bluuebunny/crossref_metadata_2025 huggingface dataset:
Matched and Mismatched Unrelated Donor Versus Unmanipulated Haploidentical Donors for Hematopoietic Cell Transplantation in Acute Leukemia in Remission: A Pair Matched Analysis on Behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Authors: Piemontese Simona , Ciceri Fabio , Labopin Myriam , Arcese William , Kyrcz-Krzemien Slawomira , Santarone Stella , Huang He , Beelen Dietrich , Gorin Norbert Claude , Craddock Charles , Gulbas Zafer , Bacigalupo Andrea , Nagler Arnon , Mothy Mohamad
Published: October 2019

Background. The best donor source for adult patients with acute leukemia lacking an HLA-identical donor still remains to be established. The objective of this study was to compare the outcome after T-cell-replete hematopoietic stem cell transplantation from haploidentical donor (HAPLO) and transplant from Matched Unrelated Donor (MUD) or Mismatched Unrelated Donor at a single HLA-locus (MMUD) for patients with acute leukemia in remission.

Methods. From January 2007 to December 2012, 313 consecutive HAPLOs were performed as first allogeneic transplants in adult patients with de novo acute leukemia in CR1 or CR2 and reported to the EBMT Registry. We were able to pair match 273 of these 313 patients with another 273 patients who received a MUD and 273 who received a MMUD transplant. The matching factors were as follow: age (+/-5y), diagnosis (myeloid or lymphoblastic leukemia), disease status at transplant (CR1 or CR2) and interval from diagnosis to transplant (+/-1mo).

Results. The median follow-up was 22 months. The two-year non-relapse mortality (NRM) and relapse (RI) cumulative incidences were 28% and 30% for HAPLO, 21% and 19% for MUD, and 28% and 27% for MMUD. The two-year KM estimates of leukemia-free survival (LFS) and overall survival (OS) were 42% and 49% for HAPLO, 59% and 65% for MUD, 45% and 51% for MMUD. In multivariate analysis both NRM and RI were significantly reduced in MUD compared to HAPLO (NRM, hazard ratio (HR): 0.61, p=0.02, 95%CI: 0.40-0.91; RI, HR: 0.59, p=0.01, 95%CI: 0.39-0.89) but there was no statistical difference between HAPLO and MMUD (NRM, p=0.59; RI, p=0.52). LFS and OS were significantly higher in MUD compared to HAPLO (LFS HR: 0.61, p=0.001, 95%CI: 0.45-0.81.OS HR: 0.63, p=0.004, 95%CI: 0.46-0.86) but not statistically different between MMUD and HAPLO (LFS, p=0.45. OS, p=0.84). Of note, type of donor was neither associated with day-100 grade II-IV acute graft-versus-host disease, nor to chronic graft-versus-host disease.

Conclusion. These findings suggest that LFS and OS were significantly higher in patients with acute leukemia in remission receiving a MUD compared to patients with similar characteristics receiving a HAPLO. We didn’t find significant differences between MMUD and HAPLO. In the absence of a MUD, host/donor features and urgency of transplant should drive us towards the best choice between these alternative donor sources.

Disclosures

No relevant conflicts of interest to declare.
Haplo-Cord Transplantation Vs Unrelated Donor Stem Cell Transplantation in Patients with AML/MDS Older Than 50
Authors: Rhodes Joanna , van Besien Koen , Liu Hongtao , Gergis Usama , Tsai Stephanie B. , Mayer Sebastian , Stock Wendy , Larson Richard A. , Shore Tsiporah B. , Odenike Olatoyosi , Pearse Roger , Godley Lucy A , Mark Tomer M , Kline Justin , Bishop Michael R. , Artz Andrew S.
Published: October 2019

Haplo-cord Transplantation Vs Unrelated Donor Stem Cell Transplantation In Patients with AML/MDS older than 50

Between 2007 and 2013, 109 patients with AML/MDS who were 50 years and older and had no HLA- matched related donor underwent allogeneic hematopoietic stem cell transplant. 64 had an HLA identical unrelated donor and received fludarabine/melphalan/alemtuzumab conditioning and post transplant tacrolimus for graft vs host disease (GVHD) prophylaxis. 45 underwent haplo-cord (HC) SCT with fludarabine/melphalan/ thymoglobulin; post-transplant tacrolimus and MMF. We compared patient characteristics and transplant outcomes between both groups. (Table 1) Age distribution and ASBMT risk category were similar. There were more patient's with AML in the HC group. (P=0.01) Time to neutrophil recovery, treatment related mortality (TRM), relapse rate, progression free survival (PFS) and overall survival (OS) were nearly identical between the two groups. Time to platelet recovery was on average 5 days longer after HC (p=0.05) The incidences of acute and chronic GVHD were very low in both groups, in part due to the use of in-vivo T cell depletion.

