bluuebunny/crossref_metadata_2025 huggingface dataset:
Antilymphocyte globulin, cyclosporin, and granulocyte colony- stimulating factor in patients with acquired severe aplastic anemia (SAA): a pilot study of the EBMT SAA Working Party
Authors: Bacigalupo A , Broccia G , Corda G , Arcese W , Carotenuto M , Gallamini A , Locatelli F , Mori PG , Saracco P , Todeschini G
Published: October 2019

Patients with severe aplastic anemia (SAA) and a neutrophil (PMN) count of less than 0.5 x 10(9)/L are exposed to a high risk of early mortality when treated with antilymphocyte globulin (ALG) and steroids, with the major problem being infectious complications. The addition of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to ALG may reduce early mortality by improving neutrophil counts in the short term. To test the feasibility of this approach, the SAA Working Party of the European Group for Blood and Marrow Transplantation (EBMT) designed a pilot study that included rhG-CSF (5 micrograms/kg/d, days 1 through 90), horse ALG (HALG; 15 mg/kg/d, days 1 through 5), methylprednisolone (2 mg/kg/d, days 1 through 5, then tapering the dose), and cyclosporin A (CyA; 5 mg/kg/d orally, days 1 through 180). Patients with newly diagnosed acquired SAA (untreated) and with neutrophil counts of < or = 0.5 x 10(9)/L were eligible. Forty consecutive patients entered this study and are evaluable with a minimum follow up of 120 days: the median age was 16 years (range, 2 to 72 years), the interval from diagnosis to treatment was 24 days, and the median PMN count was 0.19 x 10(9)/L. Twenty-one patients had hemorrhages, and 19 were infected at the time of treatment. Overall, treatment was well tolerated: the median maximum PMN count during rhG- CSF administration was 12 x 10(9)/L (range, 0.4 x 10(9)/L to 44 x 10(9)/L). There were three early deaths (8%) due to infection. Four patients (10%) showed no recovery, whereas 33 patients (82%) had trilineage hematologic reconstitution and became transfusion- independent at a median interval of 115 days from treatment. Median follow up for surviving patients is 428 days (range, 122 to 1,005). Actuarial survival is 92%: 86% and 100% for patients with PMN counts less than 0.2 x 10(9)/L or between 0.2 x 10(9)/L and 0.5 x 10(9)/L, respectively. This study suggests that the addition of rhG-CSF to ALG and CyA is well tolerated, is associated with a low risk of mortality, and offers a good chance of hematologic response. This protocol would appear to be an interesting alternative treatment for SAA patients with a low PMN count who lack an HLA-identical sibling.
Organization of the gene encoding the human Kell blood group protein [published erratum appears in Blood 1996 Jun 1;87(11):4922]
Authors: Lee S , Zambas E , Green ED , Redman C
Published: October 2019

Kell is one of the major blood group systems in human erythrocytes. It is a complex system containing a large number of different antigens. Previously we cloned the Kell cDNA, which was predicted to encode an integral membrane protein with 731 amino acids. Now we have isolated overlapping genomic clones and determined the exon-intron structure of the KEL gene; it spans approximately 21.5 kb with its coding sequence being organized in 19 exons that range in size from 63 bp to 288 bp. The size of introns ranges from 93 bp to approximately 6 kb. The donor and acceptor splice sites all conform to the consensus splicing sequences. Exon 1 encodes only the initiation amino acid, methionine, and contains a consensus Sp1 binding site. The single membrane spanning region of Kell protein is encoded in exon 3 and the putative zinc endopeptidase active site is in exon 16. The amino acids encoded by the 19 exons are identical to those of a person with a common Kell phenotype, as determined by RNA polymerase chain reaction of peripheral blood. Amplification of cDNA 552 ends, derived from human fetal liver, indicated three transcription initiation sites located 30, 81, and 120 bp upstream of the initiation codon. The 552 flanking region of KEL from -176 does not contain a TATA sequence, but has possible GATA-1 binding sites and has significant promoter activity when determined by chloramphenicol acetyltransferase activity in K562 cells.
Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation steps
Authors: Vittet D , Prandini MH , Berthier R , Schweitzer A , Martin-Sisteron H , Uzan G , Dejana E
Published: October 2019

The mechanisms involved in the regulation of vasculogenesis still remain unclear in mammals. Totipotent embryonic stem (ES) cells may represent a suitable in vitro model to study molecular events involved in vascular development. In this study, we followed the expression kinetics of a relatively large set of endothelial-specific markers in ES-derived embryoid bodies (EBs). Results of both reverse transcription-polymerase chain reaction and/or immunofluorescence analysis show that a spontaneous endothelial differentiation occurs during EBs development. ES-derived endothelial cells express a full range of cell lineage-specific markers: platelet endothelial cell adhesion molecule (PECAM), Flk-1, tie-1, tie-2, vascular endothelial (VE) cadherin, MECA-32, and MEC-14.7. Analysis of the kinetics of endothelial marker expression allows the distinction of successive maturation steps. Flk-1 was the first to be detected; its mRNA is apparent from day 3 of differentiation. PECAM and tie-2 mRNAs were found to be expressed only from day 4, whereas VE-cadherin and tie-1 mRNAs cannot be detected before day 5. Immunofluorescence stainings of EBs with antibodies directed against Flk-1, PECAM, VE-cadherin, MECA-32, and MEC-14.7 confirmed that the expression of these antigens occurs at different steps of endothelial cell differentiation. The addition of an angiogenic growth factor mixture including erythropoietin, interleukin-6, fibroblast growth factor 2, and vascular endothelial growth factor in the EB culture medium significantly increased the development of primitive vascular-like structures within EBs. These results indicate that this in vitro system contains a large part of the endothelial cell differentiation program and constitutes a suitable model to study the molecular mechanisms involved in vasculogenesis.
The Common Marmoset as a Target Preclinical Primate Model for Cytokine and Gene Therapy Studies
Authors: Hibino Hitoshi , Tani Kenzaburo , Ikebuchi Kenji , Wu Ming-Shiuan , Sugiyama Hajime , Nakazaki Yukoh , Tanabe Tsuyoshi , Takahashi Satoshi , Tojo Arinobu , Suzuki Shuzo , Tanioka Yoshikuni , Sugimoto Yoshikazu , Nakahata Tatsutoshi , Asano Shigetaka
Published: October 2019

