bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial
Authors: Pidala Joseph , Hamadani Mehdi , Dawson Peter , Martens Michael , Alousi Amin M. , Jagasia Madan , Efebera Yvonne A. , Chhabra Saurabh , Pusic Iskra , Holtan Shernan G. , Ferrara James L. M. , Levine John E. , Mielcarek Marco , Anasetti Claudio , Antin Joseph H. , Bolaños-Meade Javier , Howard Alan , Logan Brent R. , Leifer Eric S. , Pritchard Theresa S. , Horowitz Mary M. , MacMillan Margaret L.
Published: November 2019

Clinical- and biomarker-based tools may identify a lower-risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced-intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus, n = 58; prednisone, n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% confidence interval [CI], 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone ≤0.25 mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs 31.7%; P < .001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2 to 3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life. This trial was registered at www.clinicaltrials.gov as #NCT02806947.
Expansion of T cells expressing low CD4 or CD8 levels in B-cell chronic lymphocytic leukemia: correlation with disease status and neoplastic phenotype
Authors: Dianzani U , Omede P , Marmont F , DiFranco D , Fusaro A , Bragardo M , Redoglia V , Giaretta F , Mairone L , Boccadoro M
Published: November 2019

Peripheral blood (PB) T cells from 56 patients with B-cell chronic lymphocytic leukemia (B-CLL) were analyzed by two- and three-color immunofluorescence (IF) to determine the expansion of distinct T-cell subsets and their relationship with the clinical and biological features of the disease. We detected the expansion of an unusual T-cell subpopulation expressing lower CD4 or CD8 levels (CD4lo, CD8lo) than classic T cells (CD4hi, CD8hi). This subpopulation also expressed low levels of the CD3/TCR alpha/beta complex and was CD19-CD13-CD14-. A phenotypic analysis probing the activation level of CD4lo, CD8lo, CD4hi, and CD8hi cells showed that they comprised increased counts of HLA-DR+, CD11b+, CD45R0+, and CD45RA+ cells. Subset expansion ranged from 2.1- to 13.6-fold. Statistical analysis showed that the size of some of these subsets was correlated to intrinsic features of the tumor. First, CD4loHLA-DR+ cell counts were higher in patients with stage A than those with stages B and C disease. Second, CD8loHLA-DR+ cell counts were higher in patients in stable remission than in those at diagnosis. Third, CD4loHLA-DR+, CD4loCD45R0+, CD4loCD45RA+, and CD4hiCD11b+ cell counts were higher in patients whose tumor cells expressed high levels of surface immunoglobulin (sIg) than in those expressing low levels. The involvement of CD4lo and CD8lo cells in most of these correlations suggests that they may be tumor-reactive cells. Similar cells described in human and murine autoimmune disease have been shown to be autoreactive anergic cells, which may derive from nonclassic pathways of T-cell development.
A Point Mutation in the Bulge of the Iron-Responsive Element of the L Ferritin Gene in Two Families With the Hereditary Hyperferritinemia-Cataract Syndrome
Authors: Martin M.E. , Fargion S. , Brissot P. , Pellat B. , Beaumont C.
Published: November 2019

The molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome is the presence of a mutation in the iron-responsive element (IRE) of the L ferritin gene, located on chromosome 19q13.3-13.4. Two mutations have been reported so far, altering adjacent nucleotides in the IRE loop, in a region that has been extensively studied in vitro and shown to mediate high affinity interaction with the iron-responsive protein. In this report, we describe two families with a new mutation in the bulge of the IRE stem, and we show that this mutation alters the protein-binding affinity of the IRE in vitro to the same extent as the loop mutation. In addition, we present evidence that some variability in the age of onset of cataract can be associated with this genetic syndrome, probably because of additional genetic or environmental factors that modulate the penetrance of the L ferritin defect in the lens. We confirm that the patients do not have increased iron stores despite the persistence of elevated serum ferritin levels and that, accordingly, they do not tolerate well venesection therapy. Further studies will be necessary to elucidate the mechanism responsible for the onset of cataract.
CD8+Tc2 cells: underappreciated contributors to severe asthma
Authors: Hinks Timothy S.C. , Hoyle Ryan D. , Gelfand Erwin W.
Published: November 2019

The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4+T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8+T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant and are comparatively insensitive to corticosteroids. Many common triggers of asthma exacerbations are mediatedviacorticosteroid-resistant pathways involving neutrophils and CD8+T-cells. Extensive murine data reveal the plasticity of CD8+T-cells and their capacity to enhance airway inflammation and airway dysfunction. In humans, Tc2 cells are predominant in fatal asthma, while in stable state, severe eosinophilic asthma is associated with greater numbers of Tc2 than Th2 cells in blood, bronchoalveolar lavage fluid and bronchial biopsies. Tc2 cells strongly express CRTH2, the receptor for prostaglandin D2, the cysteinyl leukotriene receptor 1 and the leukotriene B4 receptor. When activated, these elicit Tc2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. These factors position CD8+Tc2 cells as important and underappreciated effector cells contributing to asthma pathogenesis. Here, we review recent advances and new insights in understanding the pro-asthmatic functions of CD8+T-cells in eosinophilic asthma, especially corticosteroid-resistant asthma, and the molecular mechanisms underlying their pathologic effector function.
Recombinant human milk fat globule-EGF factor VIII (rhMFG-E8) as a therapy for sepsis after acute exposure to alcohol
Authors: Chaung Wayne W. , Brenner Max , Yen Hao-Ting , Ochani Mahendar L. , Jacob Asha , Wang Ping
Published: November 2019

