Miracle-dz/UniFAR-FTUs huggingface dataset:
The International Society of Blood Transfusion

In 1956, Dr. J. Julliard, proud of the dynamic development of the organization which is so actively involvcd in the promotion of one of the most fundamental therapeutics, wrote in brilliant French the history of the International Society of Blood Transfusion*. A first meeting, where the delegates of 20 different nations expressed their interest in the development of blood transfusion therapy, was held in Rome, in 1935. This conference was primarily devoted to blood transfusion organization, and particularly to the recruitment of blood donors, the main problem of the day. In 1937 a second congress was organized, this time in Paris, with 29 countries participating. On this occasion the International Society of Blood Transfusion was founded. It was decided to establish a permanent office in Paris, which should develop its activities in close cooperation with delegates of all national blood transfusion societies. While in 1935 the equipment for direct transfusion from donor t o patient was still a subject of discussion although the Sovjet delegates already stressed the importance of conserved blood and the use of cadaver blood -, in 1937 full attention was paid to stored blood, which would be used in such large quantities during the second world-war. The activities of the International Society were hampered during and after the second world-war, but blood transfusion therapy developed undisturbedly, and in 1948 the third congress was held in Turin. Since then meetings were organized at regular intervals, in Lisbon (1951), Paris (1954), Boston (1956), Rome (1958), Tokyo (1960) and Mexico City (1962). The next congress will be held in Stockholm, in September 1964. From the numerous blood transfusion specialists who contributed t o the prosperous development of the Society, a t least two names should be mentioned: the late Prof. Dr. Arnault Tzanck and the late Dr. J . Julliard. Prof. Tzanck, a temperamental scientist, had a great
Actual causes of death in the United States.

Objective. —To identify and quantify the major external (nongenetic) factors that contribute to death in the United States. Data Sources. —Articles published between 1977 and 1993 were identified through MEDLINE searches, reference citations, and expert consultation. Government reports and compilations of vital statistics and surveillance data were also obtained. Study Selection. —Sources selected were those that were often cited and those that indicated a quantitative assessment of the relative contributions of various factors to mortality and morbidity. Data Extraction. —Data used were those for which specific methodological assumptions were stated. A table quantifying the contributions of leading factors was constructed using actual counts, generally accepted estimates, and calculated estimates that were developed by summing various individual estimates and correcting to avoid double counting. For the factors of greatest complexity and uncertainty (diet and activity patterns and toxic agents), a conservative approach was taken by choosing the lower boundaries of the various estimates. Data Synthesis. —The most prominent contributors to mortality in the United States in 1990 were tobacco (an estimated 400000 deaths), diet and activity patterns (300 000), alcohol (100 000), microbial agents (90 000), toxic agents (60 000), firearms (35 000), sexual behavior (30 000), motor vehicles (25 000), and illicit use of drugs (20 000). Socioeconomic status and access to medical care are also important contributors, but difficult to quantify independent of the other factors cited. Because the studies reviewed used different approaches to derive estimates, the stated numbers should be viewed as first approximations. Conclusions. —Approximately half of all deaths that occurred in 1990 could be attributed to the factors identified. Although no attempt was made to further quantify the impact of these factors on morbidity and quality of life, the public health burden they impose is considerable and offers guidance for shaping health policy priorities. (JAMA. 1993;270:2207-2212)
Myeloperoxidase and its products in synovial fluid of patients with treated or untreated rheumatoid arthritis