Nonhuman primate models are useful to evaluate the safety and efficacy of new therapeutic modalities, including gene therapy, before the inititation of clinical trials in humans. With the aim of establishing safe and effective approaches to therapeutic gene transfer, we have been focusing on a small New World monkey, the common marmoset, as a target preclinical model. This animal is relatively inexpensive and easy to breed in limited space. First, we characterized marmoset blood and bone marrow progenitor cells (BMPCs) and showed that human cytokines were effective to maintain and stimulate in culture. We then examined their susceptibility to transduction by retroviral vectors. In a mixed culture system containing both marmoset stromal cells and retroviral producer cells, the transduction efficiency into BMPCs and peripheral blood progenitor cells (PBPCs) was 12% to 24%. A series of marmosets then underwent transplantation with autologous PBPCs transduced with a retroviral vector carrying the multidrug resistance 1 gene (MDR1) and were followed for the persistence of these cells in vivo. Proviral DNA was detectable by polymerase chain reaction (PCR) in peripheral blood granulocytes and lymphocytes in the recipients of gene transduced progenitors up to 400 days posttransplantation. To examine the function of the MDR1 gene in vivo, recipient maromsets were challenged with docetaxel, an MDR effluxed drug, yet the overall level of gene transfer attained in vivo (<1% in peripheral blood granulocytes) was not sufficient to prevent the neutropenia induced by docetaxel treatment. Using this model, we safely and easily performed a series of in vivo studies in our small animal center. Our results show that this small nonhuman primate, the common marmoset, is a useful model for the evaluation of gene transfer methods targeting hematopoietic stem cells.
Direct Evidence of Endothelial Injury in Acute Myocardial Infarction and Unstable Angina by Demonstration of Circulating Endothelial Cells
Authors: Mutin Murielle , Canavy Isabelle , Blann Andrew , Bory Michel , Sampol José , Dignat-George Françoise
Published: October 2019

Circulating endothelial cells (CECs) have been detected in association with endothelial injury and therefore represent proof of serious damage to the vascular tree. Our aim was to investigate, using the technique of immunomagnetic separation, whether the pathological events in unstable angina (UA) or acute myocardial infarction (AMI) could cause desquamation of endothelial cells in circulating blood compared with effort angina (EA) and noncoronary chest pain. A high CEC count was found in AMI (median, 7.5 cells/mL; interquartile range, 4.1 to 43.5, P < .01 analysis of variance [ANOVA]) and UA (4.5; 0.75 to 13.25 cells/mL, P < .01) within 12 hours after chest pain as compared with controls (0; 0 to 0 cells/mL) and stable angina (0; 0 to 0 cells/mL). CEC levels in serial samples peaked at 15.5 (2.7 to 39) cells/mL 18 to 24 hours after AMI (P < .05 repeated measures ANOVA), but fell steadily after UA. Regardless of acute coronary events, the isolated cells displayed morphologic and immunologic features of vascular endothelium. The CECs were predominantly of macrovascular origin. They did not express the activation markers intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin, although some were positive for tissue factor. CECs failed to exhibit characteristics of apoptosis (TUNEL assay) excluding this event as a possible mechanism of cell detachment. The presence of CECs provides direct evidence of endothelial injury in AMI and UA, but not in stable angina, confirming that these diseases have different etiopathogenic mechanisms.
Characterization of T-Cell Repertoire of the Bone Marrow in Immune-Mediated Aplastic Anemia: Evidence for the Involvement of Antigen-Driven T-Cell Response in Cyclosporine-Dependent Aplastic Anemia
Authors: Zeng Weihua , Nakao Shinji , Takamatsu Hideyuki , Yachie Akihiro , Takami Akiyoshi , Kondo Yukio , Sugimori Naomi , Yamazaki Hirohito , Miura Yuji , Shiobara Shintaro , Matsuda Tamotsu
Published: October 2019

To determine whether the antigen-driven T-cell response is involved in the pathogenesis of aplastic anemia (AA), we examined the complementarity-determining region 3 (CDR3) size distribution of T-cell receptor (TCR) β-chain (BV) subfamilies in the bone marrow (BM) of untreated AA patients. AA patients who did not respond to immunosuppressive therapy and those who obtained unmaintained remission early after cyclosporine (CyA) or antithymocyte globulin (ATG) therapy exhibited essentially a normal CDR3 size pattern. In contrast, five patients who needed continuous administration of CyA to maintain remission exhibited a skewed CDR3 size pattern in a number (>40%) of BV subfamilies suggestive of clonal predominance. The skewing of CDR3 size distribution became less pronounced in one of the CyA-dependent patients when the patient achieved unmaintained remission after a 4-year therapy with CyA, whereas it persisted longer than 7 years in the other patient requiring maintenance therapy. Sequencing of BV15 cDNA for which the CDR3 size pattern exhibited apparent clonal predominance in all CyA-dependent patients showed high homology of the amino acid sequence of the CDR3 between two different patients. These findings indicate that antigen-driven expansion of T cells is involved in the pathogenesis of AA characterized by CyA-dependent recovery of hematopoiesis.
Ki-4(scFv)–ETA′, a new recombinant anti-CD30 immunotoxin with highly specific cytotoxic activity against disseminated Hodgkin tumors in SCID mice
Authors: Barth Stefan , Huhn Michael , Matthey Bärbel , Tawadros Samir , Schnell Roland , Schinköthe Timo , Diehl Volker , Engert Andreas
Published: October 2019