Background

Alcohol intake predisposes to infections and sepsis. Alcohol and sepsis inhibit the expression of milk fat globule epidermal growth factor-factor VIII (MFG-E8), a glycoprotein essential for optimal efferocytosis, resulting in the release of proinflammatory molecules and increased sepsis severity. We previously reported that recombinant mouse (rm) MFG-E8 attenuates sepsis-induced organ injury in rats with acute alcohol intoxication. In order to develop a therapy that can be safely used in humans, we have produced recombinant human (rh) MFG-E8 and evaluated its efficacy to ameliorate sepsis after acute exposure to alcohol.

Methods

We induced acute alcohol intoxication with a bolus injection of alcohol (1.75 g/kg BW) followed by an intravenous infusion of 300 mg/kg/h alcohol for 10 h. Sepsis was then induced by cecal ligation and puncture (CLP). At -10, 0, and 10 h relative to CLP, rats received MFG-E8 or vehicle (albumin) intravenously. Animals were euthanized at 20 h after CLP for blood and tissue collection. Additional groups of animals were used for a survival study.

Results

Compared to vehicle, rhMFG-E8 treatment ameliorated blood levels of proinflammatory cytokines (% improvement: TNF-α 49.8%, IL-6 34.7%) and endotoxin (61.7%), as well as of transaminases (AST 36.2%, ALT 40.1%) and lactate (18.4%). Rats treated with rhMFG-E8 also had a significant histological attenuation of the acute lung injury, as well as a reduction in the number of apoptotic cells in the thymus (43.4%) and cleaved caspase 3 (38.7%) in the spleen. In addition, rhMFG-E8 improved the 10-day sepsis survival rate from 45 to 80%

Conclusion

rhMFG-E8 significantly ameliorated sepsis in rats with acute alcohol exposure, demonstrating rhMFG-E8’s potential to be developed as an effective therapy for sepsis in alcohol abusers.
Comparison of blood lipid profile/thyroid function markers between unipolar and bipolar depressed patients and in depressed patients with anhedonia or suicidal thoughts
Authors: Su Meilei , Li Enze , Tang Chong , Zhao Yongzhi , Liu Ruqing , Gao Keming
Published: November 2019

Background

This study aimed to investigate the differences in the serum levels of glucose, lipid, and thyroid function markers between unipolar and bipolar depressed patients, as well as the effect of anhedonia and suicidal thoughts on the levels of these biochemical parameters.

Methods

A total of 287 unmedicated depressed patients from January 2016 to December 2017 were included in this study, including 92 bipolar depressions and 195 unipolar depressions. Anhedonia was determined using the item 32 of Symptom Checklist (SCL-90). Suicide ideation was assessed by item 15 of SCL-90.

Results

The bipolar group had significantly lower lipid levels (including triglycerides, cholesterol, low-density lipoprotein cholesterol [LDL], very low-density lipoprotein cholesterol [VLDL]) and insulin resistance index but higher levels of prolactin, low triiodothyronine (T3) and free T3 (FT3) as well as higher incidence of anhedonia as compared with the unipolar group. Depressed patients with anhedonia had significantly higher LDL level than those without anhedonia. Depressed patients with suicidal thoughts had cholesterol and high-density lipoprotein cholesterol (HDL) level. The above-mentioned differences were confirmed by logistic regression analysis. Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve (AUC) ranged from 0.546 to 0.685.

Conclusion

Triglycerides, cholesterol, LDL, VLDL T3, FT3 levels were significantly different between unipolar and bipolar depressed patients, which might have the potential to be the markers for differential diagnosis. Patients with anhedonia had lower LDL level, while patients with suicidal thoughts had higher levels of cholesterol and HDL as compared with the corresponding control groups.
Functional connectivity studies in migraine: what have we learned?
Authors:   European Headache Federation School of Advanced Studies (EHF-SAS), Skorobogatykh Kirill , van Hoogstraten Willem Sebastiaan , Degan Diana , Prischepa Anastasia , Savitskaya Anastasya , Ileen Biondo Michela , Bentivegna Enrico , Skiba Iaroslav , D’Acunto Laura , Ferri Livia , Sacco Simona , Hansen Jakob Møller , Amin Faisal Mohammad
Published: November 2019

Background

Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder. Here, we review what we have learned from FC studies.

Methods

We performed a literature search on the PubMed website for original articles reporting data obtained from conventional resting-state FC recording in migraine patients compared with healthy controls or during and outside of migraine attacks in the same patients.

Results

We found 219 articles and included 28 in this review after screening for inclusion and exclusion criteria. Twenty-five studies compared migraine patients with healthy controls, whereas three studies investigated migraine patients during and outside of attacks. In the studies of interictal migraine more alterations of more than 20 FC networks (including amygdala, caudate nucleus, central executive, cerebellum, cuneus, dorsal attention network, default mode, executive control, fronto-parietal, hypothalamus, insula, neostriatum, nucleus accumbens, occipital lobe, periaqueductal grey, prefrontal cortex, salience, somatosensory cortex I, thalamus and visual) were reported. We found a poor level of reproducibility and no migraine specific pattern across these studies.