HC transplant with reduced intensity conditioning is a curative treatment for older patients with AML/MDS who lack HLA identical unrelated donors. Despite inclusion of many patients with high risk features, nearly two thirds were estimated to be alive one year after transplant and very few had chronic GVHD. Haplo-cord grafts are more readily available, a potential advantage over MUD grafts in situations where transplant is needed urgently. TableMatched Unrelated DonorHaplo Cord PN6445Age (range)62 (50-73)62 (50-74)AML/MDS45/2041/5 0.01ASBMTLow/Int /High21/6/3015/10/200.7KPS 9090Time to ANC >50010110.1Time to Plt >2018230.05PFS@ 1 Y (95% CI)46 (34-58)41 (26-56)0.6OS@ 1 Y (95% CI)57 (44-70)64 (49-79)0.8Cum Inc TRM @100 d (95% CI)9 (2-16)9 (0-18)0.2Cum Inc TRM @ 1 Y(95% CI)25 (14-36)29 (15-44)0.2Cum Inc Relapse @ 1Y (95% CI)30 (18-42)26 (12-40)0.5Cum Inc AGVHD @ 100 D (95% CI)25 (14-36)29 (13-43)0.7Cum Inc CGVHD @ 1 Y (95% CI)6 (0-12)7 (0-15)0.9

Disclosures

van Besien: Miltenyi: Research Funding. Mark:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Artz:Miltenyi: Research Funding.
A Mouse Model for XLP-2 Disease Uncovers a Critical Function for IL-1beta and TNF in Driving Hyper-Inflammation
Authors: Jost Philipp J. , Yabal Monica , Adler Heiko , Knies Nathalie , Groß Christina , Damgaard Rune Busk , Kanegane Hirokazu , Peschel Christian , Strasser Andreas , Groß Olaf , Ruland Jürgen , Gyrd-Hansen Mads
Published: October 2019

The hyper-inflammatory syndrome X-linked lymphoproliferative syndrome type 2 (XLP-2) is defined by mutations in BIRC4 (XIAP). XLP-2 is often diagnosed in paediatric patients and is characterized by hyper-inflammation triggered by common viral infections. Symptoms include splenomegaly, HLH, fevers, and chronic haemorrhagic colitis among others. Recent work has also shown that mutations in BIRC4 predispose to the development of early-onset IBD, which is not necessarily associated with symptoms of systemic hyper-inflammation. Symptoms of XLP-2 are mostly attributed to the aberrant activation of macrophages and dendritic cells (DC) and the subsequent accumulation of activated T-lymphocytes.

We have characterized the inflammatory response of mice deficient for BIRC4 (XIAP) to viral infections with the murine herpes virus 68 (MHV-68) as the closest murine model for human EBV-driven mononucleosis. Xiap-/- mice were capable of clearing the virus normally during early infection (day 6, 16), but failed to do so during the course of the infection measured as elevated viral genomic loads during late (day 43) and very late (day 84) latency. Xiap-/- mice responded to intranasal application of the virus with systemic hyper-inflammation exemplified by elevated IL-1beta levels, splenomegaly and increased activation of peripheral T lymphocytes such as CD4+ effector T cells, regulatory T cells (Treg), and IFNg+ T cells. In previous work, we have shown that TNF is critically required to drive the hyper-inflammatory phenotype of macrophages and dendritic cells of XIAP-deficient mice. Indeed, genetic deletion of TNF in vivo or, alternatively, anti-TNF treatment in vivo using Eternacept (Enbrel) ameliorated the symptoms of XIAP-deficient mice in response to viral infection.

Elevated IL-1beta levels were also observed in human peripheral blood-derived monocytes from XLP-2 patients (7 patients from 5 different families) when compared to healthy controls. In conclusion, this data supports the notion that anti-TNF treatment might be able to ameliorate the hyper-inflammatory responses in XLP-2 patients, when used early during an infection.

Disclosures

No relevant conflicts of interest to declare.
TET2 Regulates CD8+ T Cell Differentiation
Authors: Carty Shannon A. , Gohil Mercy , Koretzky Gary A , Jordan Martha S
Published: October 2019

Regulation of DNA methylation is critical for proper T cell differentiation and function. Antigen-specific CD8+ T cells undergo global remodeling of DNA methylation following viral infection, suggesting that DNA methylation may direct antigen-specific T cell responses. TET2 is a member of the Ten-Eleven-Translocation (TET) family, which converts 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC) and subsequent intermediates ultimately leading to DNA demethylation. How TET2 regulates T cell differentiation and function is unknown. Here we demonstrate that TET2 expression is regulated by TCR signaling in primary murine T cells. Furthermore, using a novel flow cytometric assay to measure 5hmC levels on a single cell basis, we find that TCR signaling also regulates TET activity as evidenced by a rapid increase in global 5hmC levels after TCR stimulation that is blunted in TET2-deficient T cells. To determine the role of TET2 in T cell responses, we generated mice deficient in TET2 in the T cell compartment (TET2fl/flCD4Cre+) mice. These mice develop grossly normal thymic and peripheral T cell subsets. Given the regulation of TET2’s expression and activity by TCR stimulation, we used a murine model of acute viral infection, specifically LCMV-Armstrong, to test if TET2 regulates antigen-specific T cell responses in vivo. Following viral challenge, TET2fl/flCD4Cre+ mice have similar antigen-specific CD8+ T cell expansion and effector responses but exhibit significantly enhanced memory CD8+ T cell differentiation compared to control mice. These data demonstrate that TET2 plays a critical role in directing CD8+ T cell differentiation and function. Studies are ongoing to identify specific TET2 regulated genes important in the development of CD8+ T cell memory.