The human lymphocyte activation marker CD30 is highly overexpressed on Hodgkin/Reed–Sternberg cells and represents an ideal target for selective immunotherapy. We used the murine anti-CD30 hybridoma Ki-4 to construct a new recombinant immunotoxin (rIT) for possible clinical use in patients with CD30+ lymphoma. Hybridoma V genes were polymerase chain reaction-amplified, assembled, cloned, and expressed as a mini-library for display on filamentous phage. Functional Ki-4 scFv obtained by selection of binding phage on the CD30-expressing Hodgkin lymphoma cell line L540cy was inserted into the bacterial expression vector pBM1.1 and fused to a deletion mutant ofPseudomonas exotoxin A (ETA′). Periplasmically expressed Ki-4(scFv)–ETA′ demonstrated specific activity against a variety of CD30+ lymphoma cells as assessed by different in vitro assays. To evaluate in vivo antitumor activity, severe combined immunodeficient mice challenged with human lymphoma cell lines were treated with the immunotoxin. The blood distribution time t½ of Ki-4(scFv)–ETA′ was 19 minutes, and its serum elimination time t½ was 193 minutes. A single intravenous injection of 40 μg rIT 1 day after tumor inoculation rendered 90% of the mice tumor free, extending the mean survival time to more than 200 days compared with 38.1 days in the phosphate-buffered saline control group (P < .001). This new rIT is a promising candidate for further clinical evaluation in patients with Hodgkin lymphoma or other CD30+malignancies.
Surgical and physical stress increases circulating blood dendritic cell counts independently of monocyte counts
Authors: Ho Christopher S. K. , López Jose Alejandro , Vuckovic Slavica , Pyke Christopher M. , Hockey Richard L. , Hart Derek N. J.
Published: October 2019

Dendritic cells (DCs) are specialized antigen-presenting cells that have the unique ability to initiate a primary immune response. The effect of physiologic stress on circulating blood DCs has thus far not been studied. In this study, we applied a recently developed method of counting blood DCs to test the hypothesis that significant stress to the body such as surgery and exercise might induce measurable changes in the DC numbers, subsets, phenotype, and function. Twenty-six patients scheduled for elective laparoscopic cholecystectomy, 4 for elective hysterectomy, 56 controls, and 5 volunteers who underwent a stress exercise test were enrolled in the study. Absolute DC counts increased acutely (71.7% ± 11% [SEM],P = .0001) in response to the stress of surgery and dropped below preoperative levels (−25% ± 14% [SEM],P = .05) on days 2-3. The perioperative DC subset balance remained constant. Interestingly, DC counts changed independently of monocyte counts. Exercise also induced a rise in DC counts but coincidentally with monocyte counts. Surprisingly, no phenotypic or functional activation of DCs was seen in either stress situations in vivo. DCs are rapidly mobilized into the circulation in response to surgical and exercise stress, which may serve to prepare the host's immune defenses against trauma. The independent regulation of the DC and monocyte counts reinforces the distinction between these 2 cell populations.
Recipient priming to one RBC alloantigen directly enhances subsequent alloimmunization in mice
Authors: Patel Seema R. , Bennett Ashley , Girard-Pierce Kathryn , Maier Cheryl L. , Chonat Satheesh , Arthur Connie M. , Zerra Patricia E. , Mener Amanda , Stowell Sean R.
Published: October 2019

Key Points

CD4+ T cells primed to one RBC alloantigen promote humoral immunity to a disparate RBC alloantigen when both antigens are on the same RBC. These findings provide a potential explanation for how responses to one antigen may enhance antibody formation to other RBC alloantigens.
The association between motor capacity and mobility performance: frailty as a moderator
Authors: Jansen Carl-Philipp , Toosizadeh Nima , Mohler M. Jane , Najafi Bijan , Wendel Christopher , Schwenk Michael
Published: October 2019

Background

In older adults, the linkage between laboratory-assessed ‘motor capacity’ and ‘mobility performance’ during daily routine is controversial. Understanding factors moderating this relationship could help developing more valid assessment as well as intervention approaches. We investigated whether the association between capacity and performance becomes evident with transition into frailty, that is, whether frailty status moderates their association.

Methods

We conducted a cross-sectional analysis of the observational Arizona Frailty Cohort Study (ClinicalTrials.gov identifier: NCT01880229) in a community-dwelling cohort in Tucson, Arizona. Participants wereN = 112 older adults aged 65 years or older who were categorized as non-frail (n = 40), pre-frail (n = 53) or frail (n = 19) based on the Fried frailty index.

Motor capacity was quantified as normal (NWS) and fast walking speed (FWS). Mobility performance was quantified as 1) cumulated physical activity (PA) time and 2) everyday walking performance (average steps per walking bout; maximal number of steps in one walking bout), measured by a motion sensor over a 48 h period. Hierarchical linear regression analyses were performed to evaluate moderation effects.