Conclusion

Based on the findings in the present review, it seems very difficult to extract knowledge of migraine pathophysiology or to identify a biomarker of migraine. There is an unmet need of guidelines for resting-state FC studies in migraine, which promote the use of homogenous terminology, public availability of protocol and the a priori hypothesis in line with for instance randomized clinical trial guidelines.
Estimating network changes from lifespan measurements using a parsimonious gene network model of cellular aging
Authors: Qin Hong
Published: November 2019

Background

Cellular aging is best studied in the budding yeast Saccharomyces cerevisiae. As an example of a pleiotropic trait, yeast lifespan is influenced by hundreds of interconnected genes. However, no quantitative methods are currently available to infer system-level changes in gene networks during cellular aging.

Results

We propose a parsimonious mathematical model of cellular aging based on stochastic gene interaction networks. This network model is made of only non-aging components: the strength of gene interactions declines with a constant mortality rate. Death of a cell occurs in the model when an essential node loses all of its interactions with other nodes, and is equivalent to the deletion of an essential gene. Stochasticity of gene interactions is modeled using a binomial distribution. We show that the exponential increase of mortality rate over time can emerge from this gene network model during the early stages of aging.We developed a maximal likelihood approach to estimate three lifespan-influencing network parameters from experimental lifespans: t0, the initial virtual age of the network system; n, the average lifespan-influencing interactions per essential node; and R, the initial mortality rate. We applied this model to yeast mutants with known effects on replicative lifespans. We found that deletion of SIR2, FOB1, and HXK2 considerably altered the initial virtual age but not the average lifespan-influencing interactions per essential node, suggesting that these mutations mainly influence the reliability of gene interactions but not the overall configurations of gene networks.We applied this model to investigate replicative lifespans of yeast natural isolates. We estimated that the average number of lifespan-influencing interactions per essential node is 7.0 (6.1–8) and the average estimated initial virtual age is 45.4 (30.6–74) cell divisions in these isolates. We also found that t0 could potentially mediate the observed Strehler-Mildvan correlation in yeast natural isolates.

Conclusions

Our theoretical model provides a parsimonious interpretation of experimental lifespan data from the perspective of gene networks. We hope that our work will stimulate more interest in developing network models to study aging as a pleiotropic trait.
Molecular cloning and characterization of a grapevine (Vitis vinifera L.) serotonin N-acetyltransferase (VvSNAT2) gene involved in plant defense
Authors: Yu Yihe , Bian Lu , Jiao Zeling , Yu Keke , Wan Yutong , Zhang Guohai , Guo Dalong
Published: November 2019

Background

Melatonin is a ubiquitous molecule and exists across kingdoms. Studies on melatonin in plants have mainly focused on its physiological influence on growth and development, and on its biosynthesis. A number of studies have been conducted on the melatonin content and exogenous melatonin treatment of grapevine (Vitis viniferaL.). However, key genes or enzymes of the melatonin biosynthetic pathway remain unclear.

Results

In this study, we cloned and identified the gene encoding serotoninN-acetyltransferase (SNAT) in grapevine (VvSNAT2).The VvSNAT2 protein was identified from a collection of 30 members of the grapevine GCN5-relatedN-acetyltransferase (GNAT) superfamily. Phylogenetic and protein sublocalization analyses showed that the candidate geneVvGNAT16isVvSNAT2. Characterization of VvSNAT2 showed that its enzymatic activity is highest at a pH of 8.8 and a temperature of 45 °C. Analysis of enzyme kinetics showed the values ofKmandVmaxof VvSNAT2 using serotonin were 392.5 μM and 836 pmol/min/mg protein, respectively. The expression of VvSNAT2 was induced by melatonin treatment and pathogen inoculation. Overexpression ofVvSNAT2in Arabidopsis resulted in greater accumulation of melatonin and chlorophyll and enhanced resistance to powdery mildew in the transgenic plants compared with the wild type (WT). Additionally, our data showed that the marker genes in the salicylic acid (SA) signaling pathway were expressed to higher levels in the transgenic plants compared with the WT.

Conclusions

TheVvSNAT2gene was cloned and identified in grapevine for the first time. Our results indicate thatVvSNAT2overexpression activates the SA and JA signaling pathways; however, the SA pathway plays a central role inVvSNAT2-mediated plant defense.
Exome resequencing and GWAS for growth, ecophysiology, and chemical and metabolomic composition of wood of Populus trichocarpa
Authors: Guerra Fernando P. , Suren Haktan , Holliday Jason , Richards James H. , Fiehn Oliver , Famula Randi , Stanton Brian J. , Shuren Richard , Sykes Robert , Davis Mark F. , Neale David B.
Published: November 2019

Background

Populus trichocarpais an important forest tree species for the generation of lignocellulosic ethanol. Understanding the genomic basis of biomass production and chemical composition of wood is fundamental in supporting genetic improvement programs. Considerable variation has been observed in this species for complex traits related to growth, phenology, ecophysiology and wood chemistry. Those traits are influenced by both polygenic control and environmental effects, and their genome architecture and regulation are only partially understood. Genome wide association studies (GWAS) represent an approach to advance that aim using thousands of single nucleotide polymorphisms (SNPs). Genotyping using exome capture methodologies represent an efficient approach to identify specific functional regions of genomes underlying phenotypic variation.