Disclosures

No relevant conflicts of interest to declare.
Metabolic Reprogramming of Acute Myeloid Leukemia Blasts By Bone Marrow Stroma Cells
Authors: Mougiakakos Dimitrios , Jitschin Regina , Braun Martina , Mackensen Andreas
Published: October 2019

Introduction: Acute myeloid leukemia (AML) represents the most common form of acute leukemia in adults. Despite the enormous efforts during the last decades treatment resistance is still observed at a high rate. Previous studies have shown that bone marrow stroma promotes an increased resilience of AML blasts towards chemotherapeutics. Furthermore, current data suggest that alterations of the malignant cells’ metabolism could represent a strong determinant for the disease’s (including AML) course and/or treatment resistance. In fact, a deregulated metabolism could lead to a reduced sensitivity towards therapy and it remains to be elucidated whether this is a mechanism contributing to the blast-protective effects elicited by the bone marrow stroma. Here, we sought out to characterize the impact of stroma cells on the AML blasts’ metabolism.

Methods and Results: The human bone marrow stroma cell-line HS-5 was utilized for establishing the in vitro niche model. We compared in our assays AML cell lines (THP-1, OCI-AML, and KG-1) as well as primary blasts cultured on a HS-5 monolayer or alone. In line with previous observations we could detect an increased proportion of AML cells in the S-phase of the cell cycle upon co-culture with HS-5. When evaluating the cells’ metabolism we observed a shift towards glycolysis despite presence of oxygen, i.e. aerobic glycolysis or the “Warburg”-effect. Basal glycolysis as well as maximal glycolytic capacity upon blocking ATP production in the mitochondrial respiratory chain was increased. Respiration (including basal respiration, coupling efficacy, and maximal respiratory capacity) was not significantly affected. However, mitochondrial biogenesis appeared reduced.

Increased glycolysis was accompanied by an increased up-take of fluorescently labeled glucose as well as an increased expression of glucose transporters. The expression of several glycolytic molecules found to be increased upon HS-5 co-culture. Noticeably, cell-to-cell contact was not a pre-requisite for the metabolic shift. Our data was further corroborated by direct observations from AML patients: AML blasts isolated from the bone marrow exhibited an up-regulated glycolysis as compared to their counterparts from the periphery collected at the same time point.

Conclusion: Taken together, our data indicates a stromal cell-mediated metabolic shift in AML blasts towards aerobic glycolysis. This metabolic phenotype is linked to an unfavorable prognosis and increased chemo resistance. The underlying molecular pathways remain to be elucidated and could represent a promising target for future interventions.

Disclosures

No relevant conflicts of interest to declare.
Amino Acid Accumulation by Human Reticulocytes
Authors: ALLEN DAVID W.
Published: October 2019

1. The concentrations of certain amino acids were measured by ion exchange chromatography in mature red cells, in red cells with a high percentage of reticulocytes, and in the plasma in which these red cells had been suspended. The concentration ratio as a measure of net accumulation of the red cells for amino acids was derived from these data.

2. Adult red cells can accumulate glycine and alanine, but not methionine, valine, isoleucine or leucine.

3. Reticulocytes can accumulate glycine best, then alanine, then methionine, isoleucine, and leucine to approximately the same extent. They were unable to maintain a concentration gradient for valine.

4. In two patients with thalassemia, no abnormality was found in the plasma or red cell levels of citrulline, proline, glycine, alanine, valine, isoleucine, tyrosine, or phenylalanine. In one of the thalassemic patients no abnormality of histidine was found. The amino acid accumulation by thalassemic, or fetal red cells was the same as for normal red cells of comparable reticulocyte percentage.
A Second Example of Blood Group B3
Authors: SUSSMAN LEON N. , PRETSHOLD HANNAH , LACHER MORTIMER J.
Published: October 2019

A second example of an unusual B gene, named B3 by Moullec, has been presented, with a family study. Absorption and elution tests and studies of the saliva of a mother and her daughter established this group as a genetically determined subgroup of B. In our opinion, the substance found in the saliva of these individuals and of so called "aberrant secretors" of groups A2 and A2B may be so specific as to require their specific cell types in order to demonstrate their presence or absence.
STUDIES ON THE PHYSIOLOGY OF THE WHITE BLOOD CELL
Authors: WAGNER RICHARD
Published: October 2019

The technic of determining glycogen in isolated white blood cells was applied to the study of the different types of leukemia and of polycythemia, in order to obtain information on the physiology of the white blood cell. From this study it is concluded that the granulated leukocyte is the only carrier of glycogen in whole blood. The "reducing substances" in lymphocytes and blast cells are not considered as true glycogen.

The glycogen content of wet white blood cells in the rabbit amounts to about 1 per cent. In the human being a range of from 0.17 to 0.67 per cent was calculated. In disease higher percentages occur, in polycythemia up to 1.64 per cent and in glycogen storage disease up to 3.05 per cent.

The glycogen concentration of normal white blood cells is within the same range as that of the striated muscle.
MYELOFIBROSIS ASSOCIATED WITH TUBERCULOSIS
Authors: CRAIL HOWARD W. , ALT HOWARD L. , NADLER WALTER H.
Published: October 2019

Myelofibrosis (fibrotic bone marrow and, usually, an increase in megakaryocytes) is characterized by generalized pains, weakness, loss of weight, enlargement of the liver and spleen and a leuko-erythroblastic anemia.