Results

Unlike in non-frail persons, the relationship between motor capacity and mobility performance was evident in pre-frail and frail persons, confirming our hypothesis. A moderating effect of frailty status was found for 1) the relationship between both NWS and FWS and maximal number of steps in one bout and 2) NWS and the average steps per bout. No moderation was found for the association between NWS and FWS with cumulated PA.

Conclusion

In pre-frail and frail persons, motor capacity is associated with everyday walking performance, indicating that functional capacity seems to better represent mobility performance in this impaired population. The limited relationship found in non-frail persons suggests that other factors account for their mobility performance. Our findings may help to inform tailored assessment approaches and interventions taking into consideration a person’s frailty status.
Prognoses of different pathological subtypes of colorectal cancer at different stages: A population-based retrospective cohort study
Authors: Wu Xiaoli , Lin Han , Li Shaotang
Published: October 2019

Background

Whether the prognoses of different pathological subtypes of colorectal cancer (CRC) at different stages are distinct is unclear.

Methods

We extracted data on all cases of CRC from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. The incidence of different pathological subtypes, clinical characteristics, and five-year overall survival (OS) and cause-specific survival (CSS) were analyzed.

Results

A total of 384,996 cases diagnosed as adenocarcinoma (AC), mucinous adenocarcinoma (MAC), and signet ring cell carcinoma (SRCC) were included in this analysis. Compared with AC, MAC and SRCC were more likely to reach T4, N2, M1, stages III and IV, and grades III and IV, and patients were generally of a younger age (P < 0.001). Compared with those with AC, patients with MAC and SRCC showed poorer OS (50.6 and 26.8% vs. 60.2%,P < .001), with corresponding HR values of 1.238 (95% CI, 1.213–1.263,P < .001) and 1.592 (95% CI, 1.558–1.627,P < .001), respectively. The MAC and SRCC groups also showed poorer overall CCS (60.9 and 32.5% vs. 67.8%,P < .001), with corresponding HR values of 1.271 (95% CI, 1.242–1.302,P < .001) and 1.724 (95% CI, 1.685–1.765,P < .001), respectively. Compared with patients with AC, those with MAC showed poor OS at every stage and poor CSS at every stage except stage II (P < .05), while patients with SRCC revealed poor OS and CSS at every stage except stage 0 (P < .05).

Conclusions

Patients of different pathological subtypes minimally differed at early stages. However, patients with AC have significantly better prognoses in advanced CRC (stages III and IV) than those with MAC or SRCC. Distinct treatment strategies should be applied depending on a particular histological subtype in advanced CRC.
Prevalence of Potentially Inappropriate Medication use in older drivers
Authors:   The LongROAD Research Team, Li Guohua , Andrews Howard F. , Chihuri Stanford , Lang Barbara H. , Leu Cheng Shiun , Merle David P. , Gordon Abigail , Mielenz Thelma J. , Strogatz David , Eby David W. , Betz Marian E. , DiGuiseppi Carolyn , Jones Vanya C. , Molnar Lisa J. , Hill Linda L.
Published: October 2019

Background

Potentially Inappropriate Medication (PIM) use has been studied in a variety of older adult populations across the world. We sought to examine the prevalence and correlates of PIM use in older drivers.

Methods

We applied the American Geriatrics Society 2015 Beers Criteria to baseline data collected from the “brown-bag” review of medications for participants of the Longitudinal Research on Aging Drivers (LongROAD) study to examine the prevalence and correlates of PIM use in a geographically diverse, community-dwelling sample of older drivers (n = 2949). Proportions of participants who used one or more PIMs according to the American Geriatrics Society 2015 Beers Criteria, and estimated odds ratios (ORs) and 95% confidence intervals (CIs) of PIM use associated with participant characteristics were calculated.

Results

Overall, 18.5% of the older drivers studied used one or more PIM. The most commonly used therapeutic category of PIM was benzodiazepines (accounting for 16.6% of the total PIMs identified), followed by nonbenzodiazepine hypnotics (15.2%), antidepressants (15.2%), and first-generation antihistamines (10.5%). Compared to older drivers on four or fewer medications, the adjusted ORs of PIM use were 2.43 (95% CI 1.68–3.51) for those on 5–7 medications, 4.19 (95% CI 2.95–5.93) for those on 8–11 medications, and 8.01 (95% CI 5.71–11.23) for those on ≥12 medications. Older drivers who were female, white, or living in urban areas were at significantly heightened risk of PIM use.

Conclusion

About one in five older drivers uses PIMs. Commonly used PIMs are medications known to impair driving ability and increase crash risk. Implementation of evidence-based interventions to reduce PIM use in older drivers may confer both health and safety benefits.

Trial registration

Not applicable.
Use of intravoxel incoherent motion imaging to monitor a rat kidney chronic allograft damage model
Authors: Zhang Qiang , Yu Zexing , Zeng Song , Liang Lu , Xu Yue , Zhang Zijian , Tang Hao , Jiao Wenjiao , Xue Wenrui , Wang Wei , Zhang Xiaodong , Jiang Tao , Hu Xiaopeng
Published: October 2019

Background

Chronic allograft damage (CAD) is the leading cause of long-term graft dysfunction. A noninvasive method that can diagnose CAD early and monitor its development is needed.