Results

We identified 813 K SNPs, which were utilized for genotyping 461P. trichocarpaclones, representing 101 provenances collected from Oregon and Washington, and established in California. A GWAS performed on 20 traits, considering single SNP-marker tests identified a variable number of significant SNPs (p-value < 6.1479E-8) in association with diameter, height, leaf carbon and nitrogen contents, and δ15N. The number of significant SNPs ranged from 2 to 220 per trait. Additionally, multiple-marker analyses by sliding-windows tests detected between 6 and 192 significant windows for the analyzed traits. The significant SNPs resided within genes that encode proteins belonging to different functional classes as such protein synthesis, energy/metabolism and DNA/RNA metabolism, among others.

Conclusions

SNP-markers within genes associated with traits of importance for biomass production were detected. They contribute to characterize the genomic architecture ofP. trichocarpabiomass required to support the development and application of marker breeding technologies.
Comparison of different annotation tools for characterization of the complete chloroplast genome of Corylus avellana cv Tombul
Authors: Kahraman Kadriye , Lucas Stuart James
Published: November 2019

Background

Several bioinformatics tools have been designed for assembly and annotation of chloroplast (cp) genomes, making it difficult to decide which is most useful and applicable to a specific case. The increasing number of plant genomes provide an opportunity to accurately obtain cp genomes from whole genome shotgun (WGS) sequences. Due to the limited genetic information available for European hazelnut (Corylus avellana L.) and as part of a genome sequencing project, we analyzed the complete chloroplast genome of the cultivar ‘Tombul’ with multiple annotation tools.

Results

Three different annotation strategies were tested, and the complete cp genome of C. avellana cv Tombul was constructed, which was 161,667 bp in length, and had a typical quadripartite structure. A large single copy (LSC) region of 90,198 bp and a small single copy (SSC) region of 18,733 bp were separated by a pair of inverted repeat (IR) regions of 26,368 bp. In total, 125 predicted functional genes were annotated, including 76 protein-coding, 25 tRNA, and 4 rRNA unique genes. Comparative genomics indicated that the cp genome sequences were relatively highly conserved in species belonging to the same order. However, there were still some variations, especially in intergenic regions, that could be used as molecular markers for analyses of phylogeny and plant identification. Simple sequence repeat (SSR) analysis showed that there were 83 SSRs in the cp genome of cv Tombul. Phylogenetic analysis suggested that C. avellana cv Tombul had a close affinity to the sister group of C. fargesii and C. chinensis, and then a closer evolutionary relationship with Betulaceae family than other species of Fagales.

Conclusion

In this study, the complete cp genome of Corylus avellana cv Tombul, the most widely cultivated variety in Turkey, was obtained and annotated, and additionally phylogenetic relationships were predicted among Fagales species. Our results suggest a very accurate assembly of chloroplast genome from next generation whole genome shotgun (WGS) sequences. Enhancement of taxon sampling in Corylus species provide genomic insights into phylogenetic analyses. The nucleotide sequences of cv Tombul cp genomes can provide comprehensive genetic insight into the evolution of genus Corylus.
The ABA-induced soybean ERF transcription factor gene GmERF75 plays a role in enhancing osmotic stress tolerance in Arabidopsis and soybean
Authors: Zhao Meng-Jie , Yin Li-Juan , Liu Ying , Ma Jian , Zheng Jia-Cheng , Lan Jin-Hao , Fu Jin-Dong , Chen Ming , Xu Zhao-Shi , Ma You-Zhi
Published: November 2019

Background

Ethylene-responsive factors (ERFs) play important roles in plant growth and development and the response to adverse environmental factors, including abiotic and biotic stresses.

Results

In the present study, we identified 160 soybean ERF genes distributed across 20 chromosomes that could be clustered into eight groups based on phylogenetic relationships. A highly ABA-responsive ERF gene, GmERF75, belonging to Group VII was further characterized. Subcellular localization analysis showed that the GmERF75 protein is localized in the nucleus, and qRT-PCR results showed that GmERF75 is responsive to multiple abiotic stresses and exogenous hormones. GmERF75-overexpressing Arabidopsis lines showed higher chlorophyll content compared to WT and mutants under osmotic stress. Two independent Arabidopsis mutations of AtERF71, a gene homologous to GmERF75, displayed shorter hypocotyls, and overexpression of GmERF75 in these mutants could rescue the short hypocotyl phenotypes. Overexpressing GmERF75 in soybean hairy roots improved root growth under exogenous ABA and salt stress.