Four cases of myelofibrosis associated with generalized tuberculosis have been reviewed in detail. Autopsy examination of the 4 cases revealed acute, caseating tuberculosis which was considered to be responsible for the bone marrow and generalized fibrosis observed. A similar type of tuberculosis occurred in 7 of 91 cases of myelofibrosis reveiwed in the literature. The pathogenesis of myelofibrosis associated with tuberculosis is discussed.

In the diagnosis of this syndrome, attention is called to the importance of obtaining a bone marrow biopsy and making a complete bacteriologic and pathologic study of this tissue for tuberculosis.

The 4 tuberculous cases here reported as compared with 5 cases of idiopathic type, are younger, have hyperpyrexia, less splenic but greater lymph node enlargement and run a shorter course before death.
OSMOMETRIC BEHAVIOR OF NORMAL AND ABNORMAL HUMAN ERYTHROCYTES
Authors: GUEST GEORGE M.
Published: October 2019

Normal human erythrocytes suspended in the series of hypotonic salt solutions employed for testing red cell fragility behave like nearly perfect osmometers throughout the series, with their maximum swelling, usually around 175 per cent of their initial volume, sharply defined by their mean surface area. The same principles govern the swelling and hemolysis of some abnormal types of erythrocytes with different characteristics of abnormal fragility or resistance to osmotic hemolysis. The red cells of congenital hemolytic icterus exhibit essentially normal osmotic behavior, but since the spherocytes can swell very little within the limits of their surface area they rupture at higher tonicities, with the maximal swelling in most instances around 150 per cent of their initial volume. Thin cells are capable of greater swelling than normal cells. Moderately hypochromic erythrocytes from patients with mild anemia behaved like perfect osmometers throughout the series, to attain a maximal swelling of around 200 per cent, this value agreeing with predictions based on their mean surface area.

Erythrocytes of patients with thalassemia, sicklemia and pernicious anemia exhibited less than the expected osmometric swelling throughout the series of hypotonic solutions. The cells behaving as imperfect osmometers displayed varying patterns of hemolysis, and of maximal swelling in relation to predicted values. The increased osmotic resistance characteristic of the cells of thalassemia is accounted for by two mechanisms: they swell less than normal cells at each tonicity; and, being thin, they undergo greater swelling (around 220 per cent) before they are hemolyzed.
CORRELATION BETWEEN THE MEAN CORPUSCULAR VOLUME AND RETICULOCYTOSIS IN PHENYLHYDRAZINE ANEMIA IN SWINE
Authors: LAWRASON F. DOUGLAS , ELTZHOLTZ D. C. , SIPE C. R. , SCHORK P. K.
Published: October 2019

1. Six adult swine were given phenylhydrazine hydrochloride orally and intravenously. Hematologic observations, which included periodic bone marrow studies were made before, during, and after the administration of the drug.

2. Five swine responded to the drug in the usual manner with progressive anemia, reticulocytosis, and erythrocytic hyperplasia of the bone marrow. Three animals died between the thirty-ninth and fiftieth day of the experiment after receiving a total dose of 0.30 to 0.35 Gm. per kilogram of body weight. Two swine survived and recovered after receiving a similar dose.

3. One animal died on the fourteenth day of the experiment and exhibited a course which closely resembled that of benzol poisoning. Rapid and progressive granulocytopenia, anemia, and extreme universal hypoplasia of the bone marrow were observed.

4. A direct correlation between the mean corpuscular volume of the red cell and the per cent reticulocytes was found within the limits of 0 to 80 per cent reticulocytosis. With each increment of 10 per cent in the reticulocytes the mean corpuscular volume increased approximately 6.8 cubic microns.
Towards a reliable prediction of the aquatic toxicity of dyes
Authors: Umbuzeiro Gisela de A. , Albuquerque Anjaina F. , Vacchi Francine I. , Szymczyk Malgorzata , Sui Xinyi , Aalizadeh Reza , von der Ohe Peter C. , Thomaidis Nikolaos S. , Vinueza Nelson R. , Freeman Harold S.
Published: October 2019

Background

The Max Weaver Dye Library (MWDL) from North Carolina State University is a repository of around 98,000 synthetic dyes. Historically, the uses for these dyes included the coloration of textiles, paper, packaging, cosmetic and household products. However, little is reported about their ecotoxicological properties. It is anticipated that prediction models could be used to help provide this type information. Thus, the purpose of this work was to determine whether a recently developed QSAR (quantitative structure–activity relationships) model, based on ACO-SVM techniques, would be suitable for this purpose.

Results

We selected a representative subset of the MWDL, composed of 15 dyes, for testing under controlled conditions. First, the molecular structure and purity of each dye was confirmed, followed by predictions of their solubility and pKa to set up the appropriate test conditions. Only ten of the 15 dyes showed acute toxicity in Daphnia, with EC50 values ranging from 0.35 to 2.95 mg L−1. These values were then used to determine the ability of the ACO-SVM model to predict the aquatic toxicity. In this regard, we observed a good prediction capacity for the 10 dyes, with 90% of deviations within one order of magnitude. The reasons for this outcome were probably the high quality of the experimental data, the consideration of solubility limitations, as well as the high purity and confirmed chemical structures of the tested dyes. We were not able to verify the ability of the model to predict the toxicity of the remaining 5 dyes, because it was not possible to determine their EC50.