Methods

Kidneys from Fisher rats were transplanted into Lewis rats to establish a CAD model (n = 20). The control group underwent syngeneic kidney transplantation (n = 20). The serum creatinine of the rats was monitored. At 4, 12, and 20 weeks after modeling, a magnetic resonance imaging (MRI) examination was performed. The apparent diffusion coefficient (ADC), pseudo diffusion coefficient (D*), true diffusion coefficient (D) and perfusion fraction (f) of the two groups were analyzed. Chronic allograft damage index (CADI) scoring was used to evaluate the transplanted kidney specimens. Immunohistochemistry was used to detect the expression of fibrosis markers in the transplanted kidney tissues and to analyze their correlations with all MRI parameters.

Results

The transplanted kidneys in the experimental group developed CAD changes before the appearance of elevated creatinine. The MRI parameters in the experimental group [ADC (1.460 ± 0.109 VS 2.095 ± 0.319, P < 0.001), D (1.435 ± 0.102 VS 1.969 ± 0.305, P < 0.001), and f (26.532 ± 2.136 VS 32.255 ± 4.013, P < 0.001)] decreased, and D* (20.950 ± 2.273 VS 21.415 ± 1.598, P = 0.131) was not significantly different from those in the control group. ADC, D and f were negatively correlated with the CADI and the α-SMA and vimentin expression levels.

Conclusion

Intravoxel incoherent motion (IVIM) imaging could detect CAD earlier than creatinine and reflect the degree of fibrosis in grafts quantitatively.
Assessing the effectiveness of mindfulness-based programs on mental health during pregnancy and early motherhood - a randomized control trial
Authors: Pan Wan-Lin , Chang Chiung-Wen , Chen Shin-Ming , Gau Meei-Ling
Published: October 2019

Background

The process of entering motherhood is highly stressful for women, with 15–85% of new mothers experiencing postpartum blues or depression. This study was designed to evaluate the efficacy of a mindfulness-based childbirth and parenting program in improving psychological health during the postpartum period.

Methods

This research was a randomized controlled trial with single blinding. Recruitment began after the participating hospital granted formal approval. A total of 74 women between 13 and 28-weeks gestation were allocated either to the intervention group or to the comparison group. The intervention program included a series of eight, 3-h classes held once weekly and 1 day of 7-h silent meditation. Psychological health was assessed at baseline and 3-months postpartum.

Results

Significant differences in stress and depression were observed in both groups over time. Stress scores and depression scores were significantly better in the intervention group than in the comparison group at 3-months postpartum (F = 7.19, p = .009 and F = 7.36, p = .008, respectively). No significant difference between the groups was identified for mindfulness scores at 3-months postpartum.

Conclusions

The intervention program effectively reduced postpartum self-perceived stress and depression, suggesting that this program provides acceptable and long-term benefits to women during pregnancy and the postpartum period. The teaching and practice of mindfulness meditation and parenting education during pregnancy may help reduce stress and depression in pregnant women as they transition into parenthood.

Trial registration

The ClinicalTrials.gov identifier for this study is: NCT03185910. The study was retrospectively registered on 14 June 2017.
Intra-arterial EmboCept S® and DC Bead® effectively inhibit tumor growth of colorectal rat liver metastases
Authors: Ziemann Christian , Roller Jonas , Malter Markus M. , Keller Kira , Kollmar Otto , Glanemann Matthias , Menger Michael D. , Sperling Jens
Published: October 2019

Background

Intra-arterial therapy with embolics is established for the treatment of malignancies of the liver. However, there are no studies comparing the different effects of various embolics used in clinical practice. Herein, we analyzed the effect of 3 different embolics on tumor growth in a rat model of colorectal liver metastases.

Methods

Eight days after subcapsular implantation of 5 × 105 colorectal cancer cells (CC531) in the left liver lobe of WAG/Rij rats were randomized into 4 groups (n = 8) and underwent intra-arterial hepatic therapy. Animals received either EmboCept S®, DC Bead® or Lipiodol® Ultra-Fluid. Animals of the control group received a comparable amount of saline. Tumor growth was measured on day 8 and 11 using a three-dimensional 40 MHz ultrasound device. On day 11 tumor and liver tissue were removed for histological and immunohistochemical analyses.

Results

On day 11 animals of the control group showed a tumor growth of ~ 60% compared to day 8. Application of Lipiodol Ultra-Fluid® did not significantly influence tumor growth (~ 40%). In contrast, treatment with EmboCept S® or DC Bead® completely inhibited tumor growth. Of interest, application of EmboCept S® did not only completely inhibit tumor growth but even decreased tumor size. Immunohistochemical analysis showed a significant increase of necrotic areas within the tumors after application of EmboCept S® and DC Bead® compared to Lipiodol® Ultra-Fluid.

Conclusion

The present study demonstrates that an intra-arterial therapy with EmboCept S® and DC Bead®, but not Lipiodol® Ultra-Fluid, results in a complete inhibition of rat colorectal liver metastatic growth.
Prevalence, clinical outcomes and rainfall association of acute respiratory infection by human metapneumovirus in children in Bogotá, Colombia
Authors: Evelyn Obando , Jaime Fernández-Sarmiento , David Montoya , Lorena Acevedo , Jenifer Arroyave , Oscar Gamboa
Published: October 2019

Background

Acute respiratory infections (ARIs) are one of the main causes of morbidity and mortality in children. Viruses are the main etiological agents, and their behavior tends to be seasonal and vary by geographical location. Human metapneumovirus (HMPV) has recently been described as a cause of severe acute respiratory infection and its prevalence and clinical behavior in children at moderate altitudes is unknown.