Conclusions

These results suggested that GmERF75 is an important plant transcription factor that plays a critical role in enhancing osmotic tolerance in both Arabidopsis and soybean.
The influences of morphine or ketamine pre-treatment on hemodynamic, acid-base status, biochemical markers of brain damage and early survival in rats after asphyxial cardiac arrest
Authors: Kuklin Vladimir , Akhatov Nurlan , Kondratiev Timofei , Konkayev Aidos , Baigenzhin Abai , Konkayeva Maiya , Karibekov Temirlan , Barlow Nicholas , Tveita Torkjel , Dahl Vegard
Published: November 2019

Background

In different models of hypoxia, blockade of opioid or N-methyl-D-aspartate (NMDA) receptors shows cardio- and neuroprotective effects with a consequent increase in animal survival. The aim of the study was to investigate effects of pre-treatment with Morphine or Ketamine on hemodynamic, acid-base status, early survival, and biochemical markers of brain damage in a rat model of asphyxial cardiac arrest (ACA).

Methods

Under anaesthesia with Thiopental Sodium 60 mg/kg, i.p., Wistar rats (n = 42) were tracheostomized and catheters were inserted in a femoral vein and artery. After randomization, the rats were pre-treated with: Morphine 5 mg/kg i.v. (n = 14); Ketamine 40 mg/kg i.v. (n = 14); or equal volume of i.v. NaCl 0.9% as a Control (n = 14). ACA was induced by corking of the tracheal tube for 8 min, and defined as a mean arterial pressure (MAP) < 20 mmHg. Resuscitation was started at 5 min after cardiac arrest (CA). Invasive MAP was recorded during experiments. Arterial pH and blood gases were sampled at baseline (BL) and 10 min after CA. At the end of experiments, all surviving rats were euthanised, brain and blood samples for measurement of Neuron Specific Enolase (NSE), s100 calcium binding protein B (s100B) and Caspase-3 (CS-3) were retrieved.

Results

At BL no differences between groups were found in hemodynamic or acid-base status. After 3 min of asphyxia, all animals had cardiac arrest (CA). Return of spontaneous circulation (MAP > 60 mmHg) was achieved in all animals within 3 min after CA. At the end of the experiment, the Ketamine pre-treated group had increased survival (13 of 14; 93%) compared to the Control (7 of 14; 50%) and Morphine (10 of 14; 72%) groups (p = 0.035). Biochemical analysis of plasma concentration of NSE and s100B as well as an analysis of CS-3 levels in the brain tissue did not reveal any differences between the study groups.

Conclusion

In rats after ACA, pre-treatment with Morphine or Ketamine did not have any significant influence on hemodynamic and biochemical markers of brain damage. However, significantly better pH level and increased early survival were found in the Ketamine pre-treated group.
Elevated blood pressure level based on 2017 ACC/AHA guideline in relation to stroke risk in rural areas of Liaoning province
Authors: Xie Yanxia , Ma Mingfeng , Li Zhao , Guo Xiaofan , Sun Guozhe , Sun Zhaoqing , Zheng Jia , Sun Yingxian , Zheng Liqiang
Published: November 2019

Background

The new ACC/AHA hypertension guideline lower the definition of hypertension from 140/90 mmHg to 130/80 mmHg and eliminate the category of prehypertension thus increasing the prevalence of hypertension. A purpose of this study is to explore the applicability of the new guidelines in rural China.

Methods

In total, 3229 participants aged ≥35 years and free of stroke at baseline were followed for up to 4.8 years during 2012 to 2017 in a rural community-based prospective cohort study of Xifeng County. The hazard ratio (HR) and 95% Confidence interval (CI) of different blood pressure (BP) levels for risk of incident stroke were analyzed by multivariable Cox proportional hazard models.

Results

During the follow-up, 81 new strokes occurred among the 3229 participants. Compared with normal BP (Systolic BP (SBP)<120 mmHg and Diastolic BP (DBP)<80 mmHg), stage 2 hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) had approximately 2.1 greater risks for stroke (HR: 2.10, 95% CI: 1.13 to 3.91, P = 0.020). However, there was no significant association between elevated (SBP:120-129 mmHg and DBP<80 mmHg), stage1 hypertension (SBP:130-139 mmHg or DBP:80-89 mmHg) and stroke incidence (HR: 0.93, 95% CI: 0.33 to 2.61, P = 0.888; HR: 0.96, 95% CI: 0.46 to 2.02, P = 0.920, respectively). An increase of the SBP by 1-SD increases the risk for stroke by 56% (HR: 1.56, 95%CI: 1.29 to 1.88, P < 0.001). An increase of the SBP by 20 mmHg increases the risk for stroke by 51% (HR: 1.51, 95%CI: 1.27 to 1.80, P < 0.001).

Conclusions

Compared with normal BP, the stage 2 hypertension based on 2017 ACC/AHA guideline significantly increases the risk of stroke incidence, but this association was not observed between elevated, stage1 hypertension and stroke incidence in Chinese rural adults.
Development of a high number, high coverage dog rabies vaccination programme in Sri Lanka
Authors: Sánchez-Soriano Carlos , Gibson Andrew D. , Gamble Luke , Burdon Bailey Jordana L. , Green Samantha , Green Mark , Bronsvoort Barend M. deC. , Handel Ian G. , Mellanby Richard J. , Mazeri Stella
Published: November 2019

Background

Rabies is estimated to cause 59,000 deaths and economic losses of US$8.6 billion every year. Despite several years of rabies surveillance and awareness programmes, increased availability of post-exposure prophylaxis vaccinations and dog population control, the disease still remains prevalent in Sri Lanka. This study reports the roll-out of a high number, high coverage canine rabies vaccination campaign in Sri Lanka, providing estimates for the vaccination coverage achieved, analysing the local dog demographics, and identifying barriers of attendance to static vaccination clinics.