Conclusions

We observed a good prediction capacity for the 10 of the 15 tested dyes of the MWDL, but more dyes should be tested to extend the existing training set with similar dyes, to obtain a reliable prediction model that is applicable to the full MWDL.
The effects of ventilation on left-to-right shunt and regional cerebral oxygen saturation: a self-controlled trial
Authors: Li Peiyi , Zeng Jun , Wei Wei , Lin Jing
Published: October 2019

Background

Increase of pulmonary vascular resistance (PVR) is an efficient method of modulating pulmonary and systemic blood flows (Qp/Qs) for patients with left-to-right (L-R) shunt, and is also closely associated with insufficient oxygen exchange for pulmonary hypoperfusion. So that it might be a preferred regime of maintaining arterial partial pressure of carbon dioxide tension (PaCO2) within an optimal boundary via ventilation management in congenital heart disease (CHD) patients for the inconvenient measure of the PVR and Qp/Qs. However, the appropriate range of PaCO2 and patient-specific mechanical ventilation settings remain controversial for CHD children with L-R shunt.

Methods

Thirty-one pediatric patients with L-R shunt, 1–6 yr of age, were included in this observation study. Patients were ventilated with tidal volume (VT) of 10, 8 and 6 ml/kg in sequence, and 15 min stabilization period for individual VT. The velocity time integral (VTI) of L-R shunt, pulmonary artery (PA) and descending aorta (DA) were measured with transesophageal echocardiography (TEE) after an initial 15 min stabilization period for each VT, with arterial blood gas analysis. Near-infrared spectroscopy sensor were positioned on the surface of the bilateral temporal artery to monitor the change in regional cerebral oxygen saturation (rScO2).

Results

PaCO2 was 31.51 ± 0.65 mmHg at VT 10 ml/kg vs. 37.15 ± 0.75 mmHg at VT 8 ml/kg (P < 0.03), with 44.24 ± 0.99 mmHg at VT 6 ml/kg significantly higher than 37.15 ± 0.75 mmHg at VT 8 ml/kg. However, PaO2 at a VT of 6 ml/kg was lower than that at a VT of 10 ml/kg (P = 0.05). Meanwhile, 72% (22/31) patients had PaCO2 in the range of 40-50 mmHg at VT 6 ml/kg. VTI of L-R shunt and PA at VT 6 ml/kg were lower than that at VT of 8 and 10 ml/kg (P < 0.05). rScO2 at a VT of 6 ml/kg was higher than that at a VT of 8 and 10 ml/kg (P < 0.05), with a significantly correlation between rScO2 and PaCO2 (r = 0.53). VTI of PA in patients with defect diameter > 10 mm was higher that that in patients with defect diameter ≤ 10 mm.

Conclusions

Maintaining PaCO2 in the boundary of 40-50 mmHg with VT 6 ml/kg might be a feasible ventilation regime to achieve better oxygenation for patients with L-R shunt. Continue raising PaCO2 should be careful.

Trail registration

Clinical Trial Registry of China (http://www.chictr.org.cn) identifier: ChiCTR-OOC-17011338, prospectively registered on May 9, 2017.
Clozapine and desmethylclozapine: correlation with neutrophils and leucocytes counting in Mexican patients with schizophrenia
Authors: Vaquero-Baez Mayela , Díaz-Ruíz Araceli , Tristán-López Luis , Aviña-Cervantes Carlos , Torner Carlos , Ramírez-Bermúdez Jesús , Montes Sergio , Ríos Camilo
Published: October 2019

Purpose

The aim of present study is to measure plasma clozapine (CLZ) and N-desmethyl clozapine (DMC) as biomarkers to correlate drug concentrations with the appearance of preclinical adverse hematic effects.

Methods

A high-performance liquid chromatographic method, using a diode-array (ultraviolet) detector, was validated to obtain reliable concentrations of CLZ and DMC, its main metabolite, in plasma of 41 schizophrenic patients taking CLZ. Blood neutrophils and leucocytes counting were concurrently assessed as a proxy to subclinical adverse reactions.

Results

The analytical method employed was linear, reproducible, and stable to measure concentrations of CLZ between 30 and 1000 ng/mL, while 12.5–560 ng/mL of the metabolite. The method allowed us to correlate CLZ plasma concentrations, the time taking CLZ and CLZ dose as determinants of neutrophils’ counting with a R2 = 0.447, using a multiple regression analysis model. Likewise, the correlation of leucocyte counting vs CLZ plasma levels and CLZ time, showed a R2 = 0.461. DMC correlated significantly with both neutrophils and leucocytes counting, but was excluded from the regression when CLZ concentration was included in the model. Finally, no other hematological adverse reactions were recorded. One patient presented a cardiovascular complication. The negative correlation between clozapine and neutrophil count observed in patients, suggest that CLZ itself, but not DMC, could be related to hematologic side-effects.