Methods

A cross-sectional study was carried out on patients seen at a university hospital in Bogotá, Colombia between October 2015 and December 2017 in a city at a moderate altitude above sea level. Children with acute respiratory infections who had had a multiplex RT-PCR assay were selected. The prevalence of HMPV infection, its clinical outcomes and its relationship to rainfall were evaluated.

Results

Out of a total of 14,760 discharged patients, multiplex RT-PCR was performed on 502 and a virus was detected in 420 children with acute respiratory infection (ARI). The study group had a median age of 21 months (IQR 7–60), with similar proportion of males and females (56.4 and 43.6% respectively) and 5.2% (CI 95 3.3–7.8%) prevalence of HMPV infection. The group with HMPV infection showed a greater frequency of viral coinfection (22.7% vs 14% P = 0.03) compared with ARI caused by other viruses. The rate of bacterial coinfection (P = 0.31), presence of comorbidities (p = 0.75), length of hospital stay (P = 0.42), need for mechanical ventilation (P = 0.75) and mortality (P = 0.22) were similar for HMPV and other viral infections. A moderate correlation was established between HMPV infection and rainfall peaks (Spearman’s Rho 0.44 p = 0.02).

Conclusions

Human metapneumovirus was the fifth most frequently isolated virus in children with ARI, had similar clinical behavior and severity to other viruses but a higher rate of viral coinfection. Its peaks seem to correlate to rainy seasons.
Walking against or with traffic? Evaluating pedestrian fatalities and head injuries in Taiwan
Authors: Pai Chih-Wei , Chen Ping-Ling , Ma Shiao-Tzu , Wu Shan-Hong , Linkov Václav , Ma Hon-Ping
Published: October 2019

Background

Allowing contraflow cycling on one-way streets has been reported to reduce crash risks in Belgium and the United Kingdom. Similarly, walking against traffic on roadways without sidewalks substantially improves pedestrian safety. This study examined fatalities and head injuries sustained by pedestrians in against-traffic and with-traffic crashes.

Methods

Using police-reported crash data in Taiwan between 2011 and 2016, fatalities and head injuries were compared for pedestrians involved in against-traffic and with-traffic crashes.

Results

Of the 14,382 pedestrians involved in crashes, 10,749 and 3633 pedestrians in with-traffic and against-traffic crashes, respectively, were reported. Compared with pedestrians involved in against-traffic crashes, those in with-traffic crashes were more likely to sustain fatalities and head injuries. Results of logistic regression models revealed several influential factors on pedestrian fatalities and head injuries, including elderly pedestrians, male drivers, intoxicated drivers, rural roadways, unlit streets in darkness, limited sight distance, adverse weather conditions, midnight hours, and a heavy vehicle as the crash partner.

Conclusions

Pedestrians in with-traffic crashes were more likely to sustain fatalities and head injuries compared with those in against-traffic crashes. Furthermore, the negative effect of walking with traffic on injuries was more pronounced in reduced-visibility conditions.
Optimal proteome allocation strategies for phototrophic growth in a light-limited chemostat
Authors: Faizi Marjan , Steuer Ralf
Published: October 2019

Background

Cyanobacteria and other phototrophic microorganisms allow to couple the light-driven assimilation of atmospheric $$\text {CO}_{2}$$

CO
2

directly to the synthesis of carbon-based products, and are therefore attractive platforms for microbial cell factories. While most current engineering efforts are performed using small-scale laboratory cultivation, the economic viability of phototrophic cultivation also crucially depends on photobioreactor design and culture parameters, such as the maximal areal and volumetric productivities. Based on recent insights into the cyanobacterial cell physiology and the resulting computational models of cyanobacterial growth, the aim of this study is to investigate the limits of cyanobacterial productivity in continuous culture with light as the limiting nutrient.

Results

We integrate a coarse-grained model of cyanobacterial growth into a light-limited chemostat and its heterogeneous light gradient induced by self-shading of cells. We show that phototrophic growth in the light-limited chemostat can be described using the concept of an average light intensity. Different from previous models based on phenomenological growth equations, our model provides a mechanistic link between intracellular protein allocation, population growth and the resulting reactor productivity. Our computational framework thereby provides a novel approach to investigate and predict the maximal productivity of phototrophic cultivation, and identifies optimal proteome allocation strategies for developing maximally productive strains.

Conclusions

Our results have implications for efficient phototrophic cultivation and the design of maximally productive phototrophic cell factories. The model predicts that the use of dense cultures in well-mixed photobioreactors with short light-paths acts as an effective light dilution mechanism and alleviates the detrimental effects of photoinhibition even under very high light intensities. We recover the well-known trade-offs between a reduced light-harvesting apparatus and increased population density. Our results are discussed in the context of recent experimental efforts to increase the yield of phototrophic cultivation.
Biosynthesis of rhamnolipid by a Marinobacter species expands the paradigm of biosurfactant synthesis to a new genus of the marine microflora
Authors: Tripathi Lakshmi , Twigg Matthew S. , Zompra Aikaterini , Salek Karina , Irorere Victor U. , Gutierrez Tony , Spyroulias Georgios A. , Marchant Roger , Banat Ibrahim M.
Published: October 2019

Background

In comparison to synthetically derived surfactants, biosurfactants produced from microbial culture are generally regarded by industry as being more sustainable and possess lower toxicity. One major class of biosurfactants are rhamnolipids primarily produced by Pseudomonas aeruginosa. Due to its pathogenicity rhamnolipid synthesis by this species is viewed as being commercially nonviable, as such there is a significant focus to identify alternative producers of rhamnolipids.