Methods

A mass dog vaccination campaign was undertaken in Negombo, Sri Lanka. The campaign was composed of static point and door-to-door vaccination stages, with a final survey of vaccination coverage. A large volume of data on the distribution, health, and signalment of vaccinated dogs was collected through a mobile phone application. A logistic regression model was developed to investigate which socio-spatial and dog-related factors influenced attendance of owners to static vaccination points.

Results

The campaign vaccinated over 7800 dogs achieving a vaccination coverage of 75.8%. A dog:human ratio of 1:17 was estimated. Most dogs were owned, and the dog population was mostly male, adult, and non-sterilized. Unawareness, unavailability and handling problems were the most common reasons given by owners to explain failure to attend a static vaccination point. The regression analysis showed that increasing distance to a static point, in addition to young age and poor health of the dog, were associated with a decrease in the likelihood of attendance to a static vaccination points.

Conclusion

This study demonstrates the feasibility of high number, high coverage vaccination campaigns in Sri Lanka. The information on dog ecology and barriers of attendance to static point vaccination clinics will facilitate development of future vaccination campaigns.
The protocol-guided rapid evaluation of veterans experiencing new transient neurological symptoms (PREVENT) quality improvement program: rationale and methods
Authors: Bravata D. M. , Myers L. J. , Homoya B. , Miech E. J. , Rattray N. A. , Perkins A. J. , Zhang Y. , Ferguson J. , Myers J. , Cheatham A. J. , Murphy L. , Giacherio B. , Kumar M. , Cheng E. , Levine D. A. , Sico J. J. , Ward M. J. , Damush T. M.
Published: November 2019

Background

Transient ischemic attack (TIA) patients are at high risk of recurrent vascular events; timely management can reduce that risk by 70%. The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurological Symptoms (PREVENT) developed, implemented, and evaluated a TIA quality improvement (QI) intervention aligned with Learning Healthcare System principles.

Methods

This stepped-wedge trial developed, implemented and evaluated a provider-facing, multi-component intervention to improve TIA care at six facilities. The unit of analysis was the medical center. The intervention was developed based on benchmarking data, staff interviews, literature, and electronic quality measures and included: performance data, clinical protocols, professional education, electronic health record tools, and QI support. The effectiveness outcome was the without-fail rate: the proportion of patients who receive all processes of care for which they are eligible among seven processes. The implementation outcomes were the number of implementation activities completed and final team organization level. The intervention effects on the without-fail rate were analyzed using generalized mixed-effects models with multilevel hierarchical random effects. Mixed methods were used to assess implementation, user satisfaction, and sustainability.

Discussion

PREVENT advanced three aspects of a Learning Healthcare System. Learning from Data: teams examined and interacted with their performance data to explore hypotheses, plan QI activities, and evaluate change over time. Learning from Each Other: Teams participated in monthly virtual collaborative calls. Sharing Best Practices: Teams shared tools and best practices. The approach used to design and implement PREVENT may be generalizable to other clinical conditions where time-sensitive care spans clinical settings and medical disciplines.

Trial registration

clinicaltrials.gov: NCT02769338 [May 11, 2016].
Endometrial carcinoma in a gravid uterus: a case report and literature review
Authors: Shiomi Mayu , Matsuzaki Shinya , Kobayashi Eiji , Hara Takeya , Nakagawa Satoshi , Takiuchi Tsuyoshi , Mimura Kazuya , Ueda Yutaka , Tomimatsu Takuji , Kimura Tadashi
Published: November 2019

Background

Endometrial carcinoma (EC) is rarely diagnosed during pregnancy. Therefore, the histopathological findings, clinical course, and gross appearance of the resected uterus during pregnancy are not well known. We present a case of EC diagnosed during pregnancy. In addition, we reviewed the literature dating from January 1995 to March 2019 for cases of EC diagnosed during pregnancy and within 15 months after pregnancy, and we discussed this topic to improve the understanding of this rare condition.

Case presentation

A 35-year-old woman underwent an urgent cesarean delivery in gestational week 35 due to antepartum bleeding caused by placenta previa. Hysterectomy was performed with the diagnosis of placenta accreta spectrum (PAS). Remarkably, the postoperative gross and histopathological examinations revealed an endometrioid adenocarcinoma (grade 1). The histopathological findings revealed a pattern similar to that of EC not related with pregnancy. Immunohistochemistry revealed an overexpression of the estrogen and progesterone receptors; however, the p53 expression was negative. We performed laparoscopic bilateral salpingo-oophorectomy and pelvic lymphadenectomy 102 days after the cesarean hysterectomy, and confirmed surgical stage IA without metastases. Our patient has had no recurrence in 4 years after the cesarean delivery.

An electronic search of the literature revealed 25 cases of EC (including our case) diagnosed during or after pregnancy. Sixteen of the 25 patients were diagnosed after abortions in the first trimester, 9 were diagnosed within 14 months of childbirth, and our case was the first with diagnosis from a surgical specimen of peripartum hysterectomy due to the PAS. In 23 of the 25 cases endometrioid adenocarcinoma grade 1 to 2 was found, and it seemed to have a good prognosis.