Conclusion

The findings of this study, demonstrate for the first time, that plasma levels of CLZ and time taking the drug are independent determinants of blood neutrophils and leucocytes, so the monitoring of plasma CLZ may be useful in the clinic practice to determine safe dosing of the drug.
Why research ethics should add retrospective review
Authors: Dawson Angus , Lignou Sapfo , Siriwardhana Chesmal , O’Mathúna Dónal P.
Published: October 2019

Research ethics is an integral part of research, especially that involving human subjects. However, concerns have been expressed that research ethics has come to be seen as a procedural concern focused on a few well-established ethical issues that researchers need to address to obtain ethical approval to begin their research. While such prospective review of research is important, we argue that it is not sufficient to address all aspects of research ethics. We propose retrospective review as an important complement to prospective review. We offer two arguments to support our claim that prospective review is insufficient. First, as currently practiced, research ethics has become for some a ‘tick box’ exercise to get over the ‘hurdle’ of ethics approval. This fails to capture much of what is important in ethics and does not promote careful reflection on the ethical issues involved. Second, the current approach tends to be rules-based and we argue that research ethics should go beyond this to develop people’s capacity to be sensitive to the relevant moral features of their research, their ethical decision-making skills and their integrity. Retrospective review of a project’s ethical issues, and how they were addressed, could help to achieve those aims better. We believe that a broad range of stakeholders should be involved in such retrospective review, including representatives of ethics committees, participating communities and those involved in the research. All stakeholders could then learn from others’ perspectives and experiences. An open and transparent assessment of research could help to promote trust and understanding between stakeholders, as well as identifying areas of agreement and disagreement and how these can be built upon or addressed. Retrospective review also has the potential to promote critical reflection on ethics and help to develop ethical sensitivity and integrity within the research team. Demonstrating this would take empirical evidence and we suggest that any such initiatives should be accompanied by research into their effectiveness. Our article concludes with a discussion of some possible objections to our proposal, and an invitation to further debate and discussion.
Crystal structure of diamondback moth ryanodine receptor Repeat34 domain reveals insect-specific phosphorylation sites
Authors: Xu Tong , Yuchi Zhiguang
Published: October 2019

Background

Ryanodine receptor (RyR), a calcium-release channel located in the sarcoplasmic reticulum membrane of muscles, is the target of insecticides used against a wide range of agricultural pests. Mammalian RyRs have been shown to be under the regulatory control of several kinases and phosphatases, but little is known about the regulation of insect RyRs by phosphorylation.

Results

Here we present the crystal structures of wild-type and phospho-mimetic RyR Repeat34 domain containing PKA phosphorylation sites from diamondback moth (DBM), a major lepidopteran pest of cruciferous vegetables. The structure has unique features, not seen in mammalian RyRs, including an additional α-helix near the phosphorylation loop. Using tandem mass spectrometry, we identify several PKA sites clustering in the phosphorylation loop and the newly identified α-helix. Bioinformatics analysis shows that this α-helix is only present in Lepidoptera, suggesting an insect-specific regulation. Interestingly, the specific phosphorylation pattern is temperature-dependent. The thermal stability of the DBM Repeat34 domain is significantly lower than that of the analogous domain in the three mammalian RyR isoforms, indicating a more dynamic domain structure that can be partially unfolded to facilitate the temperature-dependent phosphorylation. Docking the structure into the cryo-electron microscopy model of full-length RyR reveals that the interface between the Repeat34 and neighboring HD1 domain is more conserved than that of the phosphorylation loop region that might be involved in the interaction with SPRY3 domain. We also identify an insect-specific glycerol-binding pocket that could be potentially targeted by novel insecticides to fight the current resistance crisis.

Conclusions

The crystal structures of the DBM Repeat34 domain reveals insect-specific temperature-dependent phosphorylation sites that may regulate insect ryanodine receptor function. It also reveals insect-specific structural features and a potential ligand-binding site that could be targeted in an effort to develop green pesticides with high species-specificity.
Glucosamine impedes transforming growth factor β1-mediated corneal fibroblast differentiation by targeting Krüppel-like factor 4
Authors: Chen Ying-Jen , Huang Shih-Ming , Tai Ming-Cheng , Chen Jiann-Torng , Liang Chang-Min
Published: October 2019

Background

Transforming growth factor (TGF) family members play important roles in the regulation of corneal integrity, and the pathogenesis of corneal fibrosis. Currently, there are no effective agents targeting TGF-β signaling to diminish corneal fibrosis. Glucosamine (GlcN), which is widely used in the treatment of osteoarthritis, abrogates the morphologic effects of TGF-β2 on retinal pigmented epithelial cells in a mouse disease model. Here, we sought to determine whether GlcN would exert beneficial effects against TGF-β1-induced corneal fibrosis.

Methods

In human corneal fibroblasts (HCFs) treated with GlcN, the expression of Krüppel-like factor 4 (KLF4) and its downstream signaling effects were determined in the presence and absence of TGF-β1 using immunoblot analysis. We further explored GlcN inhibition of fibroblast-to-myofibroblast differentiation via KLF4 siRNA. The effect of cycloheximide on KLF4 protein levels with or without GlcN administration was assessed to determine whether GlcN affects the stability of the KLF4 protein.

Results

In HCFs, GlcN induced the expression of KLF4, which regulated the maturation and maintenance of the ocular surface. GlcN partially suppressed the TGF-β1-induced expression of alpha-smooth muscle actin (α-SMA) and reduced the collagen contraction capacity in HCFs, suggesting a decrease in fibroblast-to-myofibroblast differentiation. This effect appeared to be mediated through suppression of Smad2 phosphorylation and ERK-dependent signaling. The levels of KLF4 mRNA were increased by GlcN and decreased by TGF-β1 and the TGF-β1-induced α-SMA mRNA expression was upregulated when the KLF4 gene was silenced. GlcN also appeared to stabilize the KLF4 protein, reducing its turnover in corneal fibroblasts.