Abstract Objective. Plasma and synovial myeloperoxidase (MPO) and its products were strongly associated with osteoarthritis (OA) and rheumatoid arthritis (RA). In addition, it is well known that there is a link between oxidative stress and cytokines. The present study aims at investigating the link between synovial MPO (and its products), interleukin (IL)-18, which is involved in the degradation of articular cartilage in RA, and IL-8, which is involved in recruitment and activation of neutrophils during inflammation. Effects of the treatment of RA on the biological parameters were also investigated. Methods. Patients (n = 105) were studied including 39 patients with OA, 33 with RA and 33 with RA receiving a specific treatment. Disease activity score (DAS-28) was calculated whereas MPO antigen/activity, neutrophils, chloro-tyrosine (Cl-Tyr), homocitrulline (Hcit), IL-8, and IL-18 were measured in synovial fluid (SF) and CRP was measured in serum. Results. DAS-28 and CRP levels were not significantly different between groups. MPO activity, and MPO, Cl-Tyr, and Hcit levels were significantly higher in SF of RA patients than OA patients. MPO specific activity (MPO activity/antigen ratio) was significantly lower in treated than in untreated RA patients as was IL-8. MPO activity and concentration were correlated with IL-8 and IL-18 in untreated but not in treated RA patients. Conclusions. MPO level is related to IL-8 and IL-18 levels in untreated RA patients. A link has been shown between treatment and decrease of IL-8, MPO specific activity and Hcit in SF. The causal role of MPO in SF inflammation and how treatment can affect MPO specific activity need further investigations.
Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival

Costimulation blockade is an effective way to prevent allograft rejection. In this study, we tested the efficacy of two negative co-signaling molecules in protecting islet allograft function. We used local expression of B7-H4 by adenoviral transduction of islets (Ad-B7-H4) and systemic administration of CTLA-4.Ig to investigate the outcomes of allograft survival. Five groups of streptozotocin-induced diabetic C57BL/6 mice received 400 islets each from BALB/c donors. The groups consisted of control (G1); CTLA-4.Ig (G2); Ad-LacZ (G3); Ad-B7-H4 (G4); and Ad-B7-H4 and CTLA-4.Ig combined (G5). G1 and G3 developed graft failure on average of two weeks. G2, G4 and G5 survived for 43.8 ± 34.8, 54.7 ± 31.2 and 77.8 ± 21.5 d, respectively. Activated T and B cells in the lymph nodes were significantly controlled by CTLA-4.Ig treatment. Significantly reduced infiltrates were also detected in the allografts of G2 compared with G1. By contrast, B7-H4 significantly inhibited Th1-associated IFN-gamma secretion in the early stage and increased Foxp3+ T cells in the long-term surviving allografts. Our study suggests that CTLA-4 and B7-H4 inhibit alloimmune responses through distinct mechanisms, and that combination therapy which activates two negative co-signaling pathways can further enhance islet allograft survival.
In vitro cell culture models for the assessment of pulmonary drug disposition

Background: Aerosol administration of therapeutics to the respiratory system represents a significant opportunity for many classes of drugs, both small molecules and macromolecules, including recently engineered peptide and protein therapeutics. However, minimally invasive assessment of drug absorption mechanisms in vivo or from the isolated organ is prevented by the complex architecture of the lung. Thus, cell culture models of the bronchial and alveolar epithelial barriers have been developed for absorption mechanisms studies and are now widely used as in vitro screening tools. Objectives: The aim of this article is to provide an update of the published work on various in vitro models of respiratory epithelium while emphasising the advantages and limitations of each model. Methods: This review summarises recent advances in the development and characterisation of in vitro cell culture models for drug disposition studies. Conclusions: A variety of cell culture systems for modelling the respiratory epithelium have been developed and are available to the scientific community. However, to allow their full exploitation in biopharmaceutical research, the currently available models have to be further characterised, particularly regarding their expression of transporter molecules and their metabolic capabilities.
Establishment of a prolonged pancreas preservation model for islet isolation research in mice

Establishing a prolonged pancreas preservation model in a small animal is important for islet isolation research. Use of a rat pancreas model has been reported, but no published reports have used a mouse pancreas for prolonged cold preservation prior to islet isolation. For the model, a mouse is preferred over a rat because of its small size, well-known immune characterization and variety of gene-modulated models. In the present study, we established a prolonged pancreas preservation model in a mouse for islet isolation research. The collagenase solution was injected successfully after 24 and 48 h cold preservations in University of Wisconsin solution, and islets could be isolated from both groups of preserved pancreata. The islet yields from the control, 24 h preserved, and 48 h preserved pancreata were 183.9 ± 13.9, 128.5 ± 15.5, and 24.6 ± 12.9 per pancreas, respectively. The propidium iodide–positive area assay was significantly increased in both preserved groups, and insulin secretion levels in response to 20.0 mM glucose and stimulation indices were significantly decreased in the 48 h preserved group. Inflammation-related genes mRNA levels were significantly upregulated in the 24 h preserved group, as previously shown in the human model. Thus, this model might be useful for prehuman islet isolation screening research, reserving research using human pancreata for the most promising approaches.
ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade

Overexpression of CD70 has been documented in a variety of solid and hematological tumors, where it is thought to play a role in tumor proliferation and evasion of immune surveillance. Here, we describe ARGX-110, a defucosylated IgG1 monoclonal antibody (mAb) that selectively targets and neutralizes CD70, the ligand of CD27. ARGX-110 was generated by immunization of outbred llamas. The antibody was germlined to 95% human identity, and its anti-tumor efficacy was tested in several in vitro assays. ARGX-110 binds CD70 with picomolar affinity. In depletion studies, ARGX-110 lyses tumor cells with greater efficacy than its fucosylated version. In addition, ARGX-110 demonstrates strong complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis activity. ARGX-110 inhibits signaling of CD27, which results in blocking of the activation and proliferation of Tregs. In a Raji xenograft model, administration of the fucosylated version of ARGX-110 resulted in a prolonged survival at doses of 0.1 mg/kg and above. The pharmacokinetics of ARGX-110 was tested in cynomolgus monkeys; the calculated half-life is 12 days. In conclusion, ARGX-110 is a potent blocking mAb with a dual mode of action against both CD70-bearing tumor cells and CD70-dependent Tregs. This antibody is now in a Phase 1 study in patients with advanced malignancies expressing CD70 (NCT01813539).
Sortase-catalyzed in vitro functionalization of a HER2-specific recombinant Fab for tumor targeting of the plant cytotoxin gelonin

We report on the preparation of a new type of immunotoxin via in vitro ligation of the αHer2 antigen binding fragment (Fab) of the clinically-validated antibody trastuzumab to the plant toxin gelonin, employing catalysis by the bacterial enzyme sortase A (SrtA). The αHer2 Fab was fused with the extended SrtA recognition motif LPET↓GLEH6 at the C-terminus of its heavy chain, thereby preventing interference with antigen binding, while the toxin was equipped with a Gly2 sequence at its N-terminus, distant to the catalytically active site in the C-terminal region. Site-specific in vitro transpeptidation led to a novel antibody-toxin conjugate wherein gelonin had effectively replaced the Fc region of a conventional (monomerized) immunoglobulin. After optimization of reaction conditions and incubation time, the resulting Fab-Gelonin ligation product was purified to homogeneity in a two-step procedure by means of Strep-Tactin affinity chromatography—utilizing the Strep-tag II appended to gelonin—and size exclusion chromatography. Binding activity of the immunotoxin for the Her2 ectodomain was indistinguishable from the unligated Fab as measured by real-time surface plasmon resonance spectroscopy. Specific cytotoxic potency of Fab-Gelonin was demonstrated against two Her2-positive cell lines, resulting in EC50 values of ~1 nM or lower, indicating a 1000-fold enhanced cell-killing activity compared with gelonin itself. Thus, our strategy provides a convenient route to the modular construction of functional immunotoxins from Fabs of established tumor-specific antibodies with gelonin or related proteotoxins, also avoiding the elevated biosafety levels that would be mandatory for the direct biotechnological preparation of corresponding fusion proteins.
Maternal depressive symptoms have a negative impact on prenatal attachment – findings from a Swedish community sample

Objective: The objective of this study was to evaluate attachment and its association to obstetric and demographic factors as well as emotional well-being using a standard measure of prenatal attachment during pregnancy. Background: The strength of the mothers’ relationship with her baby has important implications in the postnatal period, influencing the relationship she develops with her child, and the quality of the care she provides. Methods: This was a population-based longitudinal survey comprising a consecutive sample from a one-year cohort in a Swedish county. In this study the three subscales of PAI-R (Prenatal Attachment Inventory – Revised) were used for evaluation of attachment. In total, 718 pregnant women participated in this study. Results: Women with elevated levels of depression (HADS-D > 8) recorded lower attachment scores across all three PAI-R subscales. Lack of perceived support from partner was associated with lower scores on Interaction. Lack of support from own mother and own father were also associated with lower scores on all subscales. Attachment was also associated with feelings about the approaching birth and about the first weeks with the newborn, with women who reported less than positive feelings recording lower scores on each of the PAI-R subscales. Conclusion: A focus on attachment during antenatal care and the use of PAI-R during pregnancy provides a means of identifying those women who show lower levels of attachment and possible emotional problems that may impact on emotional health and the birth process.
Tratamento ortopédico da Classe III em padrões faciais distintos

