splitting of the two oxidation states (ΔE= second E1/2 - first E1/2) of tetraphenylporphyrin (H2TPP) and its zinc complex (ZnTPP) are higher than those of porphyrins and their zinc complexes with meso-substituted five-membered heterocylic rings. The ΔE values follow the trend of TPP > T(3'-thienyl)P > T(3'-furyl)P > T(2'-thienyl)P for both meso-porphyrins and their respective zinc complexes. By employing DFT calculations, we have found that the trend of ΔE values is consistent with that of highest spin density (HSD) distribution and HOMO-LUMO energy gaps of cationic radicals as well as the π-conjugation between central porphyrin and meso-substituted rings. Also, they exhibit the better resonance between the porphyrin ring with meso-substituted rings as moving from porphyrins and their zinc complexes with phenyl rings to five-membered heterocyclic rings. A good agreement between calculated and experimental results indicates that cationic radicals, especially their spin density distribution, do play an important role in half-wave oxidation potential splitting of meso-porphyrins and their zinc complexes.

Terminal deoxynucleotidyl transferase and repertoire development.

In mice, the absence of terminal deoxynucleotidyl transferase (Tdt) expression during fetal and neonatal life provides a window in development where clones of lymphocytes are generated that provide protective immunity. Introducing premature Tdt activity interferes with the development of these clones and results in an impaired ability to make protective antibodies. Conversely, gene-targeted disruption of Tdt prevents N additions at all stages of T and B-lymphocyte development and promotes the development of fetal-like T and B-cell clones into adulthood, with accompanying alterations in repertoire. The alternative splice forms of Tdt may be necessary to provide regulatory mechanisms to restrict N addition to appropriate stages of the developmental pathways, the details of which are being revealed. The evidence continues to build that Tdt is a key player in influencing the outcome of V(D)J recombination during lymphocyte and repertoire development.

Down-modulation of the ZAP-70 protein tyrosine kinase in macaque T lymphocytes infected with SIVsmmPBj14.

The simian immunodeficiency virus SIV-PBj14 is the most virulent primate lentivirus identified to date. Other SIV strains, including the parental SIVsmm9, require mitogen-activated peripheral blood mononuclear cells (PBMC) for replication in vitro; however, SIV-PBj14 replicates in quiescent pig-tailed macaque PBMC and induces cellular proliferation, consistent with its in vivo pathogenesis. To identify mechanisms involved in SIV-PBj14-induced T-cell proliferation, kinases important in early T-cell receptor-mediated activation pathways were studied. Immunoblot analyses showed that ZAP-70 protein, a tyrosine kinase, was downregulated, primarily in CD8+ T cells, as early as 30 minutes after in vitro infection of quiescent macaque PBMC with SIV-PBj 14. Furthermore, this downregulation required the presence of either CD4+ T cells or adherent cells or both cell populations. In agreement with the in vitro results, ZAP-70 expression was downregulated in macaque PBMC, spleen, and rectal lymph node cells as early as 2 days after rectal inoculation of pig-tailed macaques with SIV-PBj14. This phenomenon, however, was not observed in cells obtained from distal lymph nodes to which the virus had not disseminated, implying that the presence of SIV-PBj14 is necessary to induce downregulation of ZAP-70.

Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers.

Germline alterations of BRCA1 result in susceptibility to breast and ovarian cancer. The protein encoded by BRCA1 interacts in vivo with the BRCA1-associated RING domain (BARD1) protein. Accordingly, BARD1 is likely to be a critical factor in BRCA1-mediated tumor suppression and may also serve as a target for tumorigenic lesions in some human cancers. We have now determined the genomic structure of BARD1 and performed a mutational analysis of 58 ovarian tumors, 50 breast tumors and 60 uterine tumors. Seven polymorphisms were detected within the 2.34 kb coding sequence of BARD1 . Somatically acquired missense mutations were observed in one breast carcinoma and one endometrial tumor; in at least one of these cases, tumor formation was accompanied by loss of the wild-type BARD1 allele, following the paradigm for known tumor suppressor genes. In addition, a germline alteration of BARD1 was identified in a clear cell ovarian tumor (Gln564His); again, loss of the wild-type BARD1 allele was observed in the malignant cells of this patient. The Gln564His patient was also diagnosed with two other primary cancers: a synchronous lobular breast carcinoma and a stage IA clear cell endometrioid cancer confined to an endometrial polyp 6 years earlier. These findings suggest an occasional role for BARD1 mutations in the development of sporadic and hereditary tumors.

Crossreactivity between human and canine Ia antigens using a mouse monoclonal antibody (CIA).

A mouse monoclonal antibody (CIA) produced against human Ia antigens that reacts with 20-30% of human peripheral blood lymphocytes was found to react with more than 90% of dog lymphocytes. Less than 41% of the Ia-positive dog lymphocytes expressed surface immunoglobulins. Immunoprecipitation studies with 125I-labeled cells precipitated heavily labeled Ia bands at 28K and 35K from human cells, but from dog cells the 29K beta chain of Ia was much more heavily labeled than the alpha chain.