Conclusion

The present findings suggest that careful examination of a resected uterus is essential, even when surgery is performed for an obstetric indication. Our case is an extremely rare case of EC during pregnancy; the histopathological pattern was similar to that of typical EC, and no recurrence was noted. The high levels of estrogen and progesterone during pregnancy did not seem to promote tumor progression in our case.
Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas
Authors: Pánczél Zita , Kukor Zoltán , Supák Dorina , Kovács Bence , Kecskeméti András , Czizel Rita , Djurecz Magdolna , Alasztics Bálint , Csomó Krisztián Benedek , Hrabák András , Valent Sándor
Published: November 2019

Background

Pravastatin, a known inducer of endothelial nitric-oxide synthase (eNOS) was demonstrated in human placenta, however the exact mechanism of it’s action is not fully understood. Since placental NO (nitric oxide) synthesis is of primary importance in the regulation of placental blood flow, we aimed to clarify the effects of pravastatin on healthy (n = 6) and preeclamptic (n = 6) placentas (Caucasian participants).

Methods

The eNOS activity of human placental microsomes was determined by the conversion rate of C14 L-arginine into C14 L-citrulline with or without pravastatin and Geldanamycin. Phosphorylation of eNOS (Ser1177) was investigated by Western blot. Microsomal arginine uptake was measured by a rapid filtration method.

Results

Pravastatin significantly increased total eNOS activity in healthy (28%,p<0.05) and preeclamptic placentas (32%,p<0.05) using 1 mM Ca2+promoting the dissociation of a eNOS from it’s inhibitor caveolin. Pravastatin and Geldanamycin (Hsp90 inhibitor) cotreatment increased microsomal eNOS activity. Pravastatin treatment had no significant effects on Ser1177 phosphorylation of eNOS in either healthy or preeclamptic placentas. Pravastatin induced arginine uptake of placental microsomes in both healthy (38%,p < 0.05) and preeclamptic pregnancies (34%,p < 0.05).

Conclusions

This study provides a novel mechanism of pravastatin action on placental NO metabolism. Pravastatin induces the placental microsomal arginine uptake leading to the rapid activation of eNOS independently of Ser1177 phosphorylation. These new findings may contribute to better understanding of preeclampsia and may also have a clinical relevance.
Factors influencing adherence to the new intermittent preventive treatment of malaria in pregnancy policy in Keta District of the Volta region, Ghana
Authors: Vandy Alren O. , Peprah Nana Yaw , Jerela Joseph Yaw , Titiati Perfect , Manu Abubakar , Akamah Joseph , Maya Ernest T. , Torpey Kwasi
Published: November 2019

Background

About 25% of pregnant women in malaria-endemic areas are infected with malaria and this accounts for about 15% of maternal deaths globally. Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is one of the main strategies for prevention of malaria in pregnancy. A new recommendation was made by the World Health Organization (WHO) that at least three doses of IPTp-SP should be administered before delivery. This study sought to determine the factors influencing adherence to the new IPTp-SP policy in Keta District, Volta region, Ghana.

Methods

A cross-sectional quantitative study among 375 nursing mothers at four selected health facilities in Keta district, Ghana was conducted using a structured questionnaire to interview participants. Sampling proportionate to the size of facility was used to determine the number of nursing mothers from each facility based on the caseload. For each facility systematic random sampling was used to select eligible nursing mothers. Data was analyzed using STATA 15. Chi-square was used to test bivariate association between categorical variables and adherence. Logistic regression analysis was used to examine sociodemographic, individual and institutional factors influencing adherence to IPTp-SP.

Result

About 82.1% of participants adhered to the WHO policy recommendations of at least three doses of IPTp-SP. However, only 17.1% received Ghana’s five dose coverage recommendation. The proportion of IPTp-SP coverage for IPTp1 was 98.9%; IPTp2 95.5%; IPTp3 80.8%; IPTp4 39.5%; IPTp5 17.1%.

Conclusion

Adherence to IPTp-SP was satisfactory according to WHO’s policy recommendation, however, majority of the participants had less than the five doses recommended in Ghana. Number of Antenatal Care (ANC) visits and knowledge of malaria were the main determinants of adherence to IPTp-SP.
Synergism of wt-p53 and synthetic material in local nano-TAE gene therapy of hepatoma: comparison of four systems and the possible mechanism
Authors: Li Gaopeng , Kang Wenqin , Jin Mingliang , Zhang Lidong , Zheng Jian , Jia Kai , Ma Jinfeng , Liu Ting , Dang Xueyi , Yan Zhifeng , Gao Zefeng , Xu Jun
Published: November 2019

Background

TAE-gene therapy for hepatoma, incorporating the tumor-targeted therapeutic efficacy of trans-arterial embolization, hydroxyapatite nanoparticles (nHAP) and anti-cancer wild-type p53 gene (wt-p53), was presented in our former studies (Int J Nanomedicine 8:3757-68, 2013, Liver Int 32:998-1007, 2012). However, the incompletely antitumoral effect entails defined guidelines on searching properer materials for this novel therapy.