A ma oclusao de Classe III, de origem essencialmente esqueletica, produz uma acentuada deformidade facial. A Classe III pode ser interceptada durante a fase de crescimento e desenvolvimento craniofacial mediante o uso de aparelhos ortopedicos. O crescimento mandibular, predominantemente endocondral na cartilagem condilar, obedece essencialmente ao controle genetico. Portanto, os efeitos dos aparelhos ortopedicos que visam restringir o crescimento da mandibula mostram-se limitados, o que conduz ao pobre prognostico de tratamento precoce da Classe III determinada pelo prognatismo mandibular. Felizmente, o componente esqueletico maxilar responde melhor a aplicacao de forcas ortopedicas, ja que o crescimento osseo intramembranoso mostra-se mais susceptivel a influencias extrinsecas ou ambientais. Deste modo, a Classe III morfologicamente definida pelo retrognatismo maxilar, privilegia-se com o tratamento ortopedico. Este trabalho discute o tratamento interceptivo da Classe III por meio da tracao reversa da maxila em pacientes com padroes faciais distintos, apresentando dois casos clinicos, e ainda ressalta os aspectos atinentes a sua estabilidade.
Pain relief in labour: tramadol versus pentazocine

Background: The present study was undertaken to compare the effect of 100 mg intramuscular tramadol to 30 mg intramuscular Pentazocine for labour analgesia. Methods: A total of 60 cases with 37-40 weeks pregnancy in labour, without any foetal or maternal complications were selected. Out of them Inj. Tramadol was given to 30 cases while rest of the 30 patients received injection Pentazocine. Results: In Tramadol group pain relief was observed in 80% cases, effect started as early as 7-8 min and continued for 2.13 hrs. While in Pentazocine group pain relief was observed in only 60% cases with delayed onset (15-16 min), effect lasted for 2.67 hrs. Maternal and foetal complications were slightly more in Pentazocine group. Conclusions: Tramadol is an effective and safe labour analgesic, producing moderate to satisfactory. Besides it also significantly shortens the duration of labour.
Reversible aggregation of PABPN1 pre-inclusion structures

Increased aggregation of misfolded proteins is associated with aging, and characterizes a number of neurodegenerative disorders caused by homopolymeric amino acid expansion mutations. PABPN1 is an aggregation-prone nuclear protein. Natural aggregation of wild type (WT) PABPN1 is not known to be disease-associated, but alanine-expanded PABPN1 (expPABPN1) accumulates in insoluble intranuclear inclusions in muscle of patients with oculopharyngeal muscular dystrophy (OPMD). We applied microscopic image quantification to study PABPN1 aggregation process in living cells. We identified transitional pre-inclusion foci and demonstrate that these structures significantly differ between WT- and expPABPN1 expressing cells, while inclusions of these proteins are indistinguishable. In addition to the immobile PABPN1 in inclusions, in the nucleoplasm of expPABPN1 expressing cells we also found a fraction of immobile proteins, representing pre-aggregated species. We found that pre-aggregated and pre-inclusion structures are reverted by a PABPN1 specific affinity binder while inclusion structures are not. Together our results demonstrate that the aggregation process of WT- and expPABPN1 differs in steps preceding inclusion formation, suggesting that pre-aggregated protein species could represent the cytotoxic structures.
Effectiveness of a Custom-Made below Elbow Lateral Counterforce Splint in the Treatment of Lateral Epicondylitis (Tennis Elbow)