Conclusion

These findings shed light on a novel mechanism by which GlcN suppresses TGF-β1-induced fibroblast-to-myofibroblast differentiation through the upregulation of KLF4 expression. Current strategies for treating corneal fibrosis were not effective. Elevating KLF4 levels through the use of GlcN might provide an effective alternative to alleviate the development and progression of corneal fibrosis.
Renal resistive index: a new reversible tool for the early diagnosis and evaluation of organ perfusion in critically ill patients: a case report
Authors: Anile Antonio , Ferrario Silvia , Campanello Lorena , Orban Maria Antonietta , Castiglione Giacomo
Published: October 2019

Background

We reported a case of early detection of peripheral hypoperfusion trough the evaluation of a new index in intensive care: Renal Doppler Resistive Index (RRI).

Case presentation

We admitted a 76-year-old man who underwent ileostomy and hernioplasty because of an intestinal occlusion due to obstructive strangulated right inguinal hernia. The post-operative period was characterised by hemodynamic instability and he needed an invasive hemodynamic monitoring, administration of vasopressors and continuous renal replacement therapy (CRRT). Then, hemodynamic stability was obtained and vasopressors interrupted. RRI was lower than 0.7. In the eleventh post-operative day, despite stable macrocirculatory parameters, we found increased values of RRI. An abdomen ultrasound first and then a CT scan revealed the presence of bleeding from the previous ileostomy. Hence, the patient immediately underwent another surgical operation.

Conclusions

RRI modification appears to be more precocious than any other hemodynamic, microcirculatory and metabolic parameter routinely used. RRI has been widely used to assess renal function in critically ill patients; now, we presume that RRI could represent a common and useful tool to manage target therapy in critical condition.
Correction to: Guidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma
Authors:   The MASK study group, Bousquet J.
Published: October 2019

Following publication of the original article [1], the authors reported that one of the collaborators’ names was spelled incorrectly. In this Correction the incorrect and correct author name are shown. In the author list of this Correction article, only the corresponding author and institutional author are presented.
Schmallenberg virus: a systematic international literature review (2011-2019) from an Irish perspective
Authors: Collins Áine B. , Doherty Michael L. , Barrett Damien J. , Mee John F.
Published: October 2019

In Autumn 2011, nonspecific clinical signs of pyrexia, diarrhoea, and drop in milk yield were observed in dairy cattle near the German town of Schmallenberg at the Dutch/German border. Targeted veterinary diagnostic investigations for classical endemic and emerging viruses could not identify a causal agent. Blood samples were collected from animals with clinical signs and subjected to metagenomic analysis; a novel orthobunyavirus was identified and named Schmallenberg virus (SBV). In late 2011/early 2012, an epidemic of abortions and congenital malformations in calves, lambs and goat kids, characterised by arthrogryposis and hydranencephaly were reported in continental Europe. Subsequently, SBV RNA was confirmed in both aborted and congenitally malformed foetuses and also in Culicoides species biting midges. It soon became evident that SBV was an arthropod-borne teratogenic virus affecting domestic ruminants. SBV rapidly achieved a pan-European distribution with most countries confirming SBV infection within a year or two of the initial emergence. The first Irish case of SBV was confirmed in the south of the country in late 2012 in a bovine foetus.

Since SBV was first identified in 2011, a considerable body of scientific research has been conducted internationally describing this novel emerging virus. The aim of this systematic review is to provide a comprehensive synopsis of the most up-to-date scientific literature regarding the origin of SBV and the spread of the Schmallenberg epidemic, in addition to describing the species affected, clinical signs, pathogenesis, transmission, risk factors, impact, diagnostics, surveillance methods and control measures. This review also highlights current knowledge gaps in the scientific literature regarding SBV, most notably the requirement for further research to determine if, and to what extent, SBV circulation occurred in Europe and internationally during 2017 and 2018. Moreover, recommendations are also made regarding future arbovirus surveillance in Europe, specifically the establishment of a European-wide sentinel herd surveillance program, which incorporates bovine serology and Culicoides entomology and virology studies, at national and international level to monitor for the emergence and re-emergence of arboviruses such as SBV, bluetongue virus and other novel Culicoides-borne arboviruses.
An integrative review on methodological considerations in mental health research – design, sampling, data collection procedure and quality assurance
Authors: Badu Eric , O’Brien Anthony Paul , Mitchell Rebecca
Published: October 2019

Background

Several typologies and guidelines are available to address the methodological and practical considerations required in mental health research. However, few studies have actually attempted to systematically identify and synthesise these considerations. This paper provides an integrative review that identifies and synthesises the available research evidence on mental health research methodological considerations.

Methods

A search of the published literature was conducted using EMBASE, Medline, PsycINFO, CINAHL, Web of Science, and Scopus. The search was limited to papers published in English for the timeframe 2000–2018. Using pre-defined inclusion and exclusion criteria, three reviewers independently screened the retrieved papers. A data extraction form was used to extract data from the included papers.

Results

Of 27 papers meeting the inclusion criteria, 13 focused on qualitative research, 8 mixed methods and 6 papers focused on quantitative methodology. A total of 14 papers targeted global mental health research, with 2 papers each describing studies in Germany, Sweden and China. The review identified several methodological considerations relating to study design, methods, data collection, and quality assurance. Methodological issues regarding the study design included assembling team members, familiarisation and sharing information on the topic, and seeking the contribution of team members. Methodological considerations to facilitate data collection involved adequate preparation prior to fieldwork, appropriateness and adequacy of the sampling and data collection approach, selection of consumers, the social or cultural context, practical and organisational skills; and ethical and sensitivity issues.