Methods

Unmodified nHAP, Ca(2+) modified nHAP, poly-lysine modified nHAP and liposome were separately used to form U-nanoplex, Ca-nanoplex, Pll-nanoplex, L-nanoplex respectively with wt-p53 expressing plasmid. The four nanoplexs were then applied in vitro for human normal hepacyte L02 and hepatoma HePG2 cell line, and in vivo for rabbits with hepatic VX2 tumor by injection of nanoplexs/lipiodol emulsion into the hepatic artery in a tumor target manner. The distribution, superficial potential, physical structure, morphology and chemical compositions of nanoplexs were evaluated by TEM, SEM, EDS etc., with the objective of understanding their roles in hepatoma TAE-gene therapy.

Results

In vitro, L-nanoplex managed the highest gene transferring efficiency. Though with the second highest transfection activity, Pll-nanoplex showed the strongest tumor inhibition activity while maintaining safe to the normal hepacyte L02. In fact, only Pll-nanoplex can combine both the antitumoral effect to HePG2 and safe procedure to L02 among the four systems above. In vivo, being the only one with successful gene transference to hepatic VX2 tumor, Pll-nanoplex/lipiodol emulsion can target the tumor more specifically, which may explain its best therapeutic effect and hepatic biologic response. Further physical characterizations of the four nanoplexs suggested particle size and proper electronic organic surface may be crucial for nano-TAE gene therapy.

Conclusion

Pll-nanoplex is the most proper system for the combined therapy due to its selectively retention in liver cancer cells, secondary to its morphological and physico-chemical properties of nanometric particle size, steady emulsion, proper organic and electronic surface.
The role of secreted Hsp90α in HDM-induced asthmatic airway epithelial barrier dysfunction
Authors: Ye Cuiping , Huang Chaowen , Zou Mengchen , Hu Yahui , Luo Lishan , Wei Yilan , Wan Xuan , Zhao Haijin , Li Wei , Cai Shaoxi , Dong Hangming
Published: November 2019

Background

The dysfunction of airway epithelial barrier is closely related to the pathogenesis of asthma. Secreted Hsp90α participates in inflammation and Hsp90 inhibitor protects endothelial dysfunction. In the current study, we aimed to explore the role of secreted Hsp90α in asthmatic airway epithelial barrier function.

Methods

Male BALB/c mice were sensitized and challenged with HDM to generate asthma model. The 16HBE and Hsp90α-knockdown cells were cultured and treated according to the experiment requirements. Transepithelial Electric Resistance (TEER) and permeability of epithelial layer in vitro, distribution and expression of junction proteins both in vivo and in vitro were used to evaluate the epithelial barrier function. Western Blot was used to evaluate the expression of junction proteins and phosphorylated AKT in cells and lung tissues while ELISA were used to evaluate the Hsp90α expression and cytokines release in the lung homogenate.

Results

HDM resulted in a dysfunction of airway epithelial barrier both in vivo and in vitro, paralleled with the increased expression and release of Hsp90α. All of which were rescued in Hsp90α-knockdown cells or co-administration of 1G6-D7. Furthermore, either 1G6-D7 or PI3K inhibitor LY294002 suppressed the significant phosphorylation of AKT, which caused by secreted and recombinant Hsp90α, resulting in the restoration of epithelial barrier function.

Conclusions

Secreted Hsp90α medicates HDM-induced asthmatic airway epithelial barrier dysfunction via PI3K/AKT pathway, indicating that anti-secreted Hsp90α therapy might be a potential treatment to asthma in future.
Extreme bone lengthening by bone transport with a unifocal tibial corticotomy: a case report
Authors: Wen Hongjie , Yang Huagang , Xu Yongqing
Published: November 2019

Background

Bone transport is used for the treatment of extensive limb bone defects. The application of ring or unilateral external fixators combined with single or double corticotomy are well documented; however, there are few cases adopting a single corticotomy to repair bone defects > 24 cm.

Case presentation

The present case study describes an 18-year-old male, who was involved in a traffic accident and was diagnosed with open fracture of the right tibia. The patient received emergency surgery in a local hospital and was transferred to The Second People’s Hospital of Yunnan for further treatment 3 months later. The patient was diagnosed with fracture nonunion and infection following admission. Complete debridement was performed three times to control the infection. The infection was resolved after 26 days and the 24.5 cm massive tibia defect remained the biggest challenge. The bone transport technique involving a unilateral external fixator and single corticotomy was employed to treat the bone defect. Docking site union was achieved and bone consolidation was complete 40 months after corticotomy. The external fixator was subsequently removed. The bone healing index was 1.6 months/cm. The Association for the Study and Application of the Method of Ilizarov criteria (ASAMI) revealed a good functional and bone repair result. Similarly, Knee Society Score (KSS) yielded good result and the The Lower Extremity Functional Scale (LEFS) was 65. A total of 45 months after injury, the patient was able to walk painlessly without ambulatory assistive devices and resumed daily activities successfully. Eighteen months after the bone and soft tissue wound have healed, the SF-36 score was 86, and the LEFS was 70.

Conclusion

To the best of the authors’ knowledge, the present study described the longest bone defect repair performed using bone transport with single level corticotomy.