The purpose of the study was to determine the effectiveness of a custom-made below elbow lateral counterforce splint along with standard physiotherapy compared with physiotherapy alone, for the treatment of lateral epicondylitis. It was hypothesized that the recovery from lateral epicondylitis is greater following four weeks of standard physiotherapy and the use of the splint, than following four weeks of standard physiotherapy alone. The experimental group (with the splint and physiotherapy) demonstrated a significant improvement in pain (p = 0.05) and maximum grip strength (p = 0.025) of the affected arm compared to the control group. The experimental group showed a greater improvement in function approaching but not reaching significance. The results indicate that this custom-made splint is of value in facilitating the recovery from lateral epicondylitis.
Formulation and evaluation of metformin hydrochloride-loaded niosomes as controlled release drug delivery system

Abstract Lactic acidosis is a serious, metabolic complication that may occur due to metformin hydrochloride (MH) accumulation during the treatment of diabetes mellitus. The aim of this study is to enhance the bioavailability of MH by oral route. Span 40 and cholesterol were used for the preparation of MH-loaded niosomes by the reverse phase evaporation technique. Dicetyl phosphate (DCP) and 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) were used to obtain negatively and positively charged vesicles, respectively. The mean particle size ranged from 223.5 to 384.6 nm and the MH-loaded niosomes’ surface was negatively charged in the absence of charge inducing agents (−16.6 ± 1.4 mV) and also with DCP (−26.9 ± 1.0 mV), while it was positively charged (+8.7 ± 1.2 mV) with DOTAP. High entrapment efficiency was observed in all the formulations. MH-loaded niosomes were found to effectively sustain the release of drug, particularly with positively charged niosomes. The bioavailability of MH-loaded niosomes was assessed by measuring the serum values of glucose and metformin in the different studied Wistar rats groups. The pharmacokinetic data of MH-loaded niosomal preparation showed a significant prolongation and increased intensity of hypoglycemic effect more than that observed for free MH solution. Area above the blood glucose levels–time curve (AAC), maximum hypoglycemic response and time of maximum response (Tmax) were significantly higher (p < 0.001) when MH was administered in niosomal form compared to free drug solution. It could be concluded that MH-loaded niosome is promising extended-release preparation with better hypoglycemic efficiency.
CST for the grand finale of telomere replication

Telomeric DNA at eukaryotic chromosome ends terminates with single stranded 3′ G-rich overhangs. The overhang is generated by the interplay of several dynamic processes including semiconservative DNA replication, 3′ end elongation by telomerase, C-strand fill-in synthesis and nucleolytic processing. The mammalian CST (CTC1-STN1-TEN1) complex is directly involved at several stages of telomere end formation. Elucidation of its structural organization and identification of interaction partners support the notion that mammalian CST is, as its yeast counterpart, a RPA-like complex. CST binding at mammalian telomere 3′ overhangs increases upon their elongation by telomerase. Formation of a trimeric CST complex at telomeric 3′overhangs leads to telomerase inhibition and at the same time mediates a physical interaction with DNA polymerase-α. Thus CST seems to play critical roles in coordinating telomerase elongation and fill-in synthesis to complete telomere replication.
Computational image analysis of nuclear morphology associated with various nuclear-specific aging disorders

Computational image analysis is used in many areas of biological and medical research, but advanced techniques including machine learning remain underutilized. Here, we used automated segmentation and shape analyses, with pre-defined features and with computer generated components, to compare nuclei from various premature aging disorders caused by alterations in nuclear proteins. We considered cells from patients with Hutchinson-Gilford progeria syndrome (HGPS) with an altered nucleoskeletal protein; a mouse model of XFE progeroid syndrome caused by a deficiency of ERCC1-XPF DNA repair nuclease; and patients with Werner syndrome (WS) lacking a functional WRN exonuclease and helicase protein. Using feature space analysis, including circularity, eccentricity, and solidity, we found that XFE nuclei were larger and significantly more elongated than control nuclei. HGPS nuclei were smaller and rounder than the control nuclei with features suggesting small bumps. WS nuclei did not show any significant shape changes from control. We also performed principle component analysis (PCA) and a geometric, contour based metric. PCA allowed direct visualization of morphological changes in diseased nuclei, whereas standard, feature-based approaches required pre-defined parameters and indirect interpretation of multiple parameters. Both methods yielded similar results, but PCA proves to be a powerful pre-analysis methodology for unknown systems.