Results

To achieve this, we phenotypically screened marine bacteria for biosurfactant production resulting in the identification of rhamnolipid biosynthesis in a species belonging to the Marinobacter genus. Preliminary screening showed the strain to reduce surface tension of cell-free supernatant to 31.0 mN m−1. A full-factorial design was carried out to assess the effects of pH and sea salt concentration for optimising biosurfactant production. When cultured in optimised media Marinobacter sp. MCTG107b produced 740 ± 28.3 mg L−1 of biosurfactant after 96 h of growth. Characterisation of this biosurfactant using both HPLC–MS and tandem MS showed it to be a mixture of different rhamnolipids, with di-rhamnolipid, Rha-Rha-C10-C10 being the most predominant congener. The strain exhibited no pathogenicity when tested using the Galleria mellonella infection model.

Conclusions

This study expands the paradigm of rhamnolipid biosynthesis to a new genus of bacterium from the marine environment. Rhamnolipids produced from Marinobacter have prospects for industrial application due to their potential to be synthesised from cheap, renewable feed stocks and significantly reduced pathogenicity compared to P. aeruginosa strains.
Optimization of Saccharomyces cerevisiae α-galactosidase production and application in the degradation of raffinose family oligosaccharides
Authors: Álvarez-Cao María-Efigenia , Cerdán María-Esperanza , González-Siso María-Isabel , Becerra Manuel
Published: October 2019

Background

α-Galactosidases are enzymes that act on galactosides present in many vegetables, mainly legumes and cereals, have growing importance with respect to our diet. For this reason, the use of their catalytic activity is of great interest in numerous biotechnological applications, especially those in the food industry directed to the degradation of oligosaccharides derived from raffinose. The aim of this work has been to optimize the recombinant production and further characterization of α-galactosidase ofSaccharomyces cerevisiae.

Results

TheMEL1gene coding for the α-galactosidase ofS. cerevisiae(ScAGal) was cloned and expressed in theS. cerevisiaestrain BJ3505. Different constructions were designed to obtain the degree of purification necessary for enzymatic characterization and to improve the productive process of the enzyme. ScAGal has greater specificity for the synthetic substratep-nitrophenyl-α-d-galactopyranoside than for natural substrates, followed by the natural glycosides, melibiose, raffinose and stachyose; it only acts on locust bean gum after prior treatment with β-mannosidase. Furthermore, this enzyme strongly resists proteases, and shows remarkable activation in their presence. Hydrolysis of galactose bonds linked to terminal non-reducing mannose residues of synthetic galactomannan-oligosaccharides confirms that ScAGal belongs to the first group of α-galactosidases, according to substrate specificity. Optimization of culture conditions by the statistical model of Response Surface helped to improve the productivity by up to tenfold when the concentration of the carbon source and the aeration of the culture medium was increased, and up to 20 times to extend the cultivation time to 216 h.

Conclusions

ScAGal characteristics and improvement in productivity that have been achieved contribute in making ScAGal a good candidate for application in the elimination of raffinose family oligosaccharides found in many products of the food industry.
From marginal to essential: the golden thread between nutrient sensing, medium composition and Plasmodium vivax maturation in in vitro culture
Authors: Thomson-Luque Richard , Adams John H. , Kocken Clemens H. M. , Pasini Erica M.
Published: October 2019

Historically neglected, due to its biological peculiarities, the absence of a continuous long-term in vitro blood stage culture system and a propensity towards high morbidity rather than mortality,Plasmodium vivaxwas put back on the agenda during the last decade by the paradigm shift in the fight against malaria from malaria control to malaria eradication. While the incidence of the deadliest form of malaria,Plasmodium falciparummalaria, has declined since this paradigm shift took hold, the prospects of eradication are now threatened by the increase in the incidence of other human malaria parasite species.Plasmodium vivaxis geographically the most widely distributed human malaria parasite, characterized by millions of clinical cases every year and responsible for a massive economic burden. The urgent need to tackle the unique biological challenges posed by this parasite led to renewed efforts aimed at establishing a continuous, long-term in vitroP. vivaxblood stage culture. Based on recent discoveries on the role of nutrient sensing inPlasmodium’s pathophysiology, this review article critically assesses the extensive body of literature concerningPlasmodiumculture conditions with a specific focus on culture media used in attempts to culture differentPlasmodiumspp. Hereby, the effect of specific media components on the parasite’s in vitro fitness and the maturation of the parasite’s host cell, the reticulocyte, is analysed. Challenging the wide-held belief that it is sufficient to find the right parasite isolate and give it the right type of cells to invade forP. vivaxto grow in vitro, this review contends that a healthy side-by-side maturation of both the parasite and its host cell, the reticulocyte, is necessary in the adaptation ofP. vivaxto in vitro growth and argues that culture conditions and the media in particular play an essential role in this maturation process.
Food sources, energy and nutrient intakes of adults: 2013 Philippines National Nutrition Survey
Authors: Angeles-Agdeppa Imelda , Sun Ye , Denney Liya , Tanda Keith V. , Octavio Royce Ann D. , Carriquiry Alicia , Capanzana Mario V.
Published: October 2019

Background

Comprehensive assessment of dietary intakes of foods and nutrients in Filipino adults are lacking. This study evaluated energy and nutrient intakes and food sources of key nutrients consumed by Filipino adults.