Conclusion

The evidence confirms that studies on methodological considerations in conducting mental health research largely focus on qualitative studies in a transcultural setting, as well as recommendations derived from multi-site surveys. Mental health research should adequately consider the methodological issues around study design, sampling, data collection procedures and quality assurance in order to maintain the quality of data collection.
Spatial distribution of Anopheles gambiae sensu lato larvae in the urban environment of Yaoundé, Cameroon
Authors: Djamouko-Djonkam Landre , Mounchili-Ndam Souleman , Kala-Chouakeu Nelly , Nana-Ndjangwo Stella Mariette , Kopya Edmond , Sonhafouo-Chiana Nadége , Talipouo Abdou , Ngadjeu Carmene Sandra , Doumbe-Belisse Patricia , Bamou Roland , Toto Jean Claude , Tchuinkam Timoléon , Wondji Charles Sinclair , Antonio-Nkondjio Christophe
Published: October 2019

Background

The rapid and unplanned urbanization of African cities is considered to increase the risk of urban malaria transmission. The present study objective was to assess factors influencing the spatio-temporal distribution of Anopheles gambiae s.l. larvae in the city of Yaoundé, Cameroon.

Methods

All water bodies were checked once every 2 months for the presence of mosquito larvae from March 2017 to May 2018 in 32 districts of Yaoundé. Physico-chemical characteristics including the size, depth, turbidity, pH, temperature, conductivity, sulfates, organophosphates, hydrogen peroxide (H2O2), conductivity, iron and calcium were recorded and analyzed according to anopheline larvae presence or absence. High resolution satellite images from landsat sentinel Enhanced Thematic Mapper were used for spatial mapping of both field and environmental variables. Bivariate and multivariate logistic regression models were used to identify variables closely associated with anopheline larvae distribution.

Results

A total of 18 696 aquatic habitats were checked and only 2942 sites (15.7%) contained anopheline larvae. A high number of sites with anopheline larvae (≥ 69%) presented late instar larvae (L3, L4 and pupae). Anopheline mosquito larvae were sampled from a variety of breeding sites including puddles (51.6%), tire prints (12.9%), wells (11.7%) and drains (11.3%). Bivariate logistic regression analyses associated anopheline larvae presence with the absence of predators, absence of algae, absence of vegetation and depth of less than 1 m. Conductivity, turbidity, organophosphates, H2O2 and temperature were significantly high in breeding sites with anopheline larvae than in breeding sites without these larvae (P <  0.1). Anopheline species collected included An. coluzzii (91.1%) and An. gambiae s.s. (8.9%). GIS mapping indicated a heterogeneous distribution of anopheline breeding habitats in the city of Yaoundé. Land cover analysis indicated high variability of the city of Yaoundé’s landscape.

Conclusions

The data confirms adaptation of An. gambiae s.l. to the urban domain in the city of Yaoundé and calls for urgent actions to improve malaria vector control.
The STEM Faculty Instructional Barriers and Identity Survey (FIBIS): development and exploratory results
Authors: Sturtevant Hannah , Wheeler Lindsay
Published: October 2019

Background

As institutions and science, technology, engineering, and mathematics (STEM) departments emphasize faculty use of evidence-based instructional practices (EBIPs), various barriers and faculty perceptions hinder that process. While a large body of literature exists in this area, no survey instrument has been developed to comprehensively and systematically capture all these factors. We developed and piloted a survey instrument, the Faculty Instructional Barriers and Identity Survey (FIBIS), to delineate university STEM faculty perceptions of barriers to using EBIPs and examine the composition and sources of faculty professional identity, use of and dissatisfaction with these practices.

Results

Initial pilot study results with a small, targeted sample (n= 69) shows how FIBIS can be used to understand factors that impact instructional practices. For our sample, we found that higher perceived departmental barriers and limited supports correlate with lower work identity. Even at a research university, we do not see a negative correlation between research and teaching identities; STEM faculty can have both, despite hypothesized tensions in the literature. We also found that sense of belonging and faculty community were descriptively higher for underrepresented minority than non-underrepresented minority faculty. As previous work has suggested, use of EBIPs varied by department. Finally, descriptive differences were seen in faculty barriers for those who were and were not satisfied with EBIPs. This suggests another layer to add to models of faculty decision-making regarding the use of EBIPs: dissatisfaction with implementing these practices once they are attempted. Further work is needed to confirm and understand these initial findings.

Conclusions

Many of the exploratory findings from our pilot of FIBIS align with previous qualitative work, suggesting that FIBIS is a tool that can capture faculty identity, use of EBIPs, and barriers to instruction. While we do not intend to generalize our claims, the following suggestions for our institution may demonstrate how FIBIS can be used to try and reduce STEM faculty barriers to implementing EBIPs: (1) developing a strong teaching community (especially needed for persistence of faculty from underrepresented minorities), (2) helping faculty connect to the university as a whole, and (3) working with departments to better support implementation of EBIPs. The results presented and implications of these findings demonstrate the potential of FIBIS as a tool for examining factors that influence STEM faculty instructional practice. Future work includes further validating the FIBIS barriers component of the survey so that FIBIS can be used to identify and support change in institutions of higher education.