Methods

The participants were from the 2013 National Nutrition Survey wherein food intake of young adults aged 19–49 years (n = 12,896) and older adults aged 50 years and above (n = 7853) were collected using 24-h recalls. Usual nutrient intakes were estimated using PC-SIDE program. The Philippines Dietary Reference Intakes were used to calculate proportions of inadequate intake using Estimated Average Requirement (EAR) and Acceptable Macronutrient Distribution Ranges (AMDR). Energy adequacy was evaluated using the Institute of Medicine (IOM) equation for Estimated Energy Requirements (EER).

Results

The nutrient intakes with the highest prevalence of inadequacy (> 50%) were: iron (97–99%), vitamin C (96–98%), calcium (95–98%), riboflavin (86–91%), folate (89–90%), thiamine (73–89%), energy (67–70%), total fat (55–67%), and vitamin A (54–56%). Refined rice, pork and breads contributed most to daily intakes of energy, protein, carbohydrates, thiamine, riboflavin, and iron. Low intake of vegetables, fruits and dairy was common in both age groups.

Conclusions

This study demonstrated that intakes of many nutrients were markedly inadequate among adults in the Philippines, due to the rice-dominant dietary pattern with few nutrient-dense foods. These results can be used to support the development of specific interventions to improve the shortfalls in nutrient intakes.
Low concentrations of fine particle air pollution and mortality in the Canadian Community Health Survey cohort
Authors: Christidis Tanya , Erickson Anders C. , Pappin Amanda J. , Crouse Daniel L. , Pinault Lauren L. , Weichenthal Scott A. , Brook Jeffrey R. , van Donkelaar Aaron , Hystad Perry , Martin Randall V. , Tjepkema Michael , Burnett Richard T. , Brauer Michael
Published: October 2019

Background

Approximately 2.9 million deaths are attributed to ambient fine particle air pollution around the world each year (PM2.5). In general, cohort studies of mortality and outdoor PM2.5 concentrations have limited information on individuals exposed to low levels of PM2.5 as well as covariates such as smoking behaviours, alcohol consumption, and diet which may confound relationships with mortality. This study provides an updated and extended analysis of the Canadian Community Health Survey-Mortality cohort: a population-based cohort with detailed PM2.5 exposure data and information on a number of important individual-level behavioural risk factors. We also used this rich dataset to provide insight into the shape of the concentration-response curve for mortality at low levels of PM2.5.

Methods

Respondents to the Canadian Community Health Survey from 2000 to 2012 were linked by postal code history from 1981 to 2016 to high resolution PM2.5 exposure estimates, and mortality incidence to 2016. Cox proportional hazard models were used to estimate the relationship between non-accidental mortality and ambient PM2.5 concentrations (measured as a three-year average with a one-year lag) adjusted for socio-economic, behavioural, and time-varying contextual covariates.

Results

In total, 50,700 deaths from non-accidental causes occurred in the cohort over the follow-up period. Annual average ambient PM2.5 concentrations were low (i.e. 5.9 μg/m3, s.d. 2.0) and each 10 μg/m3 increase in exposure was associated with an increase in non-accidental mortality (HR = 1.11; 95% CI 1.04–1.18). Adjustment for behavioural covariates did not materially change this relationship. We estimated a supra-linear concentration-response curve extending to concentrations below 2 μg/m3 using a shape constrained health impact function. Mortality risks associated with exposure to PM2.5 were increased for males, those under age 65, and non-immigrants. Hazard ratios for PM2.5 and mortality were attenuated when gaseous pollutants were included in models.

Conclusions

Outdoor PM2.5 concentrations were associated with non-accidental mortality and adjusting for individual-level behavioural covariates did not materially change this relationship. The concentration-response curve was supra-linear with increased mortality risks extending to low outdoor PM2.5 concentrations.
Index of contractile asymmetry improves patient selection for CRT: a proof-of-concept study
Authors: Zaremba Tomas , Tayal Bhupendar , Riahi Sam , Thøgersen Anna Margrethe , Bruun Niels Eske , Emerek Kasper Janus Grønn , Kisslo Joseph , Hansen Thomas Fritz , Risum Niels , Søgaard Peter
Published: October 2019

Background

Nearly one-third of heart failure (HF) patients do not respond to cardiac resynchronization therapy (CRT) despite having left bundle branch block (LBBB). The aim of the study was to investigate a novel method of quantifying left ventricular (LV) contractile asymmetry in HF.

Methods

Patients with HF and LBBB undergoing CRT (n = 89, 37.1% females, 68 ± 9 years, ischemic etiology in 61%, LV ejection fraction 27.1 ± 7.1%) were analyzed. LV longitudinal systolic strain rate values were extracted from curved anatomical M-mode plots of standard long-axis 2D-echocardiography images and cubic spline interpolation was used to generate a 3D-phantom. Index of contractile asymmetry (ICA) was calculated based on standard deviation of differences in strain rate of opposing walls. Average ICA was individually assessed pairwise in 12 opposing 30-degree LV sectors. Reduction in LV end-systolic volume (ESV) ≥15% after 6 months was considered as positive response to CRT.

Results

CRT response was found in 66 (74.2%) patients. Responders with both ischemic and non-ischemic cardiomyopathy had a higher and more extensive contractile asymmetry at baseline and achieved a greater ICA reduction after CRT than non-responders. Higher baseline ICA predicted higher degree and wider extent of ICA improvement. Also, both ICA at baseline and reduction of ICA correlated with the degree of ESV reduction after CRT.

Conclusions

Quantification of asymmetrical LV activation in 3D by ICA provides valuable insights into LV contraction in case of LBBB and is a promising tool for improved patient selection for